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1.
Value in Health ; 25(12 Supplement):S342, 2022.
Article in English | EMBASE | ID: covidwho-2181160

ABSTRACT

Objectives: To review and analyze the new early access authorization program in France launched in July 2021. Method(s): Treatments that were processed under the early access authorization program between July 2021 and June 2022 were analyzed. The assessments were examined for therapy area, processing timeline, and data used in the evaluation. Result(s): As of 30 June 2022, 55 of the 66 decisions (83%) that have been published by HAS were granted early access, and 11 (17%) applications were refused. Among those granted early access, 37 (67%) already had a marketing authorization (MA), of which 25 (68%) had conditional MA and 11 (30%) were granted orphan status;18 (33%) applied to the program before obtaining regulatory approval (pre-MA). Among the treatments granted early access after MA, one received ASMR II, 15 received ASMR III, 2 Received ASMR IV, 5 received ASMR V rating, and 13 had not been evaluated for the indication. The average time taken for the processing of all applications (receipt of complete file to date of adoption) was 65 days (range, 1-121);mean time for ANSM opinion on the product's presumed efficacy and safety in the absence of MA was 55 days (range, 4-112). Oncology drugs accounted for 21 (39%) of applications. Most decisions were based on phase 2-3 clinical data for technologies with or without MA. Only two positive, pre-MA early access authorization requests used phase 1 clinical data for treatments indicated in pre-exposure prophylaxis of coronavirus 2019 and unresectable or metastatic triple-negative breast cancer. Contributions from stakeholders, including patient and user groups, were involved in 39 (59%) applications (both pre-MA and post-MA). Conclusion(s): Overall, the time taken to evaluate the early access applications is significantly lower compared with the 3-month examination period stipulated by the program, facilitating a quick access to patients with high unmet need. Copyright © 2022

2.
United European Gastroenterology Journal ; 10(Supplement 8):340, 2022.
Article in English | EMBASE | ID: covidwho-2115429

ABSTRACT

Introduction: ABX464 (obefazimod) is an oral small molecule that modulates inflammation by upregulating a specific anti-inflammatory micro- RNA (miR-124). ABX464 has demonstrated safety and efficacy in patients with moderate-to-severe ulcerative colitis (UC) in a randomized, placebocontrolled, phase 2b induction study (NCT04023396)1. This analysis presents interim data at week 48 after enrollment in the open-label (OL) maintenance study. Aims & Methods: During the 16-week induction Phase 2b, patients received placebo or obefazimod 25mg, 50mg or 100mg once daily (od) and, irrespective of their clinical response, could enter the OL 96-week maintenance study with obefazimod 50mg od. Patients were enrolled into this study from January 13, 2020. Here we present data from an interim analysis cut-off date on Feb 13, 2022. Patients were followed monthly for safety and efficacy. Non-responder imputation (NRI) was used for missing efficacy data. All subjects were assessed for safety: treatment emergent adverse events (TEAEs), TEAEs leading to study discontinuation, serious adverse events (SAEs). Result(s): Of 222 patients who completed the phase2b induction study, 217 (97.7%) were enrolled in the OL maintenance study. 33/217 (15.2%) patients dropped out prior to week 48, mainly for UC worsening (10/33). All dropouts were considered as treatment failures for this interim analysis. Main efficacy results are presented in the table below. Among the 96 patients with no clinical response after induction, 42.7% achievedde novo clinical remission at week 48 of the OL maintenance study. Among the 52 patients with clinical remission after induction, 73.1% maintained clinical remission at week 48. In total, 139/217 subjects (64.1%) reported at least one TEAE. TEAEs leading to study discontinuation were reported in 15 subjects (6.9%) and serious adverse events (SAEs) were reported in 17 subjects (7.8%). The most frequent TEAEs (>= 5%) were headache (11.5%), COVID-19 (10.1%), ulcerative colitis (6.5%) and nasopharyngitis (5.9%). No new safety risks were identified over these initial 48 weeks. Conclusion(s): Results from this 48-week interim analysis of the OL maintenance Phase 2b study confirmed excellent long-term efficacy of obefazimod 50mg od in clinical responders and non-clinical responders after induction as well as a favorable long-term safety profile.

3.
Pharmaceutical Journal ; 307(7955), 2022.
Article in English | EMBASE | ID: covidwho-2065008
4.
American Journal of Transplantation ; 22(Supplement 3):770-771, 2022.
Article in English | EMBASE | ID: covidwho-2063423

ABSTRACT

Purpose: Kidney transplant(KTx) recipients are at increased risk of COVID-19 related complications. KTx pts who have undergone therapy to induce tolerance are a unique cohort regarding SARS-CoV-2 susceptibility, clinical course following infection, and vaccine response. We have reported results of a phase 2 trial to induce tolerance through establishment of durable donor whole blood and T-cell chimerism using FCR001, an investigational cell therapy. Pts received nonmyeloablative conditioning, LD KTx, FCR001 infusion and weaning of IS as previously described (Leventhal et al STM 2012). Full withdrawal of immunosuppression (IS) was possible in 26 of 37 pts, with a low (5.5%) risk of graft versus host disease (GvHD). We evaluated the impact of COVID-19 infection and vaccination response in this cohort. Method(s): A chart review of pts was conducted;variables of interest included demographic data, clinical course, and virologic assays. Result(s): We identified 28 evaluable pts (Figure 1), 7 of which tested Covid positive. No infected pts were hospitalized;there was no evidence of renal function impairment, mean eGFR pre-infection was 57.83 mL/min/1.73 m2 and post-infection was 59.25 mL/min/1.73 m2. No change in chimerism was seen with infection. Three infected pts received casirivimab/imdevimab. Reported symptoms during COVID-19 infection were mild (Table 1). 22 pts have been vaccinated (16 Pfizer-BioNtech, 3 Johnson&Johnson(J&J), and 3 Moderna). 4 pts had serology performed (Table 2). Vaccination was well tolerated with no loss of chimerism. Conclusion(s): No KTx/FCR001 pts with COVID-19 developed a severe disease type. Infection in pts off IS was not associated with loss of chimerism. SARS-CoV-2 vaccination resulted in strong humoral responses and did not lead to loss of chimerism or allograft dysfunction.

5.
Neuro-Oncology ; 24(Supplement 2):ii88-ii89, 2022.
Article in English | EMBASE | ID: covidwho-2062942

ABSTRACT

BACKGROUND: A novel therapeutic approach using molecularly targeted radiation is currently in development for patients with recurrent GBM. Many tumor types, including GBM, overexpress the L-type amino transporter 1 (LAT-1)4, which is able to internalize the small-molecule amino acid derivative, 4-L-[131I] iodo-phenylalanine (131I-IPA). In preclinical research, combining 131I-IPA with external radiation therapy (XRT) yielded addi- tive cytotoxic effects. Tumoral accumulation of 131I-IPA was confirmed in a proof-of-principle study using single doses of 2-7 GBq 131I-IPA as a monotherapy or in combination with XRT in patients with recurrent GBM. The objective of the IPAX-1 study was to evaluate the safety, tolerability, dosing schedule, and preliminary efficacy of 131I-IPA in combination with secondline radiotherapy in patients with recurrent GBM. METHOD(S): IPAX-1 is a multi-center, open-label, single-arm, dose-finding phase 1/2 study. Key inclusion criteria: 1. Confirmed histological diagnosis of GBM with evidence of first recurrence 2. History of GBM standard therapy 3. >= 6 months since end of first-line XRT 4. Pathologically increased amino acid tumor uptake shown by molecular imaging 5. Current indication for repeat radiation 6. Gross tumour volume of up to 4.8 cm diameter. Treatment: In phase 1 of the study patients received intravenous 131I-IPA at a dose level of 2 GBq administered in one of three different dosing regimens: single dose group with 2 GBq before radiation, 3 (f)-fractionated-parallel group: 3 x 0.67 GBq during XRT and 3 (f)-fractionated-sequential group: 0.67 GBq x 1 -> XRT -> 0.67 GBq x 2. XRT is delivered in 18 fractions of 2 Gy each. RESULT(S): 10 patients were randomized;one patient with Covid related death was withdrawn from analysis. Survival from start of TLX101 therapy showed mPFS2 of 4.33 M (95% -CI 4.18 - 4.48), PFS-6: 18 % and mOS2 of 15.97 M (95% -CI 2.9 - 29.1) at data lock 09/2021. Updated results will be presented at the meeting. CONCLUSION(S): There were no clinically relevant laboratory changes over time. Urinalysis, vital signs, and ECG did not show any clinically relevant changes from baseline. There were no notable differences in safety and tolerability between groups. Injections of single or fractionated doses of 131I-IPA containing a total activity of 2 GBq in combination with XRT in patients with recurrent GBM were safe and well tolerated. Survival data look promising;extension cohort will be treated in a phase II study in Linz;phase 1/2 study in first line setting is planned.

6.
Clinical Lymphoma, Myeloma and Leukemia ; 22(Supplement 2):S411, 2022.
Article in English | EMBASE | ID: covidwho-2062040

ABSTRACT

Context: CARTITUDE-2 (NCT04133636) Cohort A is assessing cilta-cel in lenalidomide-refractory patients with progressive MM after 1-3 prior LOT. Objective(s): To present updated results from CARTITUDE-2 Cohort A. Design(s): Phase 2, multicohort study. Patient(s): Lenalidomide-refractory patients with progressive MM after 1-3 prior LOT (PI and IMiD included) and no previous exposure to BCMA-targeting agents. Intervention(s): Single cilta-cel infusion (target dose 0.75x106 CAR+ viable T-cells/kg) after lymphodepletion Main Outcome Measure(s): Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Management strategies were used to reduce risk of movement/neurocognitive adverse events (MNTs). Pharmacokinetics (PK) (Cmax/Tmax of CAR+T-cell transgene levels), cytokine release syndrome (CRS)-related cytokines over time, peak cytokine levels by response/CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+T-cell CD4/CD8 ratio by response/CRS/ICANS are being evaluated. Result(s): As of January 2022 (median follow-up [MFU] 17.1 months), 20 patients (65% male;median age 60 years;median 2 prior LOT;95% refractory to last LOT) received cilta-cel. Overall response rate was 95% (90% >=complete response;95% >=very good partial response). Median times to first and best response were 1.0 month and 2.6 months, respectively. All 16 MRD-evaluable patients achieved MRD negativity at 10-5. Median duration of response was not reached. At 12 months, event-free rate was 79% and progression-free survival rate was 75%. 95% of patients had CRS (gr3/4 10%);median time to onset was 7 days and median duration was 3 days. Neurotoxicity was reported in 30% of patients (5 gr1/2;1 gr3/4) and ICANS in 15% (all 3 gr1/2);1 patient had gr2 facial paralysis. No MNTs were observed. 1 death occurred due to COVID-19 (treatment-related), 2 due to progressive disease, and 1 due to sepsis (not treatment-related). Preliminary PK analyses showed peak CAR-T cell expansion at day 10.5;median persistence was 153.5 days. Conclusion(s): At MFU of 17.1 months, a single cilta-cel infusion resulted in deep and durable responses in lenalidomide-refractory MM patients with 1-3 prior LOT. We will present updated PK/cytokine/CAR-T subset analyses and clinical correlation to provide novel insights into biological correlates of efficacy/safety in this population. Copyright © 2022 Elsevier Inc.

7.
Chest ; 162(4):A1506-A1507, 2022.
Article in English | EMBASE | ID: covidwho-2060835

ABSTRACT

SESSION TITLE: Respiratory Care: Oxygen, Rehabilitation, and Inhalers SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: Background More than 1.5 million Americans live with supplemental oxygen that improves quality of life in adults living with chronic lung disease. After hospitalization for serious illness such as pneumonia (especially COVID), heart failure, COPD exacerbation or other lung disease, patients are discharged on supplemental oxygen. Hypoxemia often resolves after recovery from the illness and supplemental oxygen is no longer needed. As a part of “Choosing Wisely” campaign from ABIM, ATS/ACCP recommends “For patients recently discharged on supplemental home oxygen following hospitalization for an acute illness, don’t renew the prescription without assessing the patient for ongoing hypoxemia within 90 days after discharge. Objectives The primary objective of the study is to improve home oxygen reassessment after discharge from the hospital. METHODS: Study Design Subjects will be identified by electronic medical records (EMR) report and will include data from the 1st of January 2021 to 30th June 2021 (period of 6 months) Inclusion Criteria Subjects 18 years and older who were discharged from the RPH on supplemental oxygen Exclusion: Subjects 18 years and older on oxygen for palliation and hospice Study Outcomes The primary outcome measure will be assessed as percent of patients in whom oxygen requirement reassessed and percent in whom oxygen requirement was not reassessed. The secondary outcome measure will be assessed as percent of patients who had PCP follow up and percent of patients on continuous oxygen without reassessment Quality improvement PDSA: Phase I: pre-intervention data Phase II: Intervention-> education session to the providers and new epic order inclusion (BPA for reassessment and discontinuation) Phase III: post-intervention survey RESULTS: Based on chart review, 155 patients qualified for the study criteria. Among 155 patients, regarding the primary outcome-> 63 patients (40.6%) 90 days oxygen reassessment was done, 64 patients (41.2%) oxygen reassessment was not done, 10 patients (6%) died within the 90 days reassessment period and 19 patients were 90 days reassessment was not applicable (12%- 19 patients-on long term oxygen). Regarding the secondary outcomes, 113 patients (72.9%) were followed up with PCP, 16 patients (10.3%) did not have follow up, 19 patients (12.2%- no information available) had outside PCP follow up, 7 patients (4.5%- 2 died on same admission, 5 opted for hospice). Regarding patient who continued to use oxygen, 74 patients (47.7%) were continued on oxygen, 47 patients (30.3%) were discontinued of oxygen and 34 patients (22%) did not have any information available regarding oxygen use. CONCLUSIONS: From the above data, There is room for improvement regarding oxygen reassessment by educating primary care providers. Post intervention survey will be done in 6 months. CLINICAL IMPLICATIONS: Improve oxygen reassessment in patients after discharge with oxygen DISCLOSURES: No relevant relationships by Anam Aqeel No relevant relationships by Mansur Assaad No relevant relationships by Apurwa Karki No relevant relationships by Shobha Mandal No relevant relationships by Rajamurugan Meenakshisundaram

8.
Investigative Ophthalmology and Visual Science ; 63(7):453, 2022.
Article in English | EMBASE | ID: covidwho-2058398

ABSTRACT

Purpose : Autosomal recessive CEP290-LCA (LCA10) is a severe inherited retinal disease resulting in early vision loss and currently has no treatment. Sepofarsen is an RNA antisense oligonucleotide targeting the most common c.2991+1655A>G disease-causing variant in the CEP290 gene. Long-term safety and efficacy of sepofarsen in the first eye treated (FE) and safety and efficacy in the second eye treated (SE) in this extension trial (Insight;NCT03913130) were evaluated. Methods : Subjects who completed the Ph1b/2 sepofarsen trial could enroll in the extension trial for continued dosing in the FE and initiation in the SE with the 160/80μg loading/maintenance dose. Frequency and severity of adverse events, and change in best-corrected visual acuity (BCVA) and full-field stimulus testing (FST) threshold were assessed. Baseline was defined as the value measured within the same month of-or last measurement prior to-the first dosing for each eye. Due to covid-19, some participants have missed scheduled injections. As such data up to-or available measurement prior to-6 months after the last dosing have been included in the analysis for each eye. Results : At data cut-off in mid-October 2021, 9 subjects (of 11 from the Ph1b/2 trial) aged 15-45 years were followed up to 46 months, 5 of them received at least one intravitreal injection of sepofarsen in the SE. Three subjects developed cataracts in the FE and 2 in the SE, of which 2 recovered following cataract surgery. Time to onset since initial dose was 13 months or later. Between 35-46 months after the 1 injection, long term BCVA improvement was reported in 4/6 FE ranging from-0.20 to-0.54 logMAR and 5/5 FE improved in either blue FST, red FST or both ranging from-0.21 to-2.06 log cd/m2. The SE showed a similar trend as the FE in BCVA (3/5 SE showed a change ranging from-0.06 to-2.50 logMAR) and in blue and red FST (4/4 SE showed improvement ranging from-0.27 to-4.57 log cd/m2). st Conclusions : The longer-term sepofarsen safety profile is consistent with that observed in the Ph1b/2. Meaningful BCVA and FST improvements observed in the Ph1b/2 continued up to 46 months. The responses in the SE were similar to the responses seen in the FE in both visual acuity and retinal sensitivity improvements. A Phase 2/3 (ILLUMINATE;NCT03913143), multiple dose, double-masked, randomized, sham-controlled trial is ongoing.

9.
Journal of Neuromuscular Diseases ; 9:S299, 2022.
Article in English | EMBASE | ID: covidwho-2043395

ABSTRACT

Objective: Evaluate the safety and tolerability of losmapimod in the treatment for FSHD. Background: FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum is developing losmapimod, a small molecule p38 α/β MAPK inhibitor, to treat FSHD. Losmapimod has been generally well-tolerated in more than 3,600 subjects across multiple clinical studies, including >100 subjects with FSHD. Fulcrum has assessed losmapimod in FSHD in one completed phase 1 study (FIS 001-2018) and two ongoing Phase 2 studies in the open label extension period (FIS 001-2019 and FIS 002-2019). Methods: Subjects aged 18-65 years with genetically confirmed FSHD1, Clinical Severity Score 2-4, and MRI-eligible muscles for biopsy were exposed to losmapimod 7.5 or 15 mg twice daily PO for 14 days and up to 76 weeks. In study FIS 001-2018, 6 subjects were exposed to 7.5 mg and 11 subjects to 15 mg twice daily dosing for 14 consecutive days. In studies FIS 001-2019 and FIS 002-2019, 14 and 77 subjects respectively, received at least one dose of losmapimod 15 mg twice daily for up to 76 weeks. Results: A total of 108 subjects with FSHD1 have been exposed to losmapimod, with approximately 131 patient-years of exposure. Fifty-seven subjects have been exposed to losmapimod for 12 to 18 months, and 30 have been exposed for over 18 months. Most adverse events (AEs) observed during the studies were considered of mild to moderate in severity. The most common AEs were alanine aminotransferase (ALT) increase, headache, dizziness, dry skin, eczema and gastrointestinal disorders. The majority of AEs resolved with continued dosing. Dosing has been paused for 14 days in four subjects (3 in FIS 001-2019 and 1 in FIS 002-2019) subjects due to COVID-19 infection. There were no reported drug related SAEs, deaths, discontinuations due to AEs, or clinically significant changes in vital signs, clinical laboratory results, or ECG parameters. Conclusion: Losmapimod given as up to 15 mg twice daily in >100 subjects with FSHD1 for up to 76 weeks has been generally well-tolerated, consistent with that previously reported in other patient populations. Therefore, the benefit-risk profile of losmapimod for the treatment of FSHD remains favorable.

10.
Annals of Oncology ; 33:S977-S978, 2022.
Article in English | EMBASE | ID: covidwho-2041541

ABSTRACT

Background: Immune Checkpoint Blockade (ICB) is moving from metastatic to curative setting in different diseases including NSCLC. While for metastatic disease radiological endpoints are currently the standard surrogate marker of benefit from ICBs, based on RECIST or PERCIST criteria, in neoadjuvant setting they often underestimate the response and then pathological response (PR) criteria were developed to evaluate Major PR (MPR), defined as ≤10% viable tumor cells after neoadjuvant treatment, and PR, defined as less than 50% residual tumor cells. Anyway, a non-invasive approach to determine the response to treatment is still an unmet need. Methods: PRINCEPS was a phase 2 clinical trial including limited-stage (IB-IIIA) NSCLC patients who received one administration of atezolizumab before surgery. 18-F FDG PET was performed within 28 days and after 15-22 days from atezolizumab. Surgery was performed at day 22-29 from atezolizumab. PET derived parameters including MTV and TLG was extracted by experienced nuclear physicians. Results: 30 patients were enrolled, all received A and underwent surgical resection after a median of 23 days. MPR was identified in 4, pPR in 8 tumors. Paired PET were available for 28 pts. Mean time from A to PET was 18 days (IQR 3.5). Total TLG and MTV reduction was not correlated with percentage of pPR (p=0.117 and p=0.843, respectively). Reduction of MTV (Pearson correlation 0.509, p=0.006) and TLG (Pearson correlation 0.562, p=0.002) in the primary tumor were strongly correlated with pPR, while no correlation was observed between percentage of pPR and variation in tumor diameters by RECIST criteria (-0.24, p=0.2) nor metabolic response (-0.12, p=0.55). The appearance of metabolically active hilar and mediastinal, non-pathological lymph nodes (LN) was noted in 12/28 patients, and specifically in. 2 out of 4 MPR and 5 out of 8 pPR. A trend toward an higher pPR was observed with LN appearance (mean 52% reduction in pts with LN appearance vs 29% without, p 0.061), probably reflecting immune activation. LN appearance was associated with hyperplasia and histiocytosis in resected, non-metastatic LNs. Conclusions: PET is able to early detect tumor response in localized NSCLC patients treated with ICBs in neoadjuvant setting. Clinical trial identification: NCT02994576. Legal entity responsible for the study: Institut Gustave Roussy. Funding: Roche. Disclosure: N. Chaput-Gras: Financial Interests, Personal, Advisory Board, Strong-Iopredi Scientific Advisory Board: AstraZeneca;Financial Interests, Institutional, Invited Speaker, Educational Session On Immune Cell Death: Servier;Financial Interests, Institutional, Expert Testimony, Expertise On Immune Cell Death Biomarkers: Servier;Financial Interests, Personal, Invited Speaker: Cytune Pharma;Financial Interests, Institutional, Research Grant, Research grant to identify immune biomarkers associated to clinical response in patients treated with agonistic mAbs: GSK;Financial Interests, Institutional, Research Grant, Preclinical studies in mice: GSK;Financial Interests, Institutional, Research Grant, Immune profiling of Head & Neck tumors: Sanofi. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Resea ch Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. J. Remon Masip: Financial Interests, Personal, Invited Speaker: Roche, Pfizer, MSD, Boehringer-Ingelheim;Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Janssen, Takeda, Sanofi;Financial Interests, Personal, Expert Testimony: Ose Immunotherapeutics;Non-Financial Interests, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD: MSD;Non-Financial Interests, Other, Co-PI of APPLE trial (EORTC-1525): AstraZeneca. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.

11.
Annals of Oncology ; 33:S904-S905, 2022.
Article in English | EMBASE | ID: covidwho-2041538

ABSTRACT

Background: CSCC is highly immune-responsive;a prior pilot study demonstrated a high rate of pathologic complete response (pCR) or major pathologic response (MPR, ≤10% viable tumor), using cemiplimab anti-programmed death 1 (PD-1) therapy in the neoadjuvant setting. Here, we present the primary analysis of a confirmatory, open-label, multicenter, Phase 2, single-arm trial of neoadjuvant cemiplimab in pts with resectable Stage II–IV (M0) CSCC. Methods: Pts received cemiplimab 350 mg IV q3W for up to 4 doses before surgery. The primary endpoint was pCR rate per independent central pathologic review (ICPR). Key secondary endpoints included MPR rate per ICPR, objective response rate (ORR;complete response [CR] + partial response [PR]) per RECIST v1.1, investigator-assessed pCR and MPR, safety and tolerability. Results: At data cutoff date of 01 Dec 2021, 79 pts were enrolled (67 male;median age 73.0 yrs [range, 66.0–81.0];ECOG performance status 0 (n=60) and 1 (n=19) with stage II (n=5), III (n=38), or IV(M0) (n =36) disease;62 pts received all 4 doses (median number of doses given (Q1:Q3), 4 (4:4);70 pts underwent surgery. The study met its primary endpoint: pCR was observed in 40 (50.6%) pts (95% confidence interval [CI], 39.1–62.1%). MPR was observed in an additional 10 (12.7%) pts (95% CI, 6.2–22.0%). ORR was 68.4% (95% CI, 56.9–78.4) (5 CR, 49 PR, 16 stable disease, 8 progressive disease (PD), 1 non evaluable. Reasons 9 pts did not have surgery: 3 responders declined surgery, 2 lost to follow-up or noncompliance, 2 had inoperable PD, 2 due to AE. Fourteen (17.7%) pts experienced Grade ≥3 AE. Four pts died due to AEs: 1 exacerbation of cardiac failure, 2 myocardial infarctions, and 1 COVID-19 pneumonia. The most common AEs regardless of attribution (all grades) were fatigue (30.4%), rash maculo-papular (13.9%), diarrhea (13.9%) and nausea (13.9%). Conclusions: The pCR + MPR of 63.3% by ICPR in pts with Stage II–IV (M0) CSCC is the highest observed in a multicenter anti-PD-1 neoadjuvant monotherapy study for any solid tumor type. The safety profile of neoadjuvant cemiplimab is consistent with previous anti-PD-1 monotherapy experience. Ongoing follow-up will describe disease-free survival. Clinical trial identification: NCT04154943. Editorial acknowledgement: Medical writing support was provided by John G Facciponte, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., and Sanofi. Legal entity responsible for the study: Regeneron Pharmaceuticals, Inc., and Sanofi. Funding: Regeneron Pharmaceuticals, Inc., and Sanofi. Disclosure: N. Gross: Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Advisory Board: PDS Biotechnology, Shattuck Labs and Genzyme;Financial Interests, Personal, Advisory Role: PDS Biotechnology, Shattuck Labs and Genzyme. D.M. Miller: Financial Interests, Personal, Advisory Role: Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron, Sanofi Genzyme;Financial Interests, Personal, Ownership Interest: Checkpoint Therapeutics;Financial Interests, Personal, Research Grant: Kartos Therapeutics, NeoImmune Tech, Inc., Regeneron Pharmaceuticals, Inc. N. Khushanlani: Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb, HUYA Bioscience International, Merck, Novartis, GlaxoSmithKline, Celgene, Amgen;Financial Interests, Personal, Advisory Board: EMD Serono, Regeneron Pharmaceuticals, Inc., Genentech, AstraZeneca (data safety monitoring committee), Merck, Array Biopharma, Jounce Therapeutics, Immunocore, Bristol Myers Squibb, HUYA Bioscience International;Financial Interests, Personal, Other, honoraria: Sanofi;Financial Interests, Personal, Stocks/Shares: Bellicum Pharmaceuticals, Mazor Robotics, Amarin, Transenetrix. V. Divi: Financial Interests, Institutional, Research Grant: Genentech. E.S. Ruiz: Financial Interests, Personal, Advisory Board: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi;Financial Int rests, Personal, Advisory Role, consulting fees: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi;Financial Interests, Personal, Member of the Board of Directors: Checkpoint Therapeutics. E.J. Lipson: Financial Interests, Personal, Other, Advisory board and consulting fees: Bristol Myers-Squibb, Eisai, Genentech, Immunocore, Instil Bio, MacroGenics, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, OncoSec, Pfizer, Rain Therapeutics, Regeneron, Sanofi;Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Merck, Regeneron. F. Meier: Financial Interests, Personal, Other, Travel support, speaker’s fees or advisor’s honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche and Sanofi;Financial Interests, Personal, Research Grant: Novartis and Roche. P.L. Swiecicki: Financial Interests, Institutional, Research Grant: Ascentage Pharma, Pfizer;Financial Interests, Personal, Advisory Board: Prelude Therapeutics, Elevar Therapeutics, Regeneron Pharmaceuticals. J.L. Atlas: Financial Interests, Personal, Advisory Role: Regeneron Pharmaceuticals, Inc., Sanofi, and Bristol Myers Squibb. J.L. Geiger: Financial Interests, Institutional, Research Grant: Alkermes, Debio, Merck, Regeneron Pharmaceuticals, Inc., and Roche/Genentech;Financial Interests, Personal, Advisory Role: Exelixis, Merck and Regeneron Pharmaceuticals, Inc. A. Hauschild: Financial Interests, Personal and Institutional, Other, Institutional grants, speaker’s honoraria and consultancy fees: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Provectus and Roche;Financial Interests, Institutional, Other, Institutional grants and consultancy fees: EMD Serono, Philogen and Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Advisory Role: OncoSec Medical. J.H. Choe: Financial Interests, Personal, Advisory Role: Exelixis, Coherus Biosciences, Regeneron Pharmaceuticals, Inc. B.G.M. Hughes: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer and Roche;Financial Interests, Institutional, Research Grant: Amgen. S. Yoo: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. K. Fenech: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.D. Mathias: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. H. Han: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.G. Fury: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. D. Rischin: Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals, Inc., Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Merck KGaA, Bristol Myers Squibb, GlaxoSmithKline, ALX Oncology;Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, Bristol Myers Squibb;Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, Bristol Myers Squibb. All other authors have declared no conflicts of interest.

12.
Annals of Oncology ; 33:S798-S799, 2022.
Article in English | EMBASE | ID: covidwho-2041537

ABSTRACT

Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the EU as a monotherapy in patients (pts) with dMMR/MSI-H AR EC that has progressed on or after platinum-based chemotherapy;and in the US as a monotherapy in pts with dMMR AR EC that has progressed on or after platinum-based chemotherapy or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. We report on PFS and OS in 2 expansion cohorts of the GARNET trial that enrolled pts with EC. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or A2 (MMRp/MSS EC) based on local immunohistochemistry assessment. Pts received 500 mg of dostarlimab IV every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. PFS and OS are secondary efficacy endpoints. Results: 153 pts with dMMR/MSI-H and 161 pts with MMRp/MSS EC were enrolled and treated. The efficacy-evaluable population included 143 pts with dMMR/MSI-H EC and 156 pts with MMRp/MSS EC with measurable disease at baseline and ≥6 mo of follow-up. Median follow-up was 27.6 mo for dMMR/MSI-H and 33.0 mo for MMRp/MSS EC (Table). For pts with dMMR/MSI-H EC, median PFS (mPFS) was 6.0 mo, with 3-year estimated PFS rate of 40.1%. With 37.3% of pts experiencing an event, mOS was not reached;estimated 3-year OS was >50%. For pts with MMRp/MSS EC, mPFS was 2.7 mo. mOS was 16.9 mo with 68.9% of pts experiencing an event. Safety has been previously reported. [Formula presented] Conclusions: Dostarlimab demonstrated durable antitumor activity in dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with longer PFS and OS than MMRp/MSS as expected. Clinical trial identification: NCT02715284. Editorial acknowledgement: Writing and editorial support, funded by GlaxoSmithKline (Waltham, MA, USA) and coordinated by Heather Ostendorff-Bach, PhD, of GlaxoSmithKline, was provided by Shannon Morgan-Pelosi, PhD, and Jennifer Robertson, PhD, of Ashfield MedComms, an Ashfield Health company (Middletown, CT, USA). Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline. Disclosure: A.V. Tinker: Financial Interests, Institutional, Sponsor/Funding: AstraZeneca;Financial Interests, Personal, Other: AstraZeneca, Eisai, GlaxoSmithKline. B. Pothuri: Financial Interests, Institutional, Funding: AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, Takeda Pharmaceuticals, Tesaro/GSK;Financial Interests, Personal, Other: Arquer Diagnostics, AstraZeneca, Atossa, Clovis Oncology, Deciphera, Elevar Therapeutics, Imab, Mersana, Tesaro/GSK, Merck, Sutro Biopharma, Tora, GOG Partners;Financial Interests, Personal, Advisory Board: Arquer Diagnostics, AstraZeneca, Atossa, Deciphera, Clovis Oncology, Eisai, Elevar Therapeutics, Imab, Merck, Mersana, Sutro Biopharma, Tesaro/GSK, Toray;Financial Interests, Personal, Leadership Role: GOG Partners, NYOB Society Secretary, SGO Clinical Practice Committee Chair, SGO COVID-19 Taskforce Co-Chair. L. Gilbert: Financial Interests, Institutional, Funding: Alkermes, AstraZeneca, Clovis, Esperas, IMV, ImmunoGen Inc, Karyopharm, Merck Sharp & Dohme, Mersana, Novocure GmbH, OncoQuest Pharmaceuticals, Pfizer, Roche, Tesaro;Financial Interests, Personal, Other: Merck, Alkermes, AstraZeneca, Eisai, Eisai-Merck, GlaxoSmithKline. R. Sabatier: Financial Interests, Institutional, Funding: AstraZeneca, Eisai;Financial Interests, Personal, Other: AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Roche;Non-Financial Interests, Personal, Other: AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Roche. J. Brown: Financial Interests, Personal, Advisory Role: Caris, Clovis, Eisai, GlaxoSmithKline;Financial Interests, Personal, Funding: GlaxoSmithKline, Genentech. S. Ghamande: Financial Interests, Personal, Advisory Role: Seattle Genetics;Financial Interests, Personal, Speaker’s Bureau: GlaxoSmithKline;Financial Interests, Institutional, Funding: Abbv e, Advaxis, Bristol Myers Squibb, Clovis, Genentech, GlaxoSmithKline, Merck, Roche, Seattle Genetics, Takeda. C. Mathews: Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Deciphera, Moderna, GSK, Regeneron, Seattle Genetics;Financial Interests, Personal, Advisory Board: IMAB biopharma. D. O'Malley: Financial Interests, Personal, Advisory Board: AstraZeneca, Tesaro/GSK, Immunogen, Ambry, Janssen/J&J, Abbvie, Regeneron, Amgen, Novocure, Genentech/Roche, GOGFoundation, Iovance, Eisai, Agenus, Merck, SeaGen, Novartis, Mersana, Clovis, Elevar, Takeda, Toray, INXMED, SDP Oncology (BBI), Arquer Diagnostics, Roche Diagnostics MSA, Sorrento, Corcept Therapeutics, Celsion Corp;Financial Interests, Personal, Funding: AstraZeneca, Tesaro/GSK, Immunogen, Janssen/J&J, Abbvie, Regeneron, Amgen, Novocure, Genentech/Roche, VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto Inc, Ludwig Cancer Research, Stemcentrx, Inc, Cerulean Pharma, GOGFoundation, Bristol-Myers Squibb Co, Serono Inc, TRACON Pharmaceuticals, Yale University, New Mexico Cancer Care Alliance, INC Research, Inc, inVentiv Health Clinical, Iovance, PRA Intl, Eisai, Agenus, Merck, GenMab, SeaGen, Mersana, Clovis, SDP Oncology (BBI);Financial Interests, Personal, Other: Myriad Genetics, Tarveda. V. Boni: Financial Interests, Personal, Advisory Board: OncoArt, Guidepoint Global;Financial Interests, Personal, Speaker’s Bureau: Solti;Financial Interests, Personal, Other: START, Loxo, IDEAYA Biosciences;Financial Interests, Institutional, Research Grant: Sanofi, Seattle Genetics, Loxo, Novartis, CytomX Therapeutics, Pumo Biotechnology, Kura Oncology, GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, Menarini, Synthon, Janssen Oncology, Merck, Lilly, Merus, Pfizer, Bayer, Incyte, Merus, Zenith Epigenetics, Genmab, AstraZeneca, Seattle Genetics, Adaptimmune, Alkermes, Amgen, Array BioPharma, Boehringer Ingelheim, BioNTech AG, Boston Biomedical. A. Gravina: Financial Interests, Personal, Other: Gentili, Pfizer. S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen, Genmab, Immunogen, Mersana, Merck Sereno, MSD, Roche, Tesaro, AstraZeneca, GSK, Oncxerna;Financial Interests, Personal, Invited Speaker: Clovis, Pfizer, Tesaro, AstraZeneca, GSK, Takeda, Amgen, Medscape, Research to Practice, Peerview;Financial Interests, Personal, Stocks/Shares: PerciHealth;Financial Interests, Institutional, Research Grant: AstraZeneca, GSK, Tesaro;Non-Financial Interests, Principal Investigator, Phase II clinical trial Global lead, ENGOTov60/GOG3052/RAMP201: Verastem;Non-Financial Interests, Principal Investigator, ENGOT-GYN1/ATARI phase II international trial (academic sponsored): Astrazeneca;Non-Financial Interests, Advisory Role: Epsilogen;Non-Financial Interests, Other, Member of membership committee: ESGO;Non-Financial Interests, Advisory Role, Medical advisor to UK ovarian cancer charity: Ovacome Charity;Non-Financial Interests, Other, Received research funding from UK based charity I have provided medical advice (non-remunerated): Lady GardenFoundation Charity. R. Miller: Financial Interests, Personal, Other: AZD, Clovis Oncology, Ellipses, GlaxoSmithKline, MSD, Shionogi, AZD, GlaxoSmithKline;Financial Interests, Personal, Speaker’s Bureau: AZD, Clovis Oncology, GSK, Roche. J. Pikiel: Financial Interests, Personal, Other: Amgen, Clovis Oncology, GlaxoSmithKline, Incyte, Novartis, Odonate Therapeutics, Pfizer, Regeneron, Roche. M.R. Mirza: Financial Interests, Personal, Advisory Board: AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zailab;Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK, Karyopharm;Financial Interests, Personal, Stocks/Shares: Karyopharm;Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, ultimovacs, Apexigen;Financial Interests, Institutional, Invited Speaker: Deciphera;Non-Financial Interests, Advisory Role: Ultimovacs, Apexigen. T. Duan: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. G. Antony: Financial Interests, Personal, Fu l or part-time Employment: GlaxoSmithKline. S. Zildjian: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. E. Zografos: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. J. Veneris: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. A. Oaknin: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, Deciphera Pharmaceuticals, Genmab, GSK, Immunogen, Mersana Therapeutics, PharmaMar, Roche, Tesaro, Merck Sharps & Dohme de España, SA, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, prIME Oncology, Sattucklabs, Itheos, Eisai, F. Hoffmann-La Roche,;Financial Interests, Personal, Other, Travel and accomodation: AstraZeneca, PharmaMar, Roche;Financial Interests, Institutional, Funding: Abbvie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann –La Roche LTD, Regeneron Pharmaceuticals, Immunogen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Tesaro Inc., Bristol Myers Squibb;Non-Financial Interests, Leadership Role, Executive Board member as a Co-Chair: GEICO;Non-Financial Interests, Leadership Role, Phase II Committee and Cervix Cancer Committee Representative on behalf of GEICO: GCIG;Non-Financial Interests, Officer, Chair of Gynaecological Track ESMO 2019. Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022. Member of Gynaecological Cancers Faculty and Subject Editor Gyn ESMO Guidelines.: ESMO;Non-Financial Interests, Member: ESMO, ASCO, GCIG, SEOM, GOG.

13.
Annals of Oncology ; 33:S657, 2022.
Article in English | EMBASE | ID: covidwho-2041523

ABSTRACT

Background: The poly(ADP-ribose) polymerase inhibitor niraparib showed clinical activity in advanced gBRCAm ovarian and breast cancers. LUZERN aims to assess the effectiveness of niraparib plus AI in HR+/HER2–, AI-resistant ABC with a pathogenic variant in homologous recombination-related genes. Here we report findings from the stage 1 interim analysis. Methods: This open-label, single-arm, Simon’s 2-stage, phase II trial is enrolling HR+/HER2– ABC patients (pts) with gBRCAm (cohort A;n=6 in stage 1, n=7 in stage 2) and gBRCA wild-type/HRd (cohort B;n=9 in stage 2). Pts had to have received ≤1 prior line of chemotherapy for ABC, 1–2 prior lines of endocrine therapy for early or ABC with secondary endocrine resistance to the last AI regimen. Pts receive niraparib (200/300mg daily orally) plus AI (same agent given with the prior regimen) on each 28-day cycle. Primary endpoint: clinical benefit rate (CBR) as per RECIST 1.1. Secondary endpoints: overall response rate, progression-free survival (PFS), and safety per CTCAE 5.0. If ≥1/6 pts experienced clinical benefit, the trial should proceed to stage 2. Results: Six pts were enrolled in stage 1. Median age was 46 years (range 32–76), 66.7% of pts had visceral disease, and 83.3% had received prior CDK4/6 inhibitor-containing regimen for ABC. At data cut-off, 50.0% of pts were ongoing and median duration of treatment was 4.6 months (range 2.4–5.7). One patient achieved complete response, meeting the criterion to proceed to stage 2. Median investigator-assessed PFS was 5.3 months (95%CI 3.9–NA). The most frequent adverse events (AEs) of any grade (G) were nausea (3 [50.0%]), neutropenia (2 [33.3%];16.7% G3), constipation (2 [33.3%]), and vomiting (1 [16.7%]). Serious AEs occurred in 3 pts (50.0%;G3 COVID-19 pneumonia;G3 pseudomonal bacteriemia;G2 sacral pain). No treatment-related discontinuations/deaths were reported. Conclusions: Niraparib plus AI showed preliminary activity with a tolerable safety profile in gBRCAm HR+/HER2– AI-resistant ABC pts. Based on the steering committee recommendation, enrolment in cohorts A and B is ongoing. Clinical trial identification: ClinicalTrials.gov identifier: NCT04240106. Legal entity responsible for the study: MEDSIR. Funding: GlaxoSmithKline. Disclosure: J.Á. García Saenz: Financial Interests, Personal, Advisory Board: Seagen, Gilead;Financial Interests, Personal, Invited Speaker: Novartis, Celgene, Eli Lilly, Eisai, AstraZeneca, Daiichi Sankyo, MSD, Exact Sciences;Financial Interests, Institutional, Funding: AstraZeneca. J. De la Haba Rodriguez: Financial Interests, Personal, Other, Consultant and Advisory Role, Research Funding and Speaking: Pfizer, Novartis, Roche, Lilly;Financial Interests, Personal, Other, grant support: Pfizer. J.E. Ales Martínez: Financial Interests, Personal, Other, travel grant: Pfizer;Financial Interests, Personal, Research Grant: MEDSIR. E. Alba Conejo: Financial Interests, Personal, Advisory Role: Roche, Novartis, Pfizer, Lilly, BMS, Astrazeneca, Pierre Fabre, Daiichi, Exact Sciences;Financial Interests, Personal, Research Grant: Pfizer. J. Balmaña: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer;Financial Interests, Institutional, Other, Steering committee member: AstraZeneca;Financial Interests, Institutional, Principal Investigator: Medsir, Pfizer. J.M. Perez Garcia: Financial Interests, Personal, Advisory Role: Lilly,Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, Medsir;Financial Interests, Personal, Other, travel expenses: Roche. M. Sampayo-Cordero: Financial Interests, Personal, Other, honoraria: Medsir, Syntax for Science, Optimapharm, and Ability pharma;Financial Interests, Personal, Research Grant: Medsir;Financial Interests, Personal, Other, travel expenses: Medsir, Syntax for Science, Optimapharm, and Roche;Financial Interests, Personal, Other, consultant: Medsir, Syntax for Science, and Optimapharm;Financial Interests, Personal, Speaker’s Bureau: Medsir;Financial Interests, Personal, Full or part-time Employment: Me sir. A. Malfettone: Non-Financial Interests, Personal, Full or part-time Employment: MEDSIR. J. Cortés: Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, Astrazeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks;Financial Interests, Personal, Other, honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo;Financial Interests, Institutional, Research Grant: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London.;Financial Interests, Personal, Stocks/Shares: MEDSIR, Nektar Pharmaceuticals, Leuko (relative);Financial Interests, Personal, Other, travel, accomodation: Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, Astrazeneca. A. Llombart Cussac: Financial Interests, Personal, Leadership Role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD;Financial Interests, Personal, Stocks/Shares: MEDSIR and Initia-Research;Financial Interests, Personal, Advisory Role: Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, GSK;Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, and MSD;Financial Interests, Personal, Research Grant: Roche, Foundation Medicine, Pierre-Fabre, and Agendia;Financial Interests, Personal, Other, travel compensation: Roche, Lilly, Novartis, Pfizer, and AstraZeneca. All other authors have declared no conflicts of interest.

14.
Annals of Oncology ; 33:S635, 2022.
Article in English | EMBASE | ID: covidwho-2041521

ABSTRACT

Background: A subgroup of triple negative breast cancer (TNBC) expresses the androgen receptor (AR). In this trial we evaluated the efficacy and tolerability of the AR inhibitor darolutamide (D) or capecitabine (C) in patients (pts) with advanced AR-positive TNBC (NCT03383679). Methods: Pts with centrally reviewed AR-positive (≥ 10% by immunohistochemistry) TNBC treated with up to one line of chemotherapy for advanced disease were eligible. They were randomized in a 2:1 ratio to receive D 600 mg twice daily or C 1000 mg/m2 twice daily 2-weeks on/ 1-week off, until progression or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR) at 16 weeks and was assessed in the eligible population and in the sensitivity analysis population (pts with delayed tumour assessment performed in the context of COVID pandemic). Main secondary endpoints included objective response rate, overall survival, progression-free survival (PFS) and safety. Results: A total of 254 pts from 45 centres were screened;94 pts were randomized (61 in D arm, 33 in C arm) from April 2018 to July 2021. A clinical benefit was observed in D arm in 13 of 53 evaluable pts (CBR at 16 weeks 24.5%;95% CI: 12.9%-36.1%) including 2 PR and 1 CR and in C arm in 11 of 23 evaluable pts (CBR at 16 weeks 47.8%;95% CI: 27.4%-68.2%). In the sensitivity analysis, a clinical benefit was observed in D arm in 17 of 58 evaluable patients (CBR ≥ 16 weeks 29.3%;95% CI: 17.6%-41.0%) and in C arm in 19 of 32 evaluable patients (CBR ≥ 16 weeks 59.4%;95% CI: 42.3%-76.4%). 7 pts presented with drug-related serious adverse events: 3 in D arm and 4 in C arm. In D arm, asthenia (26.7%), nausea (25%) and ASAT increase (21.7%) were the most common adverse events, the majority being grade 1 or 2, similar to previous safety data. Median PFS were 1.8 months (CI 95% 1.7-3.1) and 3.6 months (1.8-9.1) in D arm and C arm respectively. Other secondary endpoints will be presented at the meeting. Conclusions: Despite not reaching the pre-specified CBR, darulotamide demonstrated clinical activity with significant benefit for a group of patients. A research program to identify predictive biomarkers of sensitivity is ongoing. Clinical trial identification: EudraCT: 2017-002284-18 NCT03383679. Legal entity responsible for the study: UNICANCER. Funding: BAYER. Disclosure: All authors have declared no conflicts of interest.

15.
Acta Pharmaceutica Hungarica ; 91(3-4):95-96, 2021.
Article in English | EMBASE | ID: covidwho-2033587

ABSTRACT

Introduction Pfizer-BioNTech collaboration started in 2018 in order to develop mRNA flu vaccine. Because of the covid19 pandemic the two companies started to focus on mRNA vaccine development for the prevention of covid19 infection. In March they signed the Letters of Intent. Initially there were four vaccine candidates including unmodified mRNA, nucleoside-modified mRNA and self-amplifying mRNA. For further development the nucleoside- modified mRNA was chosen. In April Phase 1/2 study was completed in Germany and in May in the USA. Two 30 μg doses 3 weeks apart induced neutralizing antibody titers comparable to natural infection and strong CD4+ and CD8+ Tcell responses were observed. Phase 2b/3 clinical trial started in July involving more than 43.000 participants in 153 sites. The result showed 95% efficacy with mild and moderate local and systemic events. For safety reason all participants will be followed for 2 years after the second dose. Based on rolling review regulatory agencies were able to approve within a short period of time in December 2020, first MHRA in UK, then FDA authorized for Emergency Use and EMA granted Conditional Marketing Authorization on 21 December 2021 for 16 years old and older. The first shipments were sent all European countries on 27 December. Direct shipments to vaccination centers on ultra-low temperature (minus 9060 degree of centigrade) using dry ice. Each thermal shipping container has a temperature monitoring device. All shipments are tracked via GPS monitoring device to ensure end-to-end distribution within required temperatures. In May EMA granted an extension of indication for covid-19 vaccine to include in children aged 12-15. The effect of vaccine was investigated in 2260 children aged 12-15, about half of them received dummy injection. Of the 1,005 children receiving the vaccine, none developed COVID-19 compared to 16 children out of the 978 who received the dummy injection. This means that, in this study, the vaccine was 100% effective at preventing COVID-19. The most common side effects in children aged 12 to 15 are similar like those in people aged 16 and above. They include pain at the injection site, tiredness, headache, muscle and joint pain, chills and fever. These effects are usually mild or moderate and improve within a few days from the vaccination. EMA granted approval for booster dose (third dose) for immune weakened people 28 days after the second dose, and 6 months after the second dose for 18 years of age and older. Approval is based on the clinical program evaluating the safety, tolerability and immunogenicity of a booster dose of covid-19 vaccine. A booster dose of the vaccine elicited significantly higher neutralizing antibody titers against the initial SARS-CoV-2 virus (wild type), as well as the Beta and Delta variants, when compared with the levels observed after the two-dose primary series. The reactogenicity profile within seven days after the booster dose was typically mild to moderate, and the frequency of reactions was similar to or lower than after dose two. The efficacy is this trial was 95,6%. In October 2021 FDA authorized for emergency use of covid-19 for children 5 through 111 years of age. For this age group, the vaccine is to be admin-istered in a two-dose regimen of 10 μg (0,2 ml) doses given 21 days apart. EUA is supported by clinical data showing a favorable safety profile and high vaccine efficacy of 90.7% in children 5 through 11 years of age during a period when Delta was the prevalent strain. In 2021 we have already distributed 1,8B doses to 146 countries by end of September. In 2022 we plan to distribute 4B doses. (Figure Presented).

16.
Acta Pharmaceutica Hungarica ; 90(2-3):61, 2020.
Article in English | EMBASE | ID: covidwho-2033585

ABSTRACT

Vaccines, currently used for prophylactic purposes, prevent more than three million deaths every year from diseases like diphtheria, pertussis, tetanus, poliomyelitis, measles and influenza. The general six stages of the development of a new vaccine are: i) Exploratory stage;ii) Pre-clinical stage;iii) Clinical development;iv) Regulatory review and approval;v) Manufacturing;vi) Quality control. Clinical development is a three/four-phase process. During Phase I, small groups of people receive the trial vaccine. In Phase II, the clinical study is expanded. In Phase III, the vaccine is given to thousands of people and tested for efficacy and safety. Many vaccines undergo Phase IV formal, ongoing studies after the vaccine is approved and licensed. Phase IV studies, also referred to as postmarketing surveillance studies (PMS). These processes are very similar to drug developments. However, there are several differences compared to drug development, namely: i) unlike drugs, which are given to patients, vaccines are received by healthy individuals, thus the safety margin should be very high;ii) as vaccines have to be stored under refrigeration, there are always logistical challenges during clinical trials;iii) Adjuvants are incorporated into vaccine formulations to modulate and improve the immune response (antigen/adjuvant formulation are important aspects of clinical development);iv) The immune response primarily measured during early stages of vaccine development (Phase I/II) should evaluate: Humoral/ cell-mediated/ cross-reactive antibodies or immune complexes/ immune landscape. A challenge in responding to pandemic diseases is that vaccines may not exist for them. For newly emerging threats without licensed vaccines, such as SARS, MERS, Marburg virus, Nipah virus, SARS CoV-2 and the like, the time required to develop and produce a safe, effective vaccine is unknown and would depend on the nature of the threat and the state of current vaccine research for that threat. In almost all cases, several months would be needed to respond with the first doses of vaccines. Unfortunately, six month later than WHO declared the public health emergency of international concern (27/01/2020) there are five important questions, essential for vaccine development that remain open for scientists, namely: 1) Why do people respond so differently to infection? 2)Has the virus developed any worrying mutations? 3)How well will a vaccine work? 4)Can we develop immunity and if so, how long does it last? 5)What is the origin of the virus? Until a safe, effective vaccine was ready, other public health and medical measures (social distancing, quarantine, and aspecific medications) would need to be employed to try to limit disease spread.

17.
HemaSphere ; 6:1395-1396, 2022.
Article in English | EMBASE | ID: covidwho-2032168

ABSTRACT

Background: Persistent cytopenia due to poor graft function (PGF) is a life-threatening complication in patients undergoing allogeneic HSCT (allo-HSCT). Several therapeutic approaches have been tested in this subset of patients with poor clinical results. Aims: The objective of this multicenter open-label interventional prospective phase II Novartis study (ELTION, ClinicalTrials.gov id: NCT03718533), was to analyze efficacy and safety of EPAG in patients with post-allo-HSCT poor graft function. Methods: Adult patients diagnosed with PGF (defined as severe cytopenia after day +30 post-transplant, with two or more of the following: platelets <20000/μL-mandatory-, ANC <1000/μL, hemoglobin< 10 g/dL), and full donor chimerism, were eligible to enter the trial. Study treatment consisted of EPAG. at 150 mg/day administered up to 36 weeks;dose adjustments were contemplated as per protocol on an individual basis. The primary efficacy endpoint was the overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of EPAG. Results: Although the aim of the study was to include 33 patients, recruitment stopped prematurely due to the difficulties for hospital visits posed during COVID-19 pandemic, and eventually only 10 patients were included. The decision for this premature termination is not related to any safety concern related to the drug. Patient characteristics are shown in the table 1 attached below. At EPAG. initiation, all 10 patients showed thrombocytopenia (<20000/μcL), 5 presented with anemia (Hgb <10 g/dL), and 4 had neutropenia (ANC <1000/μcL). Four patients discontinued EPAG before week 12 due to: disease progression/relapse (2 patients), protocol deviation (1 patient), and CMV infection (1 patient). In none of the cases, the event was related to study drug. At week 16, 4 patients (4/10, 40%) and at week 24, 5 patients, showed improvement in at least one of the 3 hematologic cell lines (partial response), respectively. Counts pre-and post-EPAG and global response in patients who stayed on treatment > 12 weeks are displayed below: Image: Summary/Conclusion: In our experience, EPAG worked well in subjects with PGF, an otherwise life-threatening condition for patients, and its use at 150 mg/day is safe and well tolerated in this setting. Our data suggest that eltrombopag might improve hematologic cell counts in patients with PGF, especially in those patients who remained on treatment at week 24, however further research is warranted to extend its applicability for larger cohorts.

18.
HemaSphere ; 6:161, 2022.
Article in English | EMBASE | ID: covidwho-2032164

ABSTRACT

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with faorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improed response rate and progression free-surial in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improed outcome of HR TE NDMM patients (EMN02, STAMINA). Aims: The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is ealuating an intensie strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensie strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with preiously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to seere aderse eent (COVID-19 infection, n=1 ;drug-induced hepatitis, n=1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related aderse eent (>5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-ein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Oerall response rate was 96%, including 92 % > ery good partial response. Among 37/46 ealuable patients post induction, Minimal Residual Disease negatiity rate (NGS, 10-5) was 62%. Summary/Conclusion: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to ealuate safety and efficacy of the oerall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients.

19.
HemaSphere ; 6:1985-1987, 2022.
Article in English | EMBASE | ID: covidwho-2032163

ABSTRACT

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

20.
HemaSphere ; 6:322-323, 2022.
Article in English | EMBASE | ID: covidwho-2032159

ABSTRACT

Background: Patients with relapsed or refractory (R/R) LBCL after first-line treatment who are unable to undergo high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) hae poor outcomes and limited treatment options. Aims: PILOT (NCT03483103) ealuated liso-cel, an autologous, CD19-directed chimeric antigen receptor (CAR) T cell product, as second-line treatment in patients with R/R LBCL not intended for HSCT. Methods: Eligible patients were adults with R/R LBCL after first-line treatment who were not deemed candidates for HDCT and HSCT by their physician and met ≥ 1 frailty criteria as follows: age ≥ 70 years, Eastern Cooperatie Oncology Group performance status (ECOG PS) of 2, diffusing capacity for carbon monoxide ≤ 60%, left entricular ejection fraction < 50%, creatinine clearance < 60 mL/min, or alanine aminotransferase/aspartate aminotransferase > 2 × the upper limit of normal. Bridging therapy was allowed. Patients receied lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by liso-cel infusion at a target dose of 100 × 106 CAR+ T cells. Cytokine release syndrome (CRS) was graded per Lee 2014 criteria. Neurological eents (NE) were defined as inestigator-identified neurological aderse eents related to liso-cel and graded using the National Cancer Institute Common Terminology Criteria for Aderse Eents, ersion 4.03. The primary endpoint was objectie response rate (ORR) per independent reiew committee;all patients had ≥ 6 months of follow-up from first response. Results: Of 74 patients who underwent leukapheresis, 61 receied liso-cel and 1 receied nonconforming product (ie, product wherein one of the CD8 or CD4 cell components did not meet one of the requirements to be considered lisocel). Common reasons for preinfusion dropout included death and loss of eligibility (5 each). For liso-cel-treated patients, median age was 74 years (range, 53-84;79% ≥ 70 years) and 69%, 26%, and 5% met 1, 2, and 3 frailty criteria, respectiely;26% had ECOG PS of 2 and 44% had Hematopoietic Cell Transplantation-specific Comorbidity Index score ≥ 3. After first-line treatment, 54% were chemotherapy refractory, 21% relapsed within 12 months, and 25% relapsed after 12 months;51% of patients receied bridging chemotherapy. Median (range) onstudy follow-up was 12.3 months (1.2-26.5). ORR and complete response rate were 80% and 54%, respectiely (Table). Median duration of response and progression-free surial were 12.1 months and 9.0 months, respectiely. Median oerall surial has not been reached. The most frequent treatment-emergent aderse eents (TEAE) were neutropenia (51%), fatigue (39%), and CRS (38%), with grade 3 CRS in 1 patient (2%) and no grade 4/5 CRS eents. Any-grade NEs were seen in 31% (n = 19) of patients;grade 3 NEs occurred in 5% (n = 3) of patients and no grade 4/5 NEs were reported. Seen percent (n = 4) receied tocilizumab only, 3% (n = 2) receied corticosteroids only, and 20% (n = 12) receied both tocilizumab and corticosteroids for treatment of CRS and/or NEs. Oerall, grade ≥ 3 TEAEs occurred in 79% (n = 48) of patients, with grade 5 TEAEs in 2 patients (both due to COVID-19). Two patients (3%) had grade 3/4 infections and 15 (25%) had grade ≥3 neutropenia at Day 29. Summary/Conclusion: In the PILOT study, liso-cel as second-line treatment in patients with LBCL who met ≥ 1 frailty criteria and for whom HSCT was not intended demonstrated substantial and durable oerall and complete responses, with no new safety concerns. (Table Presented).

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