Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
Haematologica ; 109(7): 2284-2289, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38268449
2.
J Clin Oncol ; 41(33): 5107-5117, 2023 Nov 20.
Article in English | MEDLINE | ID: mdl-37506346

ABSTRACT

PURPOSE: The combination of zanubrutinib plus obinutuzumab (ZO) was found to be well tolerated with an early signal of efficacy in a phase Ib study. ROSEWOOD is a phase II, randomized study that assessed the efficacy and safety of ZO versus obinutuzumab in patients with relapsed/refractory (R/R) follicular lymphoma (FL). METHODS: Patients with R/R FL who had received ≥2 lines of therapy, including an anti-CD20 antibody and an alkylating agent, were randomly assigned 2:1 to receive ZO or obinutuzumab (O). The primary end point was overall response rate (ORR) by independent central review (ICR). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival, and safety. RESULTS: A total of 217 patients were randomized (ZO, 145; O, 72). Median study follow-up was 20.2 months. The study met its primary end point: ORR by ICR was 69% (ZO) versus 46% (O; P = .001). Complete response rate was 39% (ZO) versus 19% (O); 18-month DOR rate was 69% (ZO) versus 42% (O). Median PFS was 28.0 months (ZO) versus 10.4 months (O; hazard ratio, 0.50 [95% CI, 0.33 to 0.75]; P < .001). The most common adverse events with ZO were thrombocytopenia, neutropenia, diarrhea, and fatigue; incidences of atrial fibrillation and major hemorrhage were 3% and 1%, respectively. CONCLUSION: The combination of ZO met its primary end point of a superior ORR versus O, and demonstrated meaningful activity and a manageable safety profile in patients with R/R FL. ZO had a favorable benefit-risk profile compared with O, and represents a potential combination therapy for patients with R/R FL.


Subject(s)
Lymphoma, Follicular , Piperidines , Pyrazoles , Pyrimidines , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Rituximab
4.
Lancet Haematol ; 10(1): e35-e45, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36400069

ABSTRACT

BACKGROUND: We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies. METHODS: This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437. FINDINGS: Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6). INTERPRETATION: Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib. FUNDING: BeiGene.


Subject(s)
Atrial Fibrillation , COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Male , Humans , Adult , Female , Agammaglobulinaemia Tyrosine Kinase , Atrial Fibrillation/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Protein Kinase Inhibitors/adverse effects
5.
Cancer Med ; 10(3): 1066-1073, 2021 02.
Article in English | MEDLINE | ID: mdl-33527779

ABSTRACT

BACKGROUND: Studies show that patients make lifestyle changes soon after certain solid tumor diagnoses, suggesting that this may be a teachable moment to motivate and promote healthy behaviors. There is a paucity of data regarding changes made after a diagnosis of a hematologic malignancy. METHODS: A cross-sectional study of 116 patients at a community oncology center who completed anonymous questionnaires was performed. Questions addressed lifestyle choices made with respect to smoking, alcohol consumption, recreational drug use, diet, and exercise habits before and after diagnosis of a hematologic malignancy. Support systems utilized, including psychiatry services, were also assessed. RESULTS: Patients exhibited significant reduction in smoking behavior (Χ2  = 31.0, p < 0.001). 82.4% (n = 14) of one pack per day smokers quit between the time periods, with nearly all smokers showing a reduction after diagnosis. Alcohol use overall did not change significantly, however, 10.3% (n = 12) of patients reported quitting drinking completely between time periods. Changes in dietary intake and exercise were not statistically significant overall. Utilization of external support systems correlated with improved diet as well as decrease in total smoking years. CONCLUSIONS: This study demonstrates that patients exhibited significant lifestyle changes after being diagnosed with a hematologic malignancy. Clinicians should take advantage of this 'teachable moment' to educate patients about positive health behavior changes. Advances in cancer therapeutics have led to an increase in cancer survivors, this education is crucial in reducing the risk of developing chronic comorbidities as well as secondary malignancies.


Subject(s)
Cancer Survivors/statistics & numerical data , Health Behavior , Hematologic Neoplasms/psychology , Hematologic Neoplasms/therapy , Life Style , Survivorship , Adult , Aged , Aged, 80 and over , Cancer Survivors/psychology , Cross-Sectional Studies , Diet , Exercise , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Survival Rate , Young Adult
6.
Leuk Lymphoma ; 62(6): 1353-1360, 2021 06.
Article in English | MEDLINE | ID: mdl-33448893

ABSTRACT

In indolent non-Hodgkin's lymphoma (iNHL), patients treated with rituximab, alone or in combination with various chemotherapeutic agents eventually relapse. This study evaluated the combination of ofatumumab and bendamustine, followed by maintenance ofatumumab in patients with relapsed iNHL with prior sensitivity to rituximab. Among the 49 patients enrolled, 24.5% achieved a complete response (CR) and 42.9% achieved a partial response (PR), with an overall response rate of 67.3% at the end of the induction therapy. Additionally, six patients with PR during induction phase achieved CR during the maintenance phase. Treatment-related adverse event was observed in 95.9% patients. The most common hematologic and biochemical abnormalities were decrease in lymphocytes (85.7%) and increase in glucose (91.8%), respectively. Overall, 42.9% progressed and 14.3% died during the study. Thus, ofatumumab in combination with bendamustine, followed by ofatumumab maintenance, was effective in the treatment of patients with iNHL with a manageable safety profile (NCT01294579).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Non-Hodgkin , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bendamustine Hydrochloride/therapeutic use , Humans , Lymphoma, Non-Hodgkin/drug therapy , Neoplasm Recurrence, Local/drug therapy , Rituximab/adverse effects
7.
Blood ; 134(13): 1024-1036, 2019 09 26.
Article in English | MEDLINE | ID: mdl-31331917

ABSTRACT

The outcome of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is poor, particularly in patients ineligible for stem cell transplantation or who fail induction therapy or salvage therapy. The phase 1b portion of this open-label, dose-escalation (3+3+3 design) study examined the maximum tolerated dose (MTD) and preliminary safety and activity of the regimen in transplant-ineligible adults with histologically confirmed relapsed/refractory DLBCL after at least 1 prior therapy. Patients received once-daily 560 mg ibrutinib, 375 mg/m2 intravenous rituximab day 1 of cycles 1 to 6, and 10, 15, 20, or 25 mg lenalidomide days 1 to 21 of each 28-day cycle. Forty-five patients were treated; median time since diagnosis was 14.1 months, and 51% of the patients had non-germinal center B-cell-like (non-GCB) DLBCL, 33% had transformed DLBCL, 60% were refractory, and 27% were primary refractory. Because of dose-limiting toxicities, a de-escalation cohort (10 mg lenalidomide) was initiated, and with subsequent re-escalation up to 25 mg lenalidomide, the MTD was not reached. In response-evaluable patients, the overall response rate (ORR) was 44% (complete response [CR], 28%); among them, the ORR was 65% (CR, 41%) in non-GCB and 69% and 56% in relapsed (n = 16) and secondary refractory (n = 27) disease, respectively. Overall and for non-GCB, median response duration was 15.9 months, with 2 patients receiving therapy beyond 3 years. Phase 2 was initiated with 20 mg lenalidomide in relapsed/refractory non-GCB, whereas the phase 1b 25-mg lenalidomide cohort was being completed; an additional 25-mg cohort in phase 2 is currently ongoing. This study was registered at www.clinicaltrials.gov as #NCT02077166.


Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lenalidomide/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Rituximab/therapeutic use , Adenine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Administration Schedule , Female , Humans , Lenalidomide/administration & dosage , Lenalidomide/adverse effects , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Piperidines , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Rituximab/administration & dosage , Rituximab/adverse effects , Treatment Outcome
8.
Invest New Drugs ; 37(2): 297-306, 2019 04.
Article in English | MEDLINE | ID: mdl-30132271

ABSTRACT

Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.


Subject(s)
Antibodies, Monoclonal/therapeutic use , CD27 Ligand/antagonists & inhibitors , Gene Expression Regulation, Neoplastic/drug effects , Lymphoma, B-Cell/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Neoplasm Recurrence, Local/drug therapy , Salvage Therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/pharmacokinetics , Benzodiazepines/chemistry , Biomarkers, Tumor/metabolism , CD27 Ligand/immunology , CD27 Ligand/metabolism , Drug Resistance, Neoplasm/drug effects , Female , Follow-Up Studies , Humans , Immunoconjugates/pharmacokinetics , Immunoconjugates/therapeutic use , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Mantle-Cell/immunology , Lymphoma, Mantle-Cell/metabolism , Lymphoma, Mantle-Cell/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Prognosis , Pyrroles/chemistry , Tissue Distribution
9.
Am J Hematol ; 93(10): 1199-1206, 2018 10.
Article in English | MEDLINE | ID: mdl-30016552

ABSTRACT

CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28-day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC-486 treatment cycles was 4 (range: 1-32). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3-4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC-486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on-study. No baseline gene mutation was predictive of response/nonresponse. CC-486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS: The safety profile of oral CC-486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21-day/cycle) CC-486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Azacitidine/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myelomonocytic, Chronic/drug therapy , Myelodysplastic Syndromes/drug therapy , Administration, Oral , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/pharmacokinetics , Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/adverse effects , Azacitidine/pharmacokinetics , Azacitidine/therapeutic use , DNA Methylation/drug effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Interactions , Fatigue/chemically induced , Female , Food , Food-Drug Interactions , Gastric Acidity Determination , Gastrointestinal Diseases/chemically induced , Hematologic Diseases/chemically induced , Humans , Male , Middle Aged , Proton Pump Inhibitors/pharmacology
10.
Ann Hematol ; 93(1): 89-98, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24135804

ABSTRACT

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease Progression , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Gastrointestinal Diseases/chemically induced , Hematologic Diseases/chemically induced , Humans , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/adverse effects , Indoles/administration & dosage , Indoles/adverse effects , Infections/etiology , Kaplan-Meier Estimate , Male , Maximum Tolerated Dose , Melphalan/administration & dosage , Melphalan/adverse effects , Middle Aged , Panobinostat , Recurrence , Salvage Therapy
SELECTION OF CITATIONS
SEARCH DETAIL
...