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1.
JAMA Netw Open ; 7(7): e2421485, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38990570

ABSTRACT

Importance: Patients from racial and ethnic minority groups (eg, Asian, Hispanic, and non-Hispanic Black patients) have low representation in clinical trials, especially in phase 1 trials in cancer. These trials represent valuable options for patients with advanced cancer who experience disease progression with standard therapy. Objective: To determine whether the benefit of enrollment to phase 1 cancer trials extends to Asian, Hispanic, and non-Hispanic Black patients as much as it does for non-Hispanic White patients. Data Sources: Patient records at a single institution from January 1999 to December 2016 were reviewed. Treatment-related responses, toxic effects, and deaths were recorded. Study Selection: All phase 1 studies were included. Data Extraction and Synthesis: Data underwent independent extraction by multiple observers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The primary outcome was overall survival (OS), assessed using univariate and multivariable time-to-event analyses. Results: A total of 738 patients (median [range], 60 [22-93] years; 467 [63.3] female) including 197 Hispanic patients (26.7%), 238 non-Hispanic Black patients (32.2%), and 282 non-Hispanic White patients (38.2%), were enrolled in 64 phase 1 trials, including 33 cytotoxic trials (51.5%), 21 biologic trials (32.8%), and 10 combined therapy trials (15.6%). The primary cancer diagnoses were colorectal (187 patients [25.3%]), ovarian (141 patients [19.1%]), lung (58 patients [7.9%]), uterine (49 patients [6.6%]), and breast (41 patients [5.6%]). Patients underwent a median (range) of 3 (0-13) therapies prior to trial enrollment. Among 558 patients evaluated for response, the clinical benefit rate (ie, stable disease plus response rates) was 49.1%, and the overall response rate was 6.5%. Grade 3 or 4 nonhematological toxic effects were observed in 27.8% (95% CI, 24.6%-31.3%) of patients and grade 3 or 4 hematological toxic effects were observed in 19.7% (95% CI, 17.0%-22.8%) of patients. The treatment-related mortality rate was 0.9% (95% CI, 0.4%-1.9%). Median OS was 9.6 (95% CI, 8.2-11.0) months among Hispanic patients, 8.3 (95% CI, 6.7-10.4) months among non-Hispanic Black patients, and 9.8 (95% CI, 8.5-11.4) months among non-Hispanic White patients (P = .13). In a multivariable analysis, age older than 60 years, Eastern Cooperative Oncology Group performance status score of 2 or greater, more than 2 metastatic sites, lactate dehydrogenase grade 1 or 2, grade 2 or greater low albumin, grade 1 or greater total bilirubin, and grade 2 or greater anemia were associated with worse prognosis, whereas leukocytosis greater than grade 1 was associated with better OS. Conclusions and Relevance: In this meta-analysis assessing outcomes in phase 1 cancer trials among patients from racial and ethnic minority groups, Hispanic and non-Hispanic Black patients had benefits similar to those of non-Hispanic White patients.


Subject(s)
Clinical Trials, Phase I as Topic , Ethnic and Racial Minorities , Neoplasms , Humans , Neoplasms/ethnology , Neoplasms/mortality , Neoplasms/therapy , Female , Male , Ethnic and Racial Minorities/statistics & numerical data , Middle Aged , Aged , Adult , Hispanic or Latino/statistics & numerical data , Aged, 80 and over , Black or African American/statistics & numerical data , Young Adult , Treatment Outcome
2.
Mol Cancer Ther ; 19(5): 1148-1156, 2020 05.
Article in English | MEDLINE | ID: mdl-32156785

ABSTRACT

KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150-180 mg/m2) and pelareorep (1 × 1010 TCID50-3 × 1010 TCID50)] was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS-mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1-5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-naïve patients, the highest dose of FOLFIRI/bevacizumab (180 mg/m2 irinotecan) and pelareorep (3 × 1010 TCID50) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid σ-1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/therapy , Mutation , Oncolytic Viruses/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Adult , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Apoptosis , Bevacizumab/administration & dosage , Biomarkers, Tumor/genetics , Cell Proliferation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Combined Modality Therapy , Female , Humans , Irinotecan/administration & dosage , Male , Maximum Tolerated Dose , Mice , Mice, Nude , Oncolytic Viruses/genetics , Prognosis , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
3.
Invest New Drugs ; 37(3): 490-497, 2019 06.
Article in English | MEDLINE | ID: mdl-30315379

ABSTRACT

Background Patients with metastatic colorectal cancer (mCRC) who progress on standard therapies may be eligible for phase I trials. To better delineate the risk-benefit ratio, we assessed toxicities, clinical outcomes and prognostic factors. Methods Records of mCRC patients on phase I trials at our institution over 18 years were reviewed. Univariable (UVA) and multivariable analyses (MVA) were undertaken and a prognostic model developed. Results There were 187 enrollments on 37 phase I trials. Median age was: 59 (29-83) years and number of prior therapies: 3 (0-8). The clinical benefit rate (CBR): response (5.6%) + stable disease, was 43.1%. Median progression free survival (PFS) and overall survival (OS) was 7.7 weeks and 43.7 weeks, respectively. The MVA identified age > 60 years (HR 1.63, p < 0.004), albumin<3.5 g/dL (HR 3.69, p < 0.001), direct bilirubin>ULN (HR1.69, p < 0.01), and WBC ≥ 5.2 k/uL (HR 1.97, p < 0.001) as negative prognostic factors. A risk score based on the MVA revealed that patients with a score of 0-1 had an improved OS (58.7 weeks) compared to a score of 2 (49.9 weeks, p < 0.01) and 3 (14.1 weeks, p < 0.001). Conclusions Phase 1 trials may offer similar or better clinical outcome for mCRC patients than standard third line therapies; the prognostic model could assist in selecting appropriate patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/mortality , Models, Statistical , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Female , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Metastasis , Patient Selection , Prognosis , Retrospective Studies , Survival Rate , Tissue Distribution
4.
Clin Nutr ESPEN ; 24: 54-57, 2018 04.
Article in English | MEDLINE | ID: mdl-29576363

ABSTRACT

Oral retinoids are commonly prescribed for many dermatological conditions and may induce hyperlipidemia. We document the case of a 35-year-old man taking acitretin for congenital lamellar ichthyosis associated with a homozygous deleterious mutation in NIPAL4 who developed retinoid-induced hyperlipidemia that responded dramatically to a whole-food plant-based (WFPB) diet. On presentation, his diet consisted of chicken, fish, low fat meats and dairy, grains, and some fruits and vegetables. He then adopted a WFPB diet without making changes to his medications. His serum lipid levels dropped and his exercise capacity improved. Five months later, after discontinuing the plant-based diet and returning to his baseline diet, his hyperlipidemia returned and persisted despite adjustments to his medications. After a year and a half, the patient again adopted a plant-based diet and his lipid levels fell sharply again. A WFPB diet helped improve and control serum lipid levels in a patient with retinoid-induced hyperlipidemia. Future interventions should focus on ways to help patients successfully adopt and maintain a WFPB diet, as increased adherence to a healthy lifestyle is associated with greater health benefits.


Subject(s)
Acitretin/therapeutic use , Diet, Vegan , Diet, Western/adverse effects , Hyperlipidemias/chemically induced , Ichthyosis, Lamellar/therapy , Keratolytic Agents/therapeutic use , Receptors, Cell Surface/genetics , Acitretin/adverse effects , Adult , Combined Modality Therapy , Humans , Hyperlipidemias/diet therapy , Ichthyosis, Lamellar/genetics , Ichthyosis, Lamellar/physiopathology , Keratolytic Agents/adverse effects , Male , Mutation , Patient Education as Topic , Recurrence , Treatment Outcome
5.
Clin Colorectal Cancer ; 16(4): 286-292, 2017 12.
Article in English | MEDLINE | ID: mdl-28412139

ABSTRACT

BACKGROUND: Biologic agents have improved the outcomes of patients with metastatic colorectal cancer (mCRC). However, the clinical trials included a predominately white population (85%), with Hispanic and black patients underrepresented. Thus, the real world benefit for the latter remains unknown. Comparative effectiveness research is a tool allowing for this exploration. PATIENTS AND METHODS: The demographic and clinical characteristics of patients treated for mCRC from 2000 to 2011 were extracted from the medical records of Montefiore Medical Center. A semiparametric accelerated failure time model was used to assess the survival differences between patients receiving chemotherapy (CT) alone versus CT plus biologic agents (CBT). RESULTS: Of the 290 patients (black, 45.9%; Hispanic, 26.2%; and white, 27.9%), 53.8% received biologic agents. The median overall survival was 15.2 months in the CT-alone group and 25.6 months in CBT group (P = .004). On univariate analysis, a lower number of metastatic sites, carcinoembryonic antigen < 41 ng/mL, and more lines of CT were associated with improved overall survival. In a propensity score-based analysis of the entire cohort, CBT offered a survival benefit compared with CT alone (increased median survival, 1.44-fold; 95% confidence interval [CI], 1.11-1.86; P = .038). The results of the subgroup analysis suggested a survival benefit for white patients (2.01; 95% CI, 1.26-3.23; P = .031) but not for Hispanic (1.42; 95% CI, 0.91-2.20; P = .370) or black (1.12; 95% CI, 0.76-1.66; P = .596) patients. CONCLUSION: In the present cohort, CBT was associated with longer survival, with the effect mainly driven by the outcomes for white patients, with black patients not appearing to benefit. These data are provocative and warrant further confirmation. Efforts to increase ethnic minority patients' enrollment in clinical trials is required to prospectively define the benefit from novel therapies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biological Factors/administration & dosage , Colorectal Neoplasms/drug therapy , Models, Theoretical , Adult , Black or African American/statistics & numerical data , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoembryonic Antigen/blood , Cohort Studies , Comparative Effectiveness Research , Female , Hispanic or Latino/statistics & numerical data , Humans , Male , Middle Aged , Survival Rate , Treatment Outcome , White People/statistics & numerical data
6.
Invest New Drugs ; 32(3): 445-51, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24271274

ABSTRACT

PURPOSE: The first-in-human phase 1 trial examined the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and antitumor activity of TLC388, a novel camptothecin with a unique lactone ring modification, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: TLC388 was administered intravenously to patients with metastatic chemotherapy refractory solid tumors on days 1, 8, and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8, and 15 of cycles 1 and 2. RESULTS: Fifty-four patients were enrolled at doses ranging from 1.5 to 60.0 mg/m(2) over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m(2) developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m(2), was declared as MTD. Treatment-related grade 3-4 hematologic toxicities included neutropenia (19 %), leukopenia (15 %), anemia (9 %), and thrombocytopenia (7 %). Grade 3-4 nonhematologic toxicities included diarrhea (2 %) and hyponatremia (4 %). Pharmacokinetics of both diastereomers (S,R and S,S) of TLC388, a mixture of two diastereomers, was dose independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m(2) for S,R and 996 (1333) L/m(2) for S,S, and 2174 (2526) L/h-m(2) for S,R and 2670 (2988) L/h-m(2) for S,S, respectively. The half-life values averaged 0.67 (1.15) hours for S,R and 0.64 (1.11) hours for S,S. The best overall response was stable disease in 21 (39 %) patients. Prolonged (≥ 6 months) stable disease was noted in eight patients. CONCLUSIONS: TLC388 at 50 mg/m(2) on the current treatment schedule is generally safe and well tolerated.


Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Female , Humans , Leukopenia/chemically induced , Male , Middle Aged , Neoplasms/blood , Neoplasms/urine , Thrombocytopenia/chemically induced
7.
Gynecol Oncol ; 131(1): 163-8, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23877015

ABSTRACT

OBJECTIVES: There is a scarcity of outcome data regarding phase 1 trials for patients with gynecologic malignancy. The objective of this study was to assess toxicity, clinical benefit and prognosticators in gynecologic oncology patients participating in phase 1 trials. METHODS: All phase 1 oncology trials conducted at Albert Einstein Cancer Center from 1999 to 2010 were reviewed and extracted for relevant demographic and clinical data concerning patients with gynecologic malignancy. Cox-proportional and logistic regression modeling were used for multivariate analysis. RESULTS: 120 distinct patients with gynecologic malignancy participated in 41 trials, constituting 30.6% of all phase 1 patients enrolled in the same time period. The median age is 59 years. Out of the 184 patients enrolled, 160 individual responses were evaluable. Seventeen DLT events (9.2%) occurred, including 1 (0.5%) treatment-related mortality. There were 27.2%≥ grade 3 hematologic and 24.4% non-hematologic toxicity. Eighty patients had stable disease (SD, 50%), including 21.9% with SD ≥ 4 months, 11 (6.3%) with partial response (PR), and 3 (1.9%) achieving complete response (CR). The clinical benefit rate (CBR=SD+CR+PR) was 58.1%. Albumin (Alb)≤ 3.5 g/dL and abnormal ANC were independent negative prognosticators of survival. We also found a continuous correlation between changes in Albumin (p=0.02) and LDH (p=0.02) and odds of achieving CBR≥4month. CONCLUSIONS: Our clinical outcome and safety data suggested that phase 1 trials may be a reasonable option for patients with advanced and recurrent gynecologic cancer. The potential prognosticators identified should be further validated in larger trials.


Subject(s)
Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Genital Neoplasms, Female/drug therapy , Neutrophils , Aged , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Leukocyte Count , Middle Aged , Proportional Hazards Models , Serum Albumin/metabolism , Treatment Outcome
8.
Mol Cancer Res ; 10(12): 1514-25, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23038811

ABSTRACT

Medical therapy of patients with malignancy requires a paradigm shift through development of new drugs with a good safety record and novel mechanisms of activity. While there is no dearth of such molecules, one particular agent, "reovirus" is promising by its ability to target cancer cells with aberrant signaling pathways. This double-stranded RNA virus has been therapeutically formulated and has rapidly progressed from preclinical validation of anticancer activity to a phase III registration study in platinum refractory metastatic squamous cell carcinoma of the head and neck. During this process, reovirus has shown safety both as a single agent when administered intratumorally and intravenously, as well as in combination therapy, with multiple chemotherapeutics such as gemcitabine, carboplatin/paclitaxel, and docetaxel; and similarly with radiation. The scientific rationale for its development as an anticancer agent stems from the fact that it preferentially replicates in and induces lyses of cells with an activated Kras pathway. As documented in many previous studies, the initial observation of greater tropism in Kras-compromised situation might certainly not be the sole and possibly not even the predominant reason for enhanced virulence. All the same, scientists have emphasized on Kras optimistically due to its high prevalence in various types of cancers. Incidence of Kras mutation has been found to be highest in pancreatic cancer (85%-90%) followed by colorectal (35-45%) and lung (25-30%). Reovirus, in fact has the potential not only as a therapy but also as a tool to unravel the aberrant cellular pathway leading to carcinogenicity.


Subject(s)
Neoplasms/therapy , Neoplasms/virology , Oncolytic Virotherapy/methods , Reoviridae/genetics , Animals , Clinical Trials, Phase III as Topic , Humans , Neoplasms/genetics
9.
Crit Rev Oncol Hematol ; 81(2): 163-84, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21493087

ABSTRACT

Eribulin mesylate is a non-taxane, structurally simplified, completely synthetic, halichondrin B derivative with an end poisoning, microtubule inhibitory action. Preclinical studies have demonstrated activity in various cancer cell lines and synergistic action with gemcitabine, epirubicin, trastuzumab, cisplatin, docetaxel and vinorelbine. Eribulin has recently been approved by United States Food and Drug Administration as a third line therapy for metastatic breast cancer patients, who have previously been treated with an anthracycline and a taxane. It has also advanced to phase II trials in non-small cell lung cancer, pancreatic, prostate, bladder, head and neck cancers, sarcomas and ovarian and other gynecological tumors. Combination trials with carboplatin, gemcitabine, pemetrexed, cisplatin, and erlotinib are currently ongoing. Eribulin potentially has a low incidence of peripheral neuropathy. The predominant side effects are neutropenia and fatigue, which are manageable. This article reviews the available information on eribulin with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, preclinical studies and clinical trials.


Subject(s)
Clinical Trials as Topic , Drug Evaluation, Preclinical , Furans/pharmacology , Furans/therapeutic use , Ketones/pharmacology , Ketones/therapeutic use , Neoplasms/drug therapy , Animals , Drug-Related Side Effects and Adverse Reactions , Furans/adverse effects , Furans/metabolism , Humans , Ketones/adverse effects , Ketones/metabolism
10.
Invest New Drugs ; 28(5): 641-9, 2010 Oct.
Article in English | MEDLINE | ID: mdl-19572105

ABSTRACT

BACKGROUND: Reolysin is reovirus serotype 3-Dearing strain, a double-stranded replication-competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activated ras pathway due to inhibition of the dsRNA-activated protein kinase. METHODS: This was a single center dose escalation trial of Reolysin administered intravenously every 4 weeks in doses ranging from 1 x 10(8) to 3 x 10(10) tissue culture infective dose (TCID)(50). Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. RESULTS: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a ras G12A mutation. Biopsy from her chest wall mass showed evidence of necrosis and viral replication by electron microscopy. Overall clinical benefit (1 PR + 7 stable disease) rate was 45%, and appeared higher in patients with viral shedding (67%) than those without (33%). CONCLUSION: Reolysin administered monthly as a one-hour infusion is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies.


Subject(s)
Antineoplastic Agents/administration & dosage , Mammalian orthoreovirus 3/physiology , Neoplasms/therapy , Virus Replication/physiology , Adult , Aged , Antibody Formation/immunology , Antineoplastic Agents/adverse effects , DNA Mutational Analysis , Female , Humans , Injections, Intravenous , Male , Mammalian orthoreovirus 3/ultrastructure , Middle Aged , Mutation/genetics , Neoplasms/immunology , RNA, Viral/blood , RNA, Viral/urine
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