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Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.

ABSTRACT: BACKGROUND:Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS:In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS:The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS:The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.

SUBMITTER: Tawbi HA

PROVIDER: S-EPMC3603441 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.

Tawbi H A HA Beumer J H JH Tarhini A A AA Moschos S S Buch S C SC Egorin M J MJ Lin Y Y Christner S S Kirkwood J M JM

Annals of oncology : official journal of the European Society for Medical Oncology 20121121 4

<h4>Background</h4>Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ.<h4>Patients and methods</h4>In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) ...[more]

PMID: 23172636

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Project description:PurposeTo explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy.MethodsA Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m(2)/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m(2)/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent.ResultsTwenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65%) were male, and 6 (35%) were female. Eleven (64.7%) had cutaneous melanoma, 4 (23.5%) had ocular melanoma, and 2 (11.8%) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1-6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24%), anemia (12%), neutropenia (12%), and fatigue (12%), as well as grade 2 leukopenia (30%), neutropenia (23%), nausea (23%), and lymphopenia (18%). The most common reason for study discontinuation was disease progression.ConclusionsThis triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached.

Project description:LESSONS LEARNED:The combination of the antivascular endothelial growth factor receptor 2 monoclonal antibody, ramucirumab, and the type II MET kinase inhibitor, merestinib, is tolerable. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with metastatic colorectal cancer (mCRC). Further development of this combination would likely necessitate the identification of subsets of patients with mCRC where the clinical benefit is of clinical relevance. BACKGROUND:This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan. METHODS:Open-label phase Ia/b study comprising 3+3 dose-limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28-day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations. RESULTS:Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ?3 treatment-emergent adverse events (TEAEs); 10 patients (43%) with grade ?3 treatment-related TEAEs. The most common grade ?3 treatment-related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8 ?g/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression-free survival was 3.3 months (95% confidence interval [CI]: 1.6-4.4). Median overall survival was 8.9 months (95% CI: 3.5-12.7). There were no associations between genetic alterations and efficacy. CONCLUSION:Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker-unselected, heavily pretreated patients with mCRC.

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Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.

Publications

Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.

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