Dataset Information

A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

ABSTRACT:

Background

This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC).

Methods

Patients with refractory stage IV CRC were treated with bevacizumab 5?mg?kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured.

Results

Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50?mg q.d., imatinib 400?mg q.d., and bevacizumab 5?mg?kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival.

Conclusion

The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

SUBMITTER: Kelley RK

PROVIDER: S-EPMC3790192 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Publications

A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

Kelley R K RK Hwang J J Magbanua M J M MJ Watt L L Beumer J H JH Christner S M SM Baruchel S S Wu B B Fong L L Yeh B M BM Moore A P AP Ko A H AH Korn W M WM Rajpal S S Park J W JW Tempero M A MA Venook A P AP Bergsland E K EK

British journal of cancer 20130910 7

<h4>Background</h4>This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC).<h4>Methods</h4>Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed ev ...[more]

PMID: 24022191

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Project description:ImportanceTreatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies.ObjectiveTo assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer.Design, setting, and participantsThis open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020.InterventionsPatients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent.Main outcomes and measuresPrimary outcomes were objective response rate (ORR) and progression-free survival (PFS).ResultsOf the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]).Conclusions and relevanceIn this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer.Trial registrationClinicalTrials.gov Identifier: NCT02853318.

Project description:Micro-abstractIn a Phase I dose-finding study of metronomic daily oral vinorelbine in advanced non-small-cell lung cancer, a recommended dose was established for this therapeutic approach. In addition, this trial revealed promising efficacy data and an acceptable tolerability profile. The observed vinorelbine blood concentrations suggest continuous anti-angiogenic coverage.IntroductionWe present a Phase I dose-finding study investigating metronomic daily oral vinorelbine (Navelbine® Oral, NVBo) in advanced non-small-cell lung cancer (NSCLC).Patients and methodsPatients with stage III/IV NSCLC received daily NVBo at fixed dose levels of 20-50 mg/d for 21 days of each 4-week cycle. Primary end point was the maximum tolerated dose. Secondary end points included tumor response, time to progression (TTP), overall survival (OS) and tolerability.ResultsTwenty-seven patients with advanced NSCLC were enrolled. Most of them were extensively pretreated. Daily NVBo was well tolerated up to 30 mg/d. At 40 mg/d, two of five patients experienced dose-limiting toxicities (DLTs). Three of six patients had DLTs at the 50 mg/d level. The recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2, if tolerated. Pharmacokinetic analyses showed continuous blood exposure over 21 days and only marginal accumulation. The tolerability profile was acceptable (all dose levels - all grades: decreased appetite 33%, diarrhea 33%, leukopenia 33%, nausea 30%, vomiting 26%; ≥grade 3: leukopenia 30%, lymphopenia 19%, neutropenia 19%, febrile neutropenia 15%). Disease control rate, OS and TTP signaled a treatment effect.ConclusionDaily metronomic NVBo therapy in extensively pretreated patients with advanced NSCLC is feasible and safe at the recommended dose of 30 mg/d. Escalation to 40 mg/d in the second cycle is possible. The blood concentrations of vinorelbine after daily metronomic dosing reached lower peaks than intravenous or oral conventional dosing. Blood concentrations were consistent with anti-angiogenic or immune modulating pharmacologic properties of vinorelbine. Further studies are warranted to evaluate the safety and efficacy of this novel approach in specific patient populations.

Dataset Information

A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

Background

Methods

Results

Conclusion

Publications

A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

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