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Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.

ABSTRACT: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma.Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations.Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response.The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.

SUBMITTER: Algazi AP

PROVIDER: S-EPMC3251861 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.

Algazi A P AP Weber J S JS Andrews S C SC Urbas P P Munster P N PN DeConti R C RC Hwang J J Sondak V K VK Messina J L JL McCalmont T T Daud A I AI

British journal of cancer 20111129 1

<h4>Background</h4>Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma.<h4>Methods</h4>Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for B ...[more]

PMID: 22127285

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Project description:Chemotherapy still plays an important role in metastatic melanoma, particularly for patients who are not suitable or have no access to highly efficacious new therapies. Pre-therapeutic chemosensitivity testing might be useful to identify optimal chemotherapy regimens for individual patients. This multicenter randomized phase-3 trial was aimed to test for superiority of chemosensitivity-directed combination chemotherapy compared to standard dacarbazine monochemotherapy, and to demonstrate the chemosensitivity test result as prognostic in metastatic melanoma. Chemo-naive patients with advanced melanoma were biopsied from metastatic lesions. Tumor cells were isolated and tested ex-vivo for sensitivity to chemotherapeutic agents using an ATP-based viability assay. Patients with evaluable test results were randomly assigned to receive either chemosensitivity-directed combination chemotherapy (paclitaxel+cisplatin, treosulfan+gemcitabine, treosulfan+cytarabine), or dacarbazine. The primary study endpoint was overall survival (OS). After inclusion of 287 patients and a median follow-up of 26 months, the per-protocol population (n=244) showed no difference in OS between chemosensitivity-directed therapy and dacarbazine (median 9.2 vs 9.0 months, HR=1.08, p=0.64). The disease control rate (CR+PR+SD) tended to be higher in patients treated with chemosensitivity-directed therapy (32.8% vs 23.0%, p=0.088); objective response rates (CR+PR) showed no difference between groups (10.7% vs 12.3%, p=0.90). Patients whose tumors were tested chemosensitive showed no better OS or response rate than patients with chemoresistant tumors. Severe toxicities (CTC grade 3-4) were significantly more frequently observed with chemosensitivity-directed combination chemotherapy than with dacarbazine (40.2% vs 12.3%, p<0.0001). These results indicate, that chemosensitivity-directed combination chemotherapy is not superior to dacarbazine, but leads to significantly more severe toxicities.

Project description:Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development.To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma.Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy.Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600.The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points.A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ?6 months; P?=?.02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P?=?.02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients.The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response.clinicaltrials.gov Identifier: NCT01619774.

Dataset Information

Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.

Publications

Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.

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