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A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma.

ABSTRACT: Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. METHODS. Four cohorts of patients received weekly bryostatin-1 (20 ?g/m²) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles.Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 ?g/m² every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ? 80 months, respectively. Partial responses were seen in both clear cell and papillary histology.This combination of 37.5 mg of temsirolimus with 20 ?g/m² of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.

SUBMITTER: Plimack ER

PROVIDER: S-EPMC3983829 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma.

Plimack Elizabeth R ER Tan Tingting T Wong Yu-Ning YN von Mehren Margaret M MM Malizzia Lois L Roethke Susan K SK Litwin Samuel S Li Tianyu T Hudes Gary R GR Haas Naomi B NB

The oncologist 20140327 4

<h4>Background</h4>Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. METHODS. Four cohorts of patients received weekly bryostatin-1 (20 μg/m²) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles.<h4>Results</ ...[more]

PMID: 24674872

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Project description:BackgroundPreclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.MethodsWe undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015.FindingsBetween Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%).InterpretationThe combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination.FundingNational Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.

Dataset Information

A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma.

Publications

A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma.

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