Temsirolimus and Bryostatin 1 in Treating Patients With Unresectable or Metastatic Solid Tumors

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose and recommended phase II dose of temsirolimus when given together with bryostatin 1 in patients with unresectable or metastatic solid tumors.

II. Determine the dose-limiting toxic effects of this regimen in these patients.

SECONDARY OBJECTIVES:

I. Correlate the extent and duration of inhibition of p70^S6kinase phosphorylation in peripheral blood mononuclear cells with tumor growth or reduction in these patients.

II. Correlate the phosphorylation total and phospho-AKT and total and phospho ribosomal S6 protein (indicators of mTOR activation) with antitumor effects of this regimen in these patients.

III. Correlate tumor expression of phospho-ERK1 and -ERK2 with antitumor effects of this regimen in these patients.

IV. Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a dose-escalation study of temsirolimus.

Patients receive bryostatin 1 IV over 1 hour on days 1, 8, 15, and 22 and temsirolimus IV over 30 minutes once on days 8, 15, and 22 during course 1. On subsequent courses patients receive bryostatin 1 and temsirolimus once on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of temsirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Inclusion criteria

• Histologically confirmed solid tumor, including melanoma or renal cell carcinoma

• Metastatic or unresectable disease

• Must have evidence of residual, recurrent, or metastatic disease by radiography
• Measurable disease

• At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques (CT scan, MRI, or x-ray) OR ≥ 10 mm by spiral CT scan
• Must show clear evidence of disease progression within the lesion if the only site of measurable disease is within a previously irradiated volume
• Standard curative or palliative measures do not exist OR are no longer effective
• No history of or known brain metastases
• Performance status - ECOG 0-1
• At least 3 months
• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin normal
• Creatinine ≤ 1.5 times ULN
• Creatinine clearance ≥ 50 mL/min
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• Fasting cholesterol ≤ 350 mg/dL*
• Triglycerides ≤ 400 mg/dL*
• Not pregnant or nursing
• Negative pregnancy test
• Fertile female patients must use effective contraception for ≥ 1 month before, during, and for ≥ 3 months after completion of study treatment (during and for ≥ 3 months after completion of study treatment for male patients)
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to study drugs
• No ongoing or active bacterial or viral infection
• No psychiatric illness or social situation that would preclude study compliance
• No dementia or altered mental status that would preclude giving informed consent
• No other uncontrolled illnesses
• More than 3 weeks since prior immunotherapy
• Prior biological therapy (e.g., interferon or interleukin 2, vaccine, antibody-based and tyrosine kinase inhibitors) allowed
• No concurrent prophylactic hematopoietic colony-stimulating factors except for epoetin alfa
• No prior cytotoxic chemotherapy
• No prior bryostatin 1, temsirolimus, everolimus, or AP23573 for this malignancy
• More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No concurrent steroids except for topical or inhaled use
• No other concurrent experimental agents
• No prior radiotherapy to > 25% of bone marrow
• More than 3 weeks since prior radiotherapy
• More than 3 weeks since prior major surgery, including nephrectomy

• Minor surgical procedures allowed
• Recovered from prior therapy
• More than 3 weeks since prior other anticancer investigational agents
• Concurrent CYP3A4 inducers or inhibitors allowed provided patient has been on a stable dose for ≥ 1 week before study entry
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent antineoplastic agents or therapies