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