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

National Cancer Institute (NCI)

Status and phase

Completed

Phase 1

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Recurrent Renal Cell Cancer

Stage IV Renal Cell Cancer

Recurrent Melanoma

Stage IV Melanoma

Treatments

Drug: bryostatin 1

Drug: temsirolimus

Study type

Interventional

Funder types

NIH

Identifiers

NCT00112476

04-037

FCCC-04037

CDR0000432955

NCI-2011-01382

NCI-5785

Details and patient eligibility

About

This phase I trial is studying the side effects and best dose of temsirolimus when given together with bryostatin 1 in treating patients with unresectable or metastatic solid tumors. Drugs used in chemotherapy, such as temsirolimus and bryostatin 1, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Full description

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.

Enrollment

24 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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