A Phase II Study of CCI-779 in Combination With Bevacizumab in Stage III or IV Melanoma
A Phase II Study of CCI-779 in Combination With Bevacizumab in Stage III or IV Melanoma
This phase II trial is studying how well giving temsirolimus together with bevacizumab works in treating patients with stage III or stage IV malignant melanoma. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for their growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of malignant melanoma by blocking blood flow to the tumor. Giving temsirolimus together with bevacizumab may kill more tumor cells.
PRIMARY OBJECTIVES:
I. Determine the objective tumor response rate (complete response and partial response) in patients with stage III or IV melanoma treated with temsirolimus and bevacizumab.
SECONDARY OBJECTIVES:
I. Describe the adverse event profile of this regimen in these patients. II. Determine the efficacy of this regimen, in terms of progression-free survival, in these patients.
III. Compare pre- vs post-treatment measurements of biomarkers and vascular system/immune system parameters in patients treated with this regimen.
IV. Correlate tumor and blood biomarkers with clinical response in these patients.
OUTLINE: This is a multicenter study.
Patients receive temsirolimus intravenously (IV) over 30 minutes on days 1 and 8 and bevacizumab IV over 30-90 minutes on day 8. Treatment repeats every 14 days for a maximum of 26 courses in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection on day 9 of course 2.Blood samples are collected during courses 1 and 2. Samples are examined by flow cytometry to evaluate peripheral blood mononuclear cells for molecular effects of study agents. Patients also undergo normal and tumor tissue biopsy (by core needle biopsy, incisional biopsy, or surgical resection) during courses 1 and 2. Samples are examined by immunohistochemistry, western blotting, protein array technology, gene expression analyses, DNA mutation analyses, and genomic analyses for pre-and post-treatment measurements of target molecules (epidermal growth factor receptor, B-Raf, MEK, MAPK), downstream pathway components (PI-3 kinase, AKT, mTOR), markers of angiogenesis, proliferation and apoptosis, markers that may modulate cell signaling or the response to investigational agents, and vascular and immune system parameters.
After completion of study treatment, patients are followed at 1 month, every 3 months for up to 2 years, and then periodically for up to 5 years.
Inclusion Criteria:
Histologically or cytologically confirmed melanoma
Stage III or IV disease
Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension as ≥ 20 mm with conventional techniques OR ≥ 10 mm with spiral CT scan
Prior brain metastases allowed provided all of the following criteria are met:
No more than a total of 5 brain metastases
All metastases are no more than 2.5 cm
Surgically resected or have been treated with gamma-knife or stereotactic radiosurgery
More than 30 days since prior disease progression
More than 30 days since prior steroids for managing brain metastases
Disease accessible for core needle biopsy, incisional biopsy, and/or surgical resection and meets one of the following criteria:
One large tumor deposit ≥ 5 cm³ from which biopsies can be harvested multiple times
Multiple deposits that can be biopsied or excised individually on different dates, measured as follows:
ECOG performance status 0-1
Weight ≥ 110 pounds (without clothes)
WBC ≥ 3,000 mm³
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Bilirubin normal
AST and ALT ≤ 2.5 times upper limit of normal
Creatinine normal OR creatinine clearance ≥ 60 mL/min
Urine protein: creatinine ratio < 1.0 OR 24-hour urine protein < 1,000 mg
Fasting cholesterol < 350 mg/dL (cholesterol medications are allowed)
Fasting triglycerides < 400 mg/dL
PT INR ≤ 1.5 (unless on full-dose anticoagulants)
Hematocrit < 41% (for males) or < 38% (for females)
None of the following within the past 4 weeks:
No psychiatric illness or social situations that would preclude study compliance
No clinically significant cardiovascular disease, including the following:
No uncontrolled diabetes
No significant traumatic injury within the past 28 days
No history of allergic reactions to compounds of similar chemical or biological composition to temsirolimus or bevacizumab
No hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies (e.g., infliximab)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment
HIV negative
Hepatitis C negative
See Disease Characteristics
More than 4 weeks since any of the following prior treatments and recovered:
More than 4 weeks since prior major surgery or open biopsy and recovered
No prior temsirolimus, rapamycin, bevacizumab, or systemic therapies targeted primarily to vascular endothelial growth factor (VEGF), VEGF receptors, or to mTOR inhibition
Concurrent full-dose anticoagulants (e.g., warfarin/low molecular weight heparin) with PT INR > 1.5 are allowed provided the following criteria are met:
In-range INR (usually between 2 and 3.5) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
No active, clinically significant bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
No concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of the following:
No concurrent nonstudy-related surgical procedures
No other concurrent anticancer agents or therapies
Exclusion Criteria
Participants who have received these medications or treatments at any time ≤ 4 weeks of registration:
Chemotherapy
Radiotherapy to non-target lesions and lesions that are not to be biopsied. Prior radiotherapy to target lesions or lesions to be biopsied/resected is not permitted
Immunotherapy
Cytokine therapy
Investigational reagents
Invasive procedures defined as follows:
Enzyme-inducing antiepileptic drugs (EIAEDs) or any other CYP3A4 inducer (Appendix C).
OR Participants who have not recovered from adverse events resulting from the administration of these agents/procedures > 4 weeks prior to registration.
Participants who have received nitrosureas or mitomycin C ≤ 6 weeks of registration.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to CCI-779 or bevacizumab, or with known hypersensitivity to Chinese hamster ovary cell products (t-PA) or other recombinant human antibodies (e.g., Remicade®).
Participants who have previously received CCI-779, rapamycin, bevacizumab, or systemic therapies targeted primarily to VEGF, VEGF receptors, or to mTOR inhibition.
Participants who have experienced any of the following ≤ 4 weeks prior to registration:
Potential subjects with clinically significant cardiovascular disease
Psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of their participation in the study therapy.
PT INR > 1.5, (unless the potential subject is on full dose anticoagulants and meet criteria described in Section 3.1.8).
Participants with uncontrolled diabetes, defined as having a HGBA1C ≥ 7%.