Temsirolimus and Bevacizumab in Treating Patients With Stage III or Stage IV Malignant Melanoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of CCI-779 in Combination With Bevacizumab in Stage III or IV Melanoma

Conditions
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Recurrent Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage IV Skin Melanoma

Intervention / Treatment
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* Biological: Bevacizumab
* Other: Laboratory Biomarker Analysis
* Drug: Temsirolimus
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed melanoma Stage III or IV disease Recurrent disease allowed 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 Tumor lesions in previously irradiated areas are not considered measurable disease 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 Concurrent steroids for other reasons allowed provided the dose is < that required 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: One lesion ≥ 5 cm^3 Two lesions ≥ 3 cm^3 Three lesions ≥ 2 cm^3 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: Uncontrolled intercurrent illness Ongoing or active acute (CTCAE v.3 grade 3 or 4) infection Abdominal fistula Gastrointestinal perforation Intra-abdominal abscess Serious or nonhealing wound, ulcer, or bone fracture No psychiatric illness or social situations that would preclude study compliance No clinically significant cardiovascular disease, including the following: Cerebrovascular accident within the past 6 months Transient ischemic attack within the past 6 months Myocardial ischemia within the past 6 months Myocardial infarction within the past 6 months Other thromboembolic event within the past 6 months Unstable angina within the past 6 months Uncontrolled hypertension (i.e., hypertension despite maximal therapy) New York Heart Association class II-IV heart disease Congestive heart failure Serious cardiac arrhythmia requiring medication Clinically significant peripheral vascular disease History of stroke Artificial valve, pacemaker, or similar device No uncontrolled diabetes Hemoglobin A1c < 7% 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: Chemotherapy (6 weeks for nitrosoureas or mitomycin C) Radiotherapy to nontarget lesions or lesions that are not to be biopsied Immunotherapy Cytokine therapy Enzyme-inducing antiepileptic drugs (EIAEDs) or other CYP3A4 inducers Investigational agents 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) Minimal tumor bleeding of the skin allowed at the clinician's discretion No concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of the following: Temsirolimus Bevacizumab CYP450 isoenzymes 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: Major surgical procedure, open biopsy or significant traumatic injury Anticipation of need for non-study related surgical procedures from registration until Cycle 26 (One year). 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: Uncontrolled intercurrent illness Infection, CTCAE3 grade 3 or 4 (either ongoing, chronic, or active infection) Abdominal fistula Gastrointestinal perforation Intra-abdominal abscess Serious or non-healing wound Serious or non-healing ulcer Serious or non-healing bone fracture. Potential subjects with clinically significant cardiovascular disease Recent history (defined as ≤ 6 months of registration) of thromboembolic events including cerebrovascular accident (CVA), transient ischemic attack (TIA), myocardial ischemia, myocardial infarction (MI) Uncontrolled hypertension (hypertension despite maximal therapy) Unstable angina ≤ 6 months of registration New York Heart Association Classification of ≥ class II heart disease Congestive heart failure Serious cardiac arrhythmia requiring medication Clinically significant peripheral vascular disease Have a history of stroke Have an artificial valve, pace-maker, or similar device 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%.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor, monoclonal antibody)<br>Patients receive temsirolimus 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. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;Procedure: Therapeutic Conventional Surgery<br>* Undergo tumor resection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response (Complete Response and Partial Response) and Progression in Participants With Stage III or IV Melanoma Following Treatment With Temsirolimus and Bevacizumab | Evaluated using Response Evaluation Criteria In Solid Tumor (RECIST) criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions. | Up to 18 weeks after registration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events in Participants With Stage III or IV Melanoma Treated With Temsirolimus and Bevacizumab | Defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome, or disease which either occurs during the study (having been absent at baseline) or if present at baseline, appears to worsen. Graded using scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Tabulated by type and severity: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | On days 1 and 8 of each cycle, and up to 2 years after registration. | 
| Association Between Expression or Activation of One Biomarker With Another, With Biochemical and Clinical Responses, With Alterations in Cell Proliferation and Apoptotic Markers, and With Time to Progression | Changes in the ratio of phospho-S6Kinase (pS6K) S240/244 to total S6, in the tumor, from day 1 to day 23. These were assessed by reverse-phase protein array. A linear model was fit with PROC MIXED in SAS 9.3 using the log base 10 of expression as the outcome measure. This measure type is not listed in the data table form; so the number of patients who had decreases in that ratio is listed. | Day 1 of course 1 and day 8 of course 2 | 
| Comparison of Biomarkers to Antitumor Activity/Patient Outcomes | Assessed in both tumor tissue pretreatment. Mutations in BRAF were assessed in all 16 of the patients and were assessed for any association with clinical response | Day 1 of course 1 and day 8 of course 2 | 
| Comparison of Pre- vs Post-treatment Measurements of Biomarkers and Vascular System/Immune System Parameters | Biomarker expression in tumor and normal skin will be assessed by immunohistochemistry (IHC) or Western blotting, using marker-specific antibodies. | Day 1 of course 1 and day 8 of course 2 | 
| Progression-free Survival | Defined as the duration of time from start of treatment to time of progression, death or date of last follow-up. | Day 11 of courses 4, 8, 12, 16, 20, and 24, and then annually for up to 5 years |