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

Recurrent Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00397982
• Other study ID #: NCI-2009-00133
• Secondary ID: NCI-2009-00133NC
• Status: Completed
• Phase: Phase 2
• First received: November 9, 2006
• Last updated: July 28, 2016
• Start date: May 2007

Study information

• Verified date: December 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma
• Recurrent Melanoma
• Stage IIIA Skin Melanoma
• Stage IIIB Skin Melanoma
• Stage IIIC Skin Melanoma
• Stage IV Skin Melanoma

Intervention

Biological:
• Bevacizumab
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Temsirolimus
Given IV

Procedure:
• Therapeutic Conventional Surgery
Undergo tumor resection

Locations

Country	Name	City	State
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Day 11 of courses 4, 8, 12, 16, 20, and 24	No
Secondary	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.	Days 1 and 8 of each course	Yes
Secondary	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	Biomarker expression in tumor and normal skin will be assessed by IHC or Western blotting, using marker-specific antibodies.	Day 1 of course 1 and day 8 of course 2	No
Secondary	Comparison of biomarkers to antitumor activity/patient outcomes	Assessed in both tumor tissue and in serum/plasma samples.	Day 1 of course 1 and day 8 of course 2	No
Secondary	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	No
Secondary	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	No