Ipilimumab With or Without Bevacizumab in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01950390
First received: September 23, 2013
Last updated: August 12, 2014
Last verified: August 2014
  Purpose

This randomized phase II trial studies how well ipilimumab with or without bevacizumab works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and bevacizumab, block tumor growth in different ways by targeting certain cells.


Condition Intervention Phase
Recurrent Melanoma
Stage IIIC Melanoma
Stage IV Melanoma
Biological: bevacizumab
Biological: ipilimumab
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Trial of Ipilimumab With or Without Bevacizumab in Patients With Unresectable Stage III or Stage IV Melanoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Overall survival (OS) [ Time Frame: Time from randomization to death from any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    OS distributions will be estimated using the Kaplan-Meier method. The distribution of OS will be compared using the stratified log rank test with one-sided overall type I error rate of 0.100 (adjusting for the one interim analysis) and the hazard ratio of OS will be estimated using the stratified Cox proportional hazard model and one-sided 90% repeated confidence interval will be constructed.


Secondary Outcome Measures:
  • Progression-free survival (PFS) evaluated based on international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [ Time Frame: Time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years ] [ Designated as safety issue: No ]
    Will be estimated using the Kaplan-Meier method. PFS distributions will be compared using the log rank test.

  • Incidence of adverse events (AE), defined using the Common Terminology Criteria for Adverse Events version 4.0 criteria [ Time Frame: Up to 90 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    Toxicity rate for individual AEs, categorized AEs and worst degree AEs will be compared using the Chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.

  • Immune response assessed using the utility of irRC [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    McNemar's test will be used to evaluate the agreement between irRC and RECIST-based clinical response. The landmark analysis will be conducted to evaluate the association between PFS/OS and irRC.


Estimated Enrollment: 168
Study Start Date: December 2013
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A (ipilimumab)

INDUCTION THERAPY: Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Beginning course 8, patients receive ipilimumab IV over 90 minutes on day 1. Courses repeat every 12 weeks in the absence of disease progression or unacceptable toxicity.

Biological: ipilimumab
Given IV
Other Names:
  • anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
  • MDX-010
  • MDX-CTLA-4
  • monoclonal antibody CTLA-4
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm B (ipilimumab and bevacizumab)

INDUCTION THERAPY: Patients receive ipilimumab IV over 90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive bevacizumab as in Induction Therapy. Beginning course 8, patients also receive ipilimumab IV over 90 minutes on day 1. Courses repeat every 12 weeks in the absence of disease progression or unacceptable toxicity.

Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Biological: ipilimumab
Given IV
Other Names:
  • anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
  • MDX-010
  • MDX-CTLA-4
  • monoclonal antibody CTLA-4
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare overall survival for patients receiving ipilimumab plus bevacizumab versus ipilimumab alone.

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival, response rate and safety in patients receiving ipilimumab plus bevacizumab versus ipilimumab alone.

II. To evaluate the utility of immune related response criteria (irRC) in patients receiving ipilimumab plus bevacizumab versus ipilimumab alone.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A:

INDUCTION THERAPY: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Beginning course 8, patients receive ipilimumab IV over 90 minutes on day 1. Courses repeat every 12 weeks in the absence of disease progression or unacceptable toxicity.

ARM B:

INDUCTION THERAPY: Patients receive ipilimumab IV over 90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive bevacizumab as in Induction Therapy. Beginning course 8, patients also receive ipilimumab IV over 90 minutes on day 1. Courses repeat every 12 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
  • Untreated or previously received one treatment for measurable unresectable stage III or stage IV melanoma (American Joint Committee on Cancer [AJCC] 2010) (regardless of v-raf murine sarcoma viral oncogene homolog B [BRAF] mutation status or human leukocyte antigen [HLA] type); this does not include any therapies given in the adjuvant setting
  • Prior treatment (chemo, radiation, hormone, and immune therapies) must be completed > 4 weeks prior to randomization (> 6 weeks prior to randomization for nitrosoureas, mitomycin C, and checkpoint inhibitors)
  • Patients who received prior therapy with anthracyclines should have a baseline multigated acquisition (MUGA) or echo with a normal ejection fraction within 28 days prior to randomization
  • Patients must have recovered from any acute toxicity associated with prior therapy by the start of study treatment
  • Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • All sites of disease must be evaluated within 4 weeks prior to randomization; patients must have measurable disease
  • White blood cell (WBC) >= 2000/uL
  • Absolute neutrophil count (ANC) >= 1000/uL
  • Platelets >= 75 x 10^3/uL
  • Hemoglobin >= 9 g/dL
  • Creatinine =< 2.0 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN for patients without liver metastases and =< 5 x ULN for patients with liver metastases
  • Serum bilirubin =< 2.0 x ULN (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL)
  • Patients BRAF mutation status must be known
  • No concomitant therapy with any of the following: interleukin (IL) 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids; must have been discontinued >= 4 weeks prior to randomization
  • No infection with human immunodeficiency virus (HIV)
  • No active infection with hepatitis B
  • No active or chronic infection with hepatitis C
  • Patients are ineligible if they have any history of central nervous system (CNS) metastases
  • Patients are ineligible if they have a history of any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix
  • Patients are ineligible if they have a history of autoimmune disease, as follows: Patients with a history of inflammatory bowel disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis]); patients with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and myasthenia gravis) are excluded.; patients with a history of autoimmune thyroiditis are eligible if their current thyroid disorder is treated and stable with replacement or other medical therapy
  • Patients are ineligible if they have an active infection
  • Patients are ineligible if they have a history of prior treatment with ipilimumab, bevacizumab, or prior tumor necrosis factor receptor superfamily, member 9 (CD137) agonist or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor or agonist
  • Patients are ineligible if they have a history of any underlying medical or psychiatric conditions or require any medications or treatment that in the opinion of the principal investigator may interfere with compliance, make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea
  • Patients are ineligible if they have any concurrent medical condition requiring the use of systemic steroids; (use of inhaled or topical steroids is acceptable)
  • Patients are ineligible if they have inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
  • Patients are excluded if they have any prior history of hypertensive crisis or hypertensive encephalopathy
  • Patients are excluded if they have New York Heart Association (NYHA) grade II or greater congestive heart failure
  • Patients are excluded if they have a history of myocardial infarction or unstable angina within 6 months prior to randomization
  • Patients are excluded if they have a history of stroke or transient ischemic attack within 6 months prior to randomization
  • Patients are excluded if they have known significant vascular disease (e.g., aortic aneurysm, aortic dissection)
  • Patients are excluded if they have symptomatic peripheral vascular disease
  • Patients are excluded if they have evidence of bleeding diathesis or coagulopathy
  • Patients are excluded if they have had a surgical procedure or a significant traumatic injury within 28 days prior to randomization
  • Patients are excluded if they have had a biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to randomization
  • Patients are excluded if they have history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization
  • Patients are excluded if they have a non-healing wound or ulcer
  • Patients are excluded if they have proteinuria at screening as demonstrated by either:

    • Urine dipstick for proteinuria >= 2+ (patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate =< 1g of protein in 24 hours to be eligible) OR
    • Urine protein: creatinine (UPC) ratio >= 1.0 at screening; for UPC ratio > 1, a 24 hour urine protein should be obtained and the level should be < 1000mg; NOTE: Urine protein should be screened by urine analysis for UPC ratio; a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1g
  • Patients must not have known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • Patients are excluded if they have a history of hemoptysis (bright red blood of 1/2 teaspoon or more per episode) within 3 months prior to randomization
  • Patients are excluded if they have current, ongoing treatment with full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin); subjects should have not taken full-dose warfarin or equivalent for at least 2 weeks prior to randomization
  • Patients are excluded if they have current or recent (within 10 days of enrollment) use of aspirin (> 325 mg/day) or chronic use of other non-steroidal anti-inflammatory drugs (NSAID)
  • Patients are excluded if they use medications that inhibit platelet function (e.g., dipyridamole, epoprostenol, eptifibatide, clopidogrel, cilostazol, abciximab, ticlopidine, and ibuprofen and related compounds) unless subject has been off treatment for at least 2 weeks prior to randomization
  • Patients are excluded if they have known involvement of melanoma within the gastrointestinal tract
  • Patients are excluded for any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab)
  • Women of childbearing potential and sexually active males must agree to practice abstinence or use an accepted and effective method of contraception
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01950390

  Show 224 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Frank Hodi ECOG-ACRIN Cancer Research Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01950390     History of Changes
Other Study ID Numbers: NCI-2013-01732, NCI-2013-01732, ECOG-E3612, E3612, E3612, U10CA021115, U10CA180820
Study First Received: September 23, 2013
Last Updated: August 12, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Antibodies
Antibodies, Monoclonal
Bevacizumab
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 18, 2014