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

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well giving ipilimumab with or without sargramostim (GM-CSF) works in treating patients with stage III or stage IV melanoma that cannot be removed by surgery (unresectable). Ipilimumab works by activating the patient's immune system to fight cancer. Colony-stimulating factors, such as sargramostim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of treatment. It is not yet known whether giving ipilimumab together with sargramostim is more effective than ipilimumab alone in treating melanoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the overall survival for the combination of sargramostim (GM-CSF) plus ipilimumab and ipilimumab alone in patients with advanced melanoma. SECONDARY OBJECTIVES: I. To evaluate the progression-free survival, response rate, safety and tolerability for the combination of GM-CSF plus ipilimumab and ipilimumab alone in patients with advanced melanoma. II. To explore the utility of immune related response criteria (irRC) prospectively in patients receiving ipilimumab. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive induction therapy comprising ipilimumab intravenously (IV) over 90 minutes on day 1 and sargramostim subcutaneously (SC) once daily on days 1-14. Treatment repeats every 21 days for 4 cycles. After 12 weeks of induction treatment, anti-tumor response is assessed and patients then receive maintenance therapy comprising ipilimumab IV over 90 minutes on day 1 and sargramostim SC once daily on days 1-14. Treatment with ipilimumab repeats every 12 weeks and treatment with sargramostim repeats every 21 days. After 12 weeks of maintenance therapy, anti-tumor response is reassessed and patients with responsive or stable disease then continue maintenance therapy until disease progression or unacceptable toxicity. ARM B: Patients receive induction therapy comprising ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles. After 12 weeks of induction treatment, anti-tumor response is assessed and patients then receive maintenance therapy of ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 12 weeks. After 12 weeks of maintenance therapy, anti-tumor response is reassessed and cycles repeat every 12 weeks in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients With Advanced Melanoma

Conditions
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Advanced Melanoma, Metastatic Melanoma, Recurrent Melanoma, Stage III Cutaneous Melanoma AJCC v7, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Unresectable Melanoma

Intervention / Treatment
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* Biological: Ipilimumab
* Biological: Sargramostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All sites of disease must be evaluated within 4 weeks prior to randomization; patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) No more than one prior systemic therapeutic regimen for unresectable stage III or stage IV melanoma; this includes chemotherapy, biologic therapy, biochemotherapy, or investigational treatment; this does not include any therapies given in the adjuvant setting Histologic diagnosis of metastatic melanoma; for unknown primary disease, diagnosis of metastatic disease by cytology fine needle aspiration (FNA) is not acceptable Women must not be pregnant or breast-feeding due to unknown effects of ipilimumab and GM-CSF on the unborn fetus; all women of childbearing potential must have a blood test within 72 hours prior to randomization to rule out pregnancy; women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception; women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be of childbearing potential; women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential White blood cells (WBC) >= 2000/uL (obtained =< 4 weeks prior to randomization) Absolute neutrophil count (ANC) >= 1500/mcL (obtained =< 4 weeks prior to randomization) Platelets >= 100,000/mcL (obtained =< 4 weeks prior to randomization) Hemoglobin >= 8 g/dL (obtained =< 4 weeks prior to randomization) Creatinine =< 3.0 x upper limit of normal (ULN) (obtained =< 4 weeks prior to randomization) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (obtained =< 4 weeks prior to randomization) Bilirubin =< 3.0 x ULN, (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL) (obtained =< 4 weeks prior to randomization) No concomitant therapy with any of the following: interleukin (IL) 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; must have been discontinued >= 4 weeks No infection with human immunodeficiency virus (HIV); due to the mechanism of action of ipilimumab and GM-CSF, activity and side effects in an immune compromised patient are unknown No active infection with hepatitis B No active or chronic infection with hepatitis C Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Exclusion Criteria: Patients with any history of central nervous system (CNS) metastases are excluded Patients are excluded 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 excluded if they have a history of any autoimmune disease; 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 excluded for any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea Patients are excluded for receiving any non-oncology vaccine therapy used for prevention of infectious diseases for up to four weeks (28 days) prior to or after any dose of ipilimumab Patients are excluded if they have a history of prior treatment with ipilimumab or prior cluster of differentiation (CD)137 agonist or cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor or agonist Any concurrent medical condition requiring the use of systemic steroids is not permitted (the use of inhaled or topical steroids is permitted)

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (ipilimumab and sargramostim)<br>Patients receive induction therapy comprising ipilimumab IV over 90 minutes on day 1 and sargramostim SC once daily on days 1-14. Treatment repeats every 21 days for 4 cycles. After 12 weeks of induction treatment, anti-tumor response is assessed and patients then receive maintenance therapy comprising ipilimumab IV over 90 minutes on day 1 and sargramostim SC once daily on days 1-14. Treatment with ipilimumab repeats every 12 weeks and treatment with sargramostim repeats every 21 days. After 12 weeks of maintenance therapy, anti-tumor response is reassessed and patients with responsive or stable disease then continue maintenance therapy until disease progression or unacceptable toxicity. | Biological: Ipilimumab<br>* Given IV<br>* Other names: Yervoy;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;|
| Active Comparator: Arm B (ipilimumab)<br>Patients receive induction therapy comprising ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles. After 12 weeks of induction treatment, anti-tumor response is assessed and patients then receive maintenance therapy of ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 12 weeks. After 12 weeks of maintenance therapy, anti-tumor response is reassessed and cycles repeat every 12 weeks in the absence of disease progression or unacceptable toxicity | Biological: Ipilimumab<br>* Given IV<br>* Other names: Yervoy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from randomization to death from any cause. | Assessed every 3 months for 2 years, then every 6 months for 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival is defined as the time from randomization to disease progression or death, whichever occurs first. Response and disease progression will be evaluated using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Disease progression is defined as >= 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) and the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions is also considered progression. | Assessed every 3 months for 2 years, then every 6 months for 3 years | 
| Proportion of Patients With Objective Response | Objective response was evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. Per RECIST criteria, complete response (CR) = disappearance of all target and non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial response (PR)= At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. To be assigned a status of partial response, changes in tumor measurements must be confirmed by a repeat assessment performed no less than four weeks after the criteria for response is met. Objective response = CR + PR. | Assessed every 3 months for 2 years, then every 6 months for 3 years |