Ipilimumab With Carboplatin and Paclitaxel in Patients With Unresectable Stage III and Stage IV Melanoma

Study Overview
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Brief Summary
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The safety of the combination of ipilimumab with carboplatin/paclitaxel treatment with two different dosing schedules will be investigated in patients with metastatic melanoma. This protocol will also investigate both the clinical benefit of this combination and the features of the host immune system that may predict response to ipilimumab with chemotherapy in patients with unresectable Stage III and Stage IV melanoma.

Official Title
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A Phase II Study of Ipilimumab in Combination With Carboplatin and Paclitaxel in Patients With Unresectable Stage III or Stage IV Melanoma

Conditions
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Untreated Stage III Melanoma or Stage IV Melanoma

Intervention / Treatment
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* Biological: Ipilimumab
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent. Histologic diagnosis of malignant melanoma Untreated unresectable Stage III melanoma with N3 macroscopic lymph nodes or in-transit/satellite metastases or Stage IV melanoma (note that prior adjuvant melanoma therapy is permitted). Prior treatment with BRAF inhibitors in the metastatic setting is also permitted. Measurable/evaluable disease Required values for initial laboratory tests: WBC ≥ 2000/uL ANC ≥ 1.5 x 10E9/L Platelets ≥ 100 x 10E9/L Hemoglobin ≥ 90 g/L (may be transfused) Creatinine Clearance ≥ 50 ml/min (calculated -Cockcroft-Gault) AST/ALT ≤ 2.5 x ULN for patients without liver metastasis, ≤ 5 times for liver metastases Bilirubin ≤ 2.5 x ULN No active or chronic infection with HIV, Hepatitis B, or Hepatitis C. ECOG Performance status of 0 or 1. Men and women, ≥ 18 years of age. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as: Amenorrhea ≥ 12 consecutive months without another cause, or For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35 U/L. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab. Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study [and for up to 26 weeks after the last doseof investigational product] in such a manner that the risk of pregnancy is minimized. Exclusion Criteria: Evidence of symptomatic CNS lesions as determined by the investigator (patients with asymptomatic lesions or previously irradiated or surgically resected are eligible). Any other malignancy from which the patient has been disease-free for less than one year, with the exception of adequately treated basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix. Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea. Patients with ≥ Grade 2 peripheral neuropathy. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab). A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor or agonist. Concomitant therapy with any of the following: IL 2, interferon, or other non-study immunotherapy regimens; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids. Women of childbearing potential (WOCBP), defined above, who: are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 26 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness.

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: A<br>Arm A: Carboplatin (week 1, week 4, week 7, week 10, and week 13) Paclitaxel (week 1, week 4, week 7, week 10, and week 13) Ipilimumab (week 4, week 7, week 10, and week 13) | Biological: Ipilimumab<br>* 3 mg/kg<br>* Other names: YERVOY;Drug: Carboplatin<br>* AUC = 6<br>Drug: Paclitaxel<br>* 175 mg/m2<br>|
| Experimental: B<br>Carboplatin (week 1, week 4, week 7, week 10, and week 13) Paclitaxel (week 1, week 4, week 7, week 10, and week 13) Ipilimumab (week 5, week 8, week 11, and week 14) | Biological: Ipilimumab<br>* 3 mg/kg<br>* Other names: YERVOY;Drug: Carboplatin<br>* AUC = 6<br>Drug: Paclitaxel<br>* 175 mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Incidence of adverse events |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Putative Early Cellular and/or Molecular Biomarker levels |  | 27 months | 
| To determine ORR and clinical benefit rate (ORR + SD ≥ 24 weeks), by immune related response criteria (irRC) and modified WHO criteria (mWHO) of ipilimumab when given with carboplatin and paclitaxel at two different dosing regimens. |  | 48 months | 
| To determine the overall survival (OS) of patients receiving ipilimumab with carboplatin and paclitaxel. |  | 48 months | 
| To determine progression free survival (PFS) per irRC and mWHO of patients receiving ipilimumab with carboplatin and paclitaxel. |  | 48 months |