A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy versus High-Dose Interferon Alfa-2b for Resected High-risk Melanoma


e1609 targets a patient population that is at a high and unacceptable risk of recurrence and death after standard surgical management. Patients with resectable high-risk deep cutaneous melanoma, patients with lymph node involvement by melanoma, patients with gross extra-nodal extension of disease, satellites, and/or in-transit lesions, as well as patients with completely resected stage iV disease, have the highest recurrence risk and the poorest disease-free and overall survival rates. The quality of the host immune response in the earlier adjuvant setting supports a higher likelihood of clinical benefit from immunologic interventions. This observation is supported by the our clinical experience with high dose interferon-a-2b (HDi ), which reduces relapse risk by up to 33% in the adjuvant setting, but induces response in 16% of patients with advanced inoperable disease. This provides support for the evaluation of clinically active immunological agents such as anti-CTLa4 blocking antibodies in the earlier adjuvant disease setting. Taken together with the demonstrable clinical activity of ipilimumab in advanced unresectable melanoma, this also provides support for our current proposal of adjuvant ipilimumab versus HDi for high-risk resected melanoma patients. HDi is the optimal control arm for the adjuvant study of ipilimumab in patients with high-risk resected melanoma.
Three reported national studies have evaluated the benefit of high dose interferon-a-2b (HDi) as adjuvant therapy for patients with high-risk stage iiB and iii melanoma. The first and third of these studies demonstrated significant overall survival prolongation, compared to observation (e1684) and compared to a vaccine (GMK) that was selected as the optimal vaccine candidate at the time (e1694).The larger individual patient data meta-analysis of 13 randomized trials has also shown a significant impact of interferon-a upon overall survival. in addition, no other agent has ever been demonstrated to provide similar relapse free or survival benefits for this patient population.
The advantage for patients treated with HDi amounts to a relapse frequency reduction of 24-38% and mortality reduction of 22-32% based upon the hazard ratios for patients treated with HDi or observation, or the vaccine (GMK). For stage iV melanoma, iFn-a; was the first recombinant cytokine to be investigated clinically for the therapy of advanced metastatic melanoma. HDi continues to be the only option available for patients with high-risk surgically resected melanoma outside of a clinical trial.

The trial shall consist of 3 aRMS a, B, and C; high dose interferon-alfa (HDi); high dose ipilimumab (HiP) and low dose ipilimumab (LiP).

as of april 4, 2014, patient enrollment to arm a (ipilimumab at 10 mg/kg) has been completed. all new patients will be assigned either interferon alfa-2b (arm B), or ipilimumab at a dose of 3 mg/kg (arm C).

Durable clinical benefits have been demonstrated in the advanced inoperable melanoma setting with ipilimumab, and with relative safety.

Rationale for testing the 3 mg/kg ipilimumab dose level compared to HDi in e1609 in addition to the testing of 10 mg/kg ipilimumab dose level compared to HDi is due to the positive results in metastatic melanoma. MDX010-20, published in 2010, resulted in the FDa approval of 3 mg/kg of ipilimumab in treatment of unresectable and metastic melanoma.

Participant Eligibility

* Patient must be Age > 18 years.

* Patients must have disease that is completely surgically resected in order to be eligible.

* Patients must have been surgically rendered free of disease with negative margins on resected specimen.

* Patients must have disease-free status documented by a complete physical examination and imaging studies within 4 weeks prior to randomization.

* Patients with disease recurrence after adequate surgical excision of the original primary cutaneous/unknown primary melanoma are allowed, as follows even if they don't fit the strict staging criteria but as follows:
o Recurrence in a regional lymph node basin after a prior complete lymph node dissection. Relapsed disease must be completely surgically resected with free margins.
o Recurrence in the form of in-transit or satellite metastases or distant skin/subcutaneous, nodal or lung metastases that are completely surgically resected with free margins.
o Recurrence in a regional lymph node basin. Relapsed disease must be completely surgically resected with free margins.
o Recurrence in a regional lymph node basin.

* Patients must have primary cutaneous melanoma that belong to one of the following AJCC stages (2009 AJCC Melanoma Staging System. Also see Appendix XI)
i.) IIIB T1-4b N1a M0
T1-4b N2a M0
T1-4a N1b M0
T1-4a N2b M0
T1-4a N2c M0
ii.) IIIC T1-4b N1b M0
T1-4b N2b M0
T1-4b N2c M0
Any T N3 M0
iii.) IV M1a

* Patients with stage IV melanoma must have normal LDH and either distant skin, subcutaneous, lymph node or lung metastases, but no other visceral metastases in order to be eligible. For patients with resected stage IV melanoma, LDH within the institutional upper limit of normal (ULN) must be documented within 4 weeks prior to randomization.

* Patients with unknown primary melanoma who present with cutaneous, subcutaneous, nodal and/or lung metastases that are completely surgically resected with free margins are allowed.

* Patients must be randomized within 84 days (12 weeks) of surgical resection. If more than one surgical procedure is required to render the patient disease-free, the patient must be randomized within 12 weeks of the last surgery.

* Other forms of prior treatment for melanoma (e.g., IL-2, anti-tumor vaccine, chemotherapy) are allowed if given before the resection(s) that make(s) the patient eligible for this trial, but these must have been completed at least 4 weeks prior to randomization.

* Patients must have the following required values for initial laboratory tests obtained within 4 weeks prior to randomization (ULN: institutional upper limit of normal):

* WBC >= 3000/uL WBC count: __________ Date _____________

* ANC >= 1500/uL ANC count: __________ Date _____________

* Platelets >= 100 x 103/uL Platelet count: __________ Date _____________

* Hemoglobin >= 10 g/dL Hemoglobin: __________ Date _____________

* Serum creatinine <= 1.5 mg/dl Serum creatinine: ________ Date _____________

* AST/ALT <= 2.5 x ULN AST: _________ Date _________
ULN: __________
ALT: __________ Date ________
ULN: __________

* Serum bilirubin <= 1.5 X ULN, (except patients with Gilbert[Single Quote]s Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
Serum bilirubin: __________ Date ________ ULN: __________
* Patients must have ECOG performance status of 0-1. See Appendix VI.

* Patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible.

* Patients with other malignancies are eligible if they have been continuously disease free for > 5 years prior to the time of randomization. Patients with prior history at any time of any in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ are eligible. Patients with prior history of basal or squamous skin cancer are eligible. Patients who have had multiple primary melanomas are eligible.

Women of Child Bearing Potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks afer the last dose of ipilimumab or HDI, in such a manner that the risk of pregnancy is minimized.

Spanish speaking patients are eligible to participate in this study.