Clinical trial NCT02523313: Immunotherapy With Nivolumab or Nivolumab Plus Ipilimumab vs. Double Placebo for Stage IV Melanoma w. NED
Official title: A Phase II Randomized, Double-Blind Trial of Immunotherapy With Nivolumab or Nivolumab Plus Ipilimumab Versus Double-Placebo Control as a Post-Surgical/Post-Radiation Treatment for Stage IV Melanoma With No Evidence of Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malignant Melanoma
Lead sponsor: University Hospital, Essen
Sponsor class: OTHER
First posted: 2015-08-14
Enrollment: 167
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This is a prospective, double-blind placebo-controlled, multicenter, randomized phase II trial testing the adjuvant immunotherapy with Nivolumab plus Ipilimumab Placebo or Nivolumab plus Ipilimumab versus Double Placebo Control as a post-surgical/post-radiation treatment for stage IV melanoma with no evidence of disease (NED).

Detailed description: This study will allow for direct comparison of the clinical benefit provided by Nivolumab monotherapy or Nivolumab combined with Ipilimumab versus double placebo control. Furthermore, it will also allow for direct comparison of the respective safety profiles of Nivolumab monotherapy or Nivolumab combined with Ipilimumab. Nivolumab monotherapy was chosen as one of the experimental arms because of a favourable risk-benefit ratio assessed in the large Phase 1 study (MDX1106-03/CA209-003). The combination of Nivolumab and Ipilimumab was chosen as an experimental arm because of the preliminary evidence from the Phase 1 study CA209-004 suggesting synergy between Nivolumab and Ipilimumab resulting in a higher frequency of patients with increased tumour burden reduction. Evaluating both Nivolumab monotherapy and the combination of Nivolumab and Ipilimumab will provide clinical data allowing clinicians to select the appropriate treatment for each patient based on their individual risk-benefit ratio.

Eligibility criteria: Inclusion Criteria:

* Stage IV melanoma arising from a primary cutaneous site or metastatic from an unknown primary site with no evidence of disease (NED) after surgery or radiation therapy (conducted within 8 weeks before enrolment)
* Signed written informed consent
* Known BRAF status
* Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
* Minimum life expectancy of five years excluding their melanoma diagnosis
* ECOG performance status of 0 or 1
* Tumor tissue from the resected site of disease must be provided for biomarker analyses. In order to be randomized a subject must have a PD-L 1 expression classification (positive (≥ 5% tumor cells expressing PD-L1) or negative (\< 5% tumor cells expressing PD-L1)). If an insufficient amount of tumor tissue from the resected site is provided for analysis, acquisition of additional archived tumor tissue (block and/or slides) for the biomarker analyses is required.
* Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration
* Required laboratory values
* Negative pregnancy test for female subjects and effective contraception (Pearl-Index \<1) for both male and female subjects if the risk of conception exists

Exclusion Criteria:

* History of primary uveal or mucosal melanoma
* Prior therapy with CTLA4 or PD1 antibodies
* The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
* Lack of availability for clinical follow-up assessments.
* Any immunosuppressive therapy given within the past 30 days prior to study drug administration (excluding physiologic steroid hormone replacement)
* Other malignancies within the past five years requiring treatment except basal or squamous skin carcinomas or carcinoma in situ of the cervix
* Serious cardiac, gastrointestinal, hepatic or pulmonary disease reducing life expectancy to less than five years
* Patients with serious intercurrent illness, requiring hospitalization.
* Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders.
* The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immunodeficient condition.
* Known hypersensitivity reaction to any of the components of study treatment
* Pregnancy (absence to be confirmed by ß-HCG urinary test, minimum sensitivity 25IU/L or equivalent units of HCG)) or lactation period
* Women of childbearing potential (WOCBP): Refusal or inability to use effective means of contraception (Pearl-Index \<1). WOCBP will be instructed to adhere to contraception until 31 weeks after the last dose of investigational product
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year (Pearl-Index \<1). Men receiving Nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception until 31 weeks after the last dose of investigational product
* Known alcohol or drug abuse
* Participation in another clinical study and use of any investigational or non-registered product (drug or vaccine) within the 30 days before registration
* Significant disease or condition which, in the investigator's opinion, would exclude the patient from the study
* Legal incapacity or limited legal capacity

Primary outcomes:
measure: Efficacy of adjuvant immunotherapy with Nivolumab alone or in combination with Ipilimumab (Recurrence-free survival)
timeFrame: 24 months after the last patient ended treatment
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 24 months after the last patient ended treatment
measure: Time to recurrence (TTR)
timeFrame: 24 months after the last patient ended treatment
measure: Progression/recurrence free survival 2 (PRFS2) for crossover patients of Arm C
timeFrame: 24 months after the last patient ended treatment
Other outcomes:
measure: Safety / Toxicity All adverse events ≥ Grade 3 according to CTCAE Version 4.0 criteria
timeFrame: until 90 days after discontinuation of dosing
Locations:
city: Berlin
country: Germany
facility: Charité Berlin
city: Buxtehude
country: Germany
facility: Elbe Klinikum Buxtehude
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
city: Erfurt
country: Germany
facility: HELIOS Klinikum Erfurt
city: Essen
country: Germany
facility: Studienzentrum Hautklinik Universitätsklinikum Essen (AöR) Klinik für Dermatologie
city: Gera
country: Germany
facility: SRH Wald-Klinikum Gera GmbH
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätrsklinikum Heidelberg Dermatologie / NCT
city: Heilbronn
country: Germany
facility: SLK Kliniken Heilbronn GmbH
city: Kiel
country: Germany
facility: Universitäts-Hautklinik Kiel Klinik f. Dermatologie, Venerologie u. Allergologie
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie
city: Ludwigshafen
country: Germany
facility: Klinikum der Stadt Ludwigshafen
city: Lübeck
country: Germany
facility: UKSH Campus Lübeck
city: Mainz
country: Germany
facility: Universitätsklinikum Mainz Hautklinik und Polklinik
city: Mannheim
country: Germany
facility: Klinik für Dermatologie, Venerologie und Allergologie UMM - Universitätsmedizin Mannheim
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden Hautklinik
city: München
country: Germany
facility: Universitätsklinikum München (LMU)
city: Münster
country: Germany
facility: Fachklinik Hornheide
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Tübingen
country: Germany
facility: Universitätshautklinik Tübingen
Study officials:
affiliation: Studienzentrum Hautklinik Universitätsklinikum Essen Klinik f. Dermatologie
name: Dirk Schadendorf, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Livingstone E, Zimmer L, Hassel JC, Fluck M, Eigentler TK, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kiecker F, Dippel E, Roesch A, Ziemer M, Conrad B, Korner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial. Lancet. 2022 Oct 1;400(10358):1117-1129. doi: 10.1016/S0140-6736(22)01654-3. Epub 2022 Sep 10.
citation: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rosch A, Simon JC, Conrad B, Korner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. doi: 10.1016/S0140-6736(20)30417-7.