Immunotherapy With Nivolumab or Nivolumab Plus Ipilimumab vs. Double Placebo for Stage IV Melanoma w. NED

Sponsor

Prof. Dr. med. Dirk Schadendorf (Other)

Overall Status

Completed

CT.gov ID

NCT02523313

Collaborator

(none)

167

Enrollment

Locations

Arms

69.8

Actual Duration (Months)

8.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Nivolumab + Placebo Drug: Nivolumab + Ipilimumab Drug: Double Placebo Control	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

167 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Sep 2, 2015

Actual Primary Completion Date :

Jun 27, 2021

Actual Study Completion Date :

Jun 27, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nivolumab + Placebo Nivolumab (3 mg/kg) i.v. every 2 weeks + Placebo instead of Ipilimumab on weeks 1, 4, 7 and 10 + Placebo instead of Nivolumab on weeks 4 and 10	Drug: Nivolumab + Placebo Nivolumab will be applied at a dose of 3 mg/kg given as IV infusion every 2 weeks for up to 1 year after initial dosing or until PD + Placebo instead of Ipilimumab on weeks 1, 4, 7 and 10 + Placebo instead of Nivolumab on weeks 4 and 10. Other Names: Treatment Arm A
Experimental: Nivolumab + Ipilimumab Nivolumab (1 mg/kg) and Ipilimumab (3 mg/kg) i.v. every 3 weeks for 4 doses. Both study drugs are administered on the same day over the first 12 weeks + Placebo instead of Nivolumab on weeks 3, 5, 9 and 11. After week 12: Nivolumab as maintenance and at a dose of 3 mg/kg IV every 2 weeks for up to 1 year after initial dosing (of the combination) or until PD.	Drug: Nivolumab + Ipilimumab Nivolumab (1 mg/kg) and Ipilimumab (3 mg/kg) will be applied as IV infusion every 3 weeks for 4 doses. Both study drugs are to be administered on the same day over the first 12 weeks + Nivolumab-Placebo on weeks 3, 5, 9 and 11. After week 12 Nivolumab is given as maintenance and will be applied at a dose of 3 mg/kg IV every 2 weeks for up to 1 year after initial dosing (of the combination) or until PD. Other Names: Treatment Arm B
Placebo Comparator: Double Placebo Control Placebo instead of Nivolumab and Placebo instead of Ipilimumab i.v. every 3 weeks for 4 doses. Both placebos are administered on the same day over the first 12 weeks + Placebo instead of Nivolumab on weeks 3, 5, 9 and 11. After week 12 Placebo instead of Nivolumab as maintenance and applied as IV every 2 weeks for up to 1 year after initial dosing (of the combination) or until PD.	Drug: Double Placebo Control Placebo instead of Nivolumab and Placebo instead of Ipilimumab will be applied as IV infusion every 3 weeks for 4 doses. Both placebos are to be administered on the same day over the first 12 weeks + Placebo instead of Nivolumab on weeks 3, 5, 9 and 11. After week 12 Placebo instead of Nivolumab is given as maintenance and will be applied intravenously every 2 weeks for up to 1 year after initial dosing (of the combination) or until PD. Other Names: Treatment Arm C

Arm

Intervention/Treatment

Active Comparator: Nivolumab + Placebo

Nivolumab (3 mg/kg) i.v. every 2 weeks + Placebo instead of Ipilimumab on weeks 1, 4, 7 and 10 + Placebo instead of Nivolumab on weeks 4 and 10

Drug: Nivolumab + Placebo

Nivolumab will be applied at a dose of 3 mg/kg given as IV infusion every 2 weeks for up to 1 year after initial dosing or until PD + Placebo instead of Ipilimumab on weeks 1, 4, 7 and 10 + Placebo instead of Nivolumab on weeks 4 and 10.

Other Names:

Treatment Arm A

Experimental: Nivolumab + Ipilimumab

Nivolumab (1 mg/kg) and Ipilimumab (3 mg/kg) i.v. every 3 weeks for 4 doses. Both study drugs are administered on the same day over the first 12 weeks + Placebo instead of Nivolumab on weeks 3, 5, 9 and 11. After week 12: Nivolumab as maintenance and at a dose of 3 mg/kg IV every 2 weeks for up to 1 year after initial dosing (of the combination) or until PD.

Drug: Nivolumab + Ipilimumab

Nivolumab (1 mg/kg) and Ipilimumab (3 mg/kg) will be applied as IV infusion every 3 weeks for 4 doses. Both study drugs are to be administered on the same day over the first 12 weeks + Nivolumab-Placebo on weeks 3, 5, 9 and 11. After week 12 Nivolumab is given as maintenance and will be applied at a dose of 3 mg/kg IV every 2 weeks for up to 1 year after initial dosing (of the combination) or until PD.

Other Names:

Treatment Arm B

Placebo Comparator: Double Placebo Control

Placebo instead of Nivolumab and Placebo instead of Ipilimumab i.v. every 3 weeks for 4 doses. Both placebos are administered on the same day over the first 12 weeks + Placebo instead of Nivolumab on weeks 3, 5, 9 and 11. After week 12 Placebo instead of Nivolumab as maintenance and applied as IV every 2 weeks for up to 1 year after initial dosing (of the combination) or until PD.

Drug: Double Placebo Control

Placebo instead of Nivolumab and Placebo instead of Ipilimumab will be applied as IV infusion every 3 weeks for 4 doses. Both placebos are to be administered on the same day over the first 12 weeks + Placebo instead of Nivolumab on weeks 3, 5, 9 and 11. After week 12 Placebo instead of Nivolumab is given as maintenance and will be applied intravenously every 2 weeks for up to 1 year after initial dosing (of the combination) or until PD.

Other Names:

Treatment Arm C

Outcome Measures

Primary Outcome Measures

Efficacy of adjuvant immunotherapy with Nivolumab alone or in combination with Ipilimumab (Recurrence-free survival) [24 months after the last patient ended treatment]
Recurrence-free survival (RFS) defined as the time from date of randomization until the date of the first recurrence (local or distant metastasis), new primary melanoma or death from any cause, whichever occurs first.

Secondary Outcome Measures

Overall survival (OS) [24 months after the last patient ended treatment]
The OS of a patient is defined as the time from date of randomization until date of death.
Time to recurrence (TTR) [24 months after the last patient ended treatment]
The TTR of a patient is defined as the time from date of randomization until date of disease recurrence (local or distant metastasis) or melanoma-related death.
Progression/recurrence free survival 2 (PRFS2) for crossover patients of Arm C [24 months after the last patient ended treatment]
The PRFS2 is defined as time from date of randomization until the date of first disease progression per RECIST 1.1 beyond the initial unresectable disease recurrence, the date of second recurrence in patients without evidence of disease after surgery of a resectable first recurrence or the date of death, whichever occurs first.

Other Outcome Measures

Safety / Toxicity All adverse events ≥ Grade 3 according to CTCAE Version 4.0 criteria [until 90 days after discontinuation of dosing]
All adverse events ≥ Grade 3 according to CTCAE Version 4.0 criteria, that are related to the administration of the investigational agents will be assessed

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Charité Berlin	Berlin	Germany	10117
2	Elbe Klinikum Buxtehude	Buxtehude	Germany	21614
3	Universitätsklinikum Dresden	Dresden	Germany	01307
4	HELIOS Klinikum Erfurt	Erfurt	Germany	99089
5	Studienzentrum Hautklinik Universitätsklinikum Essen (AöR) Klinik für Dermatologie	Essen	Germany	45147
6	SRH Wald-Klinikum Gera GmbH	Gera	Germany	07548
7	Medizinische Hochschule Hannover	Hannover	Germany	30625
8	Universitätrsklinikum Heidelberg Dermatologie / NCT	Heidelberg	Germany	69120
9	SLK Kliniken Heilbronn GmbH	Heilbronn	Germany	74078
10	Universitäts-Hautklinik Kiel Klinik f. Dermatologie, Venerologie u. Allergologie	Kiel	Germany	24105
11	Universitätsklinikum Leipzig Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie	Leipzig	Germany	04103
12	Klinikum der Stadt Ludwigshafen	Ludwigshafen	Germany	67063
13	UKSH Campus Lübeck	Lübeck	Germany	23538
14	Universitätsklinikum Mainz Hautklinik und Polklinik	Mainz	Germany	55131
15	Klinik für Dermatologie, Venerologie und Allergologie UMM - Universitätsmedizin Mannheim	Mannheim	Germany	68167
16	Johannes Wesling Klinikum Minden Hautklinik	Minden	Germany	32429
17	Universitätsklinikum München (LMU)	München	Germany	80337
18	Fachklinik Hornheide	Münster	Germany	48157
19	Universitätsklinikum Regensburg	Regensburg	Germany	93053
20	Universitätshautklinik Tübingen	Tübingen	Germany	72076

Sponsors and Collaborators

Prof. Dr. med. Dirk Schadendorf

Investigators

Principal Investigator: Dirk Schadendorf, Prof. Dr., Studienzentrum Hautklinik Universitätsklinikum Essen Klinik f. Dermatologie

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Prof. Dr. med. Dirk Schadendorf, Prof. Dr. med., University Hospital, Essen

ClinicalTrials.gov Identifier:

NCT02523313

Other Study ID Numbers:

IMMUNED

First Posted:

Aug 14, 2015

Last Update Posted:

Dec 13, 2021

Last Verified:

Dec 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Additional relevant MeSH terms:

Melanoma

Nivolumab

Ipilimumab

Study Results

No Results Posted as of Dec 13, 2021