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

NCT02523313 | Completed Phase 2 DMC

• 1 other identifier: IMMUNED
• Study Type: interventional
• Target: 167
• Locations: 1 country
• Sites: 20

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).

Conditions

Malignant Melanoma

Outcome Measures

Primary Outcomes (1)

• Efficacy of adjuvant immunotherapy with Nivolumab alone or in combination with Ipilimumab (Recurrence-free survival)

  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.

  24 months after the last patient ended treatment

Secondary Outcomes (3)

• Overall survival (OS)

  24 months after the last patient ended treatment

• Time to recurrence (TTR)

  24 months after the last patient ended treatment

• Progression/recurrence free survival 2 (PRFS2) for crossover patients of Arm C

  24 months after the last patient ended treatment

Other Outcomes (1)

• Safety / Toxicity All adverse events ≥ Grade 3 according to CTCAE Version 4.0 criteria

  until 90 days after discontinuation of dosing

Study Arms (3)

Nivolumab + Placebo

ACTIVE COMPARATOR

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 + Ipilimumab

EXPERIMENTAL

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

Double Placebo Control

PLACEBO COMPARATOR

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

Interventions

Nivolumab + Placebo DRUG

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.

Also known as: Treatment Arm A

Nivolumab + Placebo

Nivolumab + Ipilimumab DRUG

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.

Also known as: Treatment Arm B

Nivolumab + Ipilimumab

Double Placebo Control DRUG

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.

Also known as: Treatment Arm C

Double Placebo Control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Prof. Dr. med. Dirk Schadendorf: lead

Study Sites (20)

Charité Berlin

Berlin, 10117, Germany

Location

Elbe Klinikum Buxtehude

Buxtehude, 21614, Germany

Location

Universitätsklinikum Dresden

Dresden, 01307, Germany

Location

HELIOS Klinikum Erfurt

Erfurt, 99089, Germany

Location

Studienzentrum Hautklinik Universitätsklinikum Essen (AöR) Klinik für Dermatologie

Essen, 45147, Germany

Location

SRH Wald-Klinikum Gera GmbH

Gera, 07548, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Universitätrsklinikum Heidelberg Dermatologie / NCT

Heidelberg, 69120, Germany

Location

SLK Kliniken Heilbronn GmbH

Heilbronn, 74078, Germany

Location

Universitäts-Hautklinik Kiel Klinik f. Dermatologie, Venerologie u. Allergologie

Kiel, 24105, Germany

Location

Universitätsklinikum Leipzig Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie

Leipzig, 04103, Germany

Location

Klinikum der Stadt Ludwigshafen

Ludwigshafen, 67063, Germany

Location

UKSH Campus Lübeck

Lübeck, 23538, Germany

Location

Universitätsklinikum Mainz Hautklinik und Polklinik

Mainz, 55131, Germany

Location

Klinik für Dermatologie, Venerologie und Allergologie UMM - Universitätsmedizin Mannheim

Mannheim, 68167, Germany

Location

Johannes Wesling Klinikum Minden Hautklinik

Minden, 32429, Germany

Location

Universitätsklinikum München (LMU)

München, 80337, Germany

Location

Fachklinik Hornheide

Münster, 48157, Germany

Location

Universitätsklinikum Regensburg

Regensburg, 93053, Germany

Location

Universitätshautklinik Tübingen

Tübingen, 72076, Germany

Location

Related Publications (2)

• 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.

  PMID: 36099927 DERIVED

• 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.

  PMID: 32416781 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Dirk Schadendorf, Prof. Dr.

  Studienzentrum Hautklinik Universitätsklinikum Essen Klinik f. Dermatologie

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: August 5, 2015
• First Posted: August 14, 2015
• Study Start: September 2, 2015
• Primary Completion: June 27, 2021
• Study Completion: June 27, 2021
• Last Updated: April 9, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (20)