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

NCT ID: NCT02523313

Last Updated: 2025-04-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 167 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-02
• Study Completion Date: 2021-06-27

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.

Conditions

Malignant Melanoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Nivolumab + Placebo

Intervention Type: 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.

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.

Group Type: EXPERIMENTAL

Nivolumab + Ipilimumab

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

Double Placebo Control

Intervention Type: 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Treatment Arm A; Treatment Arm B; Treatment Arm C

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Prof. Dr. med. Dirk Schadendorf

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. med. Dirk Schadendorf

Prof. Dr. med.

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Dirk Schadendorf, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Studienzentrum Hautklinik Universitätsklinikum Essen Klinik f. Dermatologie

Locations

Charité Berlin

Berlin, , Germany

Elbe Klinikum Buxtehude

Buxtehude, , Germany

Universitätsklinikum Dresden

Dresden, , Germany

HELIOS Klinikum Erfurt

Erfurt, , Germany

Studienzentrum Hautklinik Universitätsklinikum Essen (AöR) Klinik für Dermatologie

Essen, , Germany

SRH Wald-Klinikum Gera GmbH

Gera, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Universitätrsklinikum Heidelberg Dermatologie / NCT

Heidelberg, , Germany

SLK Kliniken Heilbronn GmbH

Heilbronn, , Germany

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

Kiel, , Germany

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

Leipzig, , Germany

Klinikum der Stadt Ludwigshafen

Ludwigshafen, , Germany

UKSH Campus Lübeck

Lübeck, , Germany

Universitätsklinikum Mainz Hautklinik und Polklinik

Mainz, , Germany

Klinik für Dermatologie, Venerologie und Allergologie UMM - Universitätsmedizin Mannheim

Mannheim, , Germany

Johannes Wesling Klinikum Minden Hautklinik

Minden, , Germany

Universitätsklinikum München (LMU)

München, , Germany

Fachklinik Hornheide

Münster, , Germany

Universitätsklinikum Regensburg

Regensburg, , Germany

Universitätshautklinik Tübingen

Tübingen, , Germany

Countries

Germany

References

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.

Reference Type: DERIVED

PMID: 36099927 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32416781 (View on PubMed)

Other Identifiers

IMMUNED

Identifier Type: -

Identifier Source: org_study_id