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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02523313
Recruitment Status : Active, not recruiting
First Posted : August 14, 2015
Last Update Posted : October 14, 2020
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen

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.

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Study Type : Interventional  (Clinical Trial)
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 : September 2, 2015
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

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 Name: 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 Name: 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 Name: Treatment Arm C




Primary Outcome Measures :
  1. Efficacy of adjuvant immunotherapy with Nivolumab alone or in combination with Ipilimumab (Recurrence-free survival) [ Time Frame: 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 :
  1. Overall survival (OS) [ Time Frame: 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.

  2. Time to recurrence (TTR) [ Time Frame: 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.

  3. Progression/recurrence free survival 2 (PRFS2) for crossover patients of Arm C [ Time Frame: 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:
  1. Safety / Toxicity All adverse events ≥ Grade 3 according to CTCAE Version 4.0 criteria [ Time Frame: 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02523313


Locations
Show Show 20 study locations
Sponsors and Collaborators
Prof. Dr. med. Dirk Schadendorf
Investigators
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Principal Investigator: Dirk Schadendorf, Prof. Dr. Studienzentrum Hautklinik Universitätsklinikum Essen Klinik f. Dermatologie
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Prof. Dr. med. Dirk Schadendorf, Prof. Dr. med., University Hospital, Essen
ClinicalTrials.gov Identifier: NCT02523313    
Other Study ID Numbers: IMMUNED
First Posted: August 14, 2015    Key Record Dates
Last Update Posted: October 14, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents