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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT04949113
Other study ID # M21NDN
Secondary ID CA209-6FR
Status Active, not recruiting
Phase Phase 3
First received
Last updated
Start date July 8, 2021
Est. completion date December 19, 2028

Study information

Verified date March 2024
Source The Netherlands Cancer Institute
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This is an international (Australia, Europe, and USA) open-label two-arm randomized phase 3 trial including 420 stage III (≤3 resectable in-transit metastases allowed) cutaneous or unknown primary melanoma patients. Patients will be randomized 1:1 to receive either 2 cycles of neoadjuvant ipilimumab 80 mg + nivolumab 240 mg every 3 weeks followed by a total lymph node dissection (TLND) and, if applicable, resection of in-transit metastases (arm A) versus standard upfront TLND +/- resection of in-transit metastases followed by 12 cycles adjuvant nivolumab 480 mg every 4 weeks (arm B). Patients with a pathologic partial or non-response in arm A will also receive adjuvant nivolumab 480 mg every 4 weeks for 46 weeks (11 cycles). In case of BRAF V600E/K mutation-positivity, patients from arm A with a pathologic partial or non-response (>10% viable tumor) will be treated with adjuvant dabrafenib plus trametinib for 46 weeks. Patients will be treated in the study in both arms until melanoma progression to irresectable stage III or stage IV disease, disease recurrence, unacceptable toxicity, subject withdrawal of consent or until end of study treatment. An interim analysis will be performed after 60 events have occurred. The data safety monitory board (DSMB) will be ad hoc consulted when unexpected toxicities are reported. Patients will be followed by 12 weekly CT scans until end of year 3 and then until year 5 according to the institute's standards.


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Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Neoadjuvant ipilimumab + nivolumab
2 cycles ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by total lymph node dissection
Adjuvant nivolumab
Upfront total lymph node dissection followed by 12 cycles of nivolumab (480mg) every 4 weeks.

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Sponsors (2)

Lead Sponsor Collaborator
The Netherlands Cancer Institute Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Netherlands, 

Outcome

Type Measure Description Time frame Safety issue
Primary Comparison of event-free survival (EFS) in the neoadjuvant and adjuvant group. EFS is defined as time from randomization to melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first. Occurrence of a new primary melanoma during treatment/follow-up is also regarded as an event. Presurgical resectable progression to stage III disease in arm A is not defined as an event, even as death to another reason than melanoma or the study treatment. Analysis will be performed after 132 events, though not later than after 2 years follow-up of all patients.
Secondary Recurrence free survival (RFS) RFS is defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first. Up to 5 years after randomization
Secondary Distant metastases-free survival (DMFS) DMFS is defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first. Up to 5 years after randomization
Secondary Overall survival (OS) OS is defined as time between date of randomization and date of death. Up to 5 years after randomization
Secondary Pathologic response rate in the neoadjuvant arm and evaluation of association between pathologic response rate and RFS, DMFS and OS. The pathologic response rate will be categorized into pathologic complete response (pCR), near-pCR, major pathologic response (MPR), pathologic partial response (pPR), pathologic no response (pNR), according to International Neoadjuvant Melanoma Consortium (INMC) criteria. Up to 5 years after randomization
Secondary Rate of immune-related adverse events Frequency of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0. Up to 5 years after randomization
Secondary Duration of immune-related adverse events Duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0. Up to 5 years after randomization
Secondary Description of type of immune-related adverse events Type of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0. Up to 5 years after randomization
Secondary Description of surgical morbidity Surgical complication rates according to Clavien-Dindo surgical classification. Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by EORTC Quality of Life Questionnaire-core 30 (QLQ C30). The QLQ-C30 is scored on 4 point Likert-scales: "Not at all", "A little", "Quite a bit", and "Very much." and is composed of both multi-item scales and single-item measures. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by the Melanoma Subscale and Melanoma Surgery Subscale of Functional Assessment of Cancer Therapy - Melanoma (FACT-M). The FACT-M is scored on a 5 point Likert-scale: "Not at all", "A little bit", "Somewhat", "Quite a bit", and "Very much.". A Higher score represents higher Health Related Quality of Life (HRQoL). Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by the Cancer Worry Scale. The Cancer Worry Scale is scored on a 4 point Likert-scale: "Almost never", "Sometimes", "Often", and "Almost always". Higher scores indicate more worrying about cancer. Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by the Hospital Anxiety and Depression Scale (HADS) questionnaire. The HADS is a questionnaire that is scored on several 4 point Likert-scales. Higher score on the HADS questionnaire indicates more hospital-related anxiety and depression. Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by the 5-level EuroQOL-5D questionnaire (EQ-5D-5L). Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by an immunotherapy-specific questionnaire. Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by an assessment of work performance. Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by a questionnaire on sexual health. Up to 5 years after randomization
Secondary Evaluation of health-related quality of life (HRQoL) in both treatment arms Quality of life as measured by the Amsterdam Cognition Scale. Up to 5 years after randomization
Secondary Health technology assessments, consisting of a cost-effectiveness analysis comparing the neoadjuvant arm with the standard adjuvant arm Cost-effectiveness measured by an incremental cost-effectiveness ratio (ICER) (e.g., incremental cost per quality-adjusted life-year (QALY) gained). Up to 5 years after randomization
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