Intradermal Ipilimumab and Nivolumab in High Risk Stage II Melanoma (MARIANE)

Multicenter Phase 1b/2 Trial Testing Neoadjuvant Intradermal Ipilimumab and Nivolumab in High Risk Stage II Melanoma - MARIANE

This open label, single country trial will test if local injection of low-dose ipilimumab and nivolumab, is safe and reduces the sentinel node positivity in high-risk stage II melanoma patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Melanoma
• Intervention / Treatment: Drug: Ipilimumab; Drug: Nivolumab; Drug: Nivolumab

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Christian Blank, Prof; Phone Number: +31205129111; Email: c.blank@nki.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam University Medical Center
    • Contact: Fons van den Eertwegh, Prof.
  • Amsterdam, Netherlands
    • Antoni van Leeuwenhoek Hospital
    • Contact: Christian Blank, Prof.
  • Groningen, Netherlands
    • University Medical Center Groningen
    • Contact: Hilde Jalving, Dr.
  • Leiden, Netherlands
    • Leiden University Medical Center
    • Contact: Ellen Kapiteijn, Dr.
  • Rotterdam, Netherlands
    • Erasmus University Medical Center
    • Contact: Astrid van der Veldt, Dr.
  • Utrecht, Netherlands
    • University Medical Center Utrecht
    • Contact: Karijn Suijkerbuijk, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women, at least 18 years of age;
• World Health Organization (WHO) Performance Status 0 or 1;
• Histologically confirmed, excised stage IIB or IIC cutaneous melanoma (Breslow thickness 2.1-4.0mm with ulceration, or Breslow thickness >4.0mm with or without ulceration; according to AJCC criteria 8th edition);
• Having ≥50% risk for SN positivity as assessed by the MIA Sentinel Node Metastasis Risk prediction tool (melanomarisk.org.au/SNLForm)1;
• Excision of primary melanoma took place ≤4 weeks prior to informed consent;
• Naïve for re-excision of the primary melanoma site and for sentinel node procedure;
• No other solid, distantly metastasized malignancies, no hematological malignancies and no malignancies for which systemic treatment is administered within 6 months prior to study inclusion;
• No prior immunotherapy targeting CTLA-4, PD-1, PD-L1 or LAG-3;
• No prior targeted therapy with BRAF/MEK inhibition;
• No immunosuppressive medications within 6 months prior to study inclusion (steroids equivalent to prednisolone ≤10 mg are allowed);
• Screening laboratory values must meet the following criteria: WBC ≥2.0x109/L, neutrophils ≥1.5x109/L, platelets ≥100x109/L, hemoglobin ≥5.5 mmol/L, creatinine ≤1.5xupper limit of normal (ULN), AST ≤1.5x ULN, ALT ≤1.5x ULN, bilirubin ≤1.5x ULN (except for subjects with Gilbert syndrome who must have a total bilirubin <3.0 mg/dL)
• LDH level ≤ULN;
• Women of childbearing potential (WOCP) must use appropriate method(s) of contraception, i.e. methods with a failure rate of <1% per year when used consistently and correctly, to avoid pregnancy for 23 weeks post last ipilimumab + nivolumab infusion;
• Patient willing and able to understand the protocol requirements and comply with the treatment schedule, scheduled visits, electronic patient outcome reporting, tumor biopsies and extra blood withdrawal during screening, and other requirements of the study;

Exclusion Criteria:

• Acral, uveal/ocular or mucosal melanoma;
• A concurrent second, primary melanoma;
• Regionally or distantly metastasized melanoma, including in-transit metastases and macroscopic lymph node metastases;
• No suspect lymph nodes detectable by ultrasound in the draining lymph node region(s);
• Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications. Subjects with resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll;
• Prior surgery, including prior sentinel node procedure or lymph node dissection, in the affected lymph node region(s);
• Prior radiotherapy targeting the affected lymph node region(s);
• Subjects will be excluded if they test positive for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. Subjects treated and being at least one year free from HCV are allowed to participate;
• Subjects will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
• Subjects with history of allergy to study drug components or history of severe hypersensitivity reaction to monoclonal antibodies;
• Subjects with underlying medical conditions or active infection that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events;
• Women who are pregnant or breastfeeding;
• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids >10 mg prednisolone daily equivalent;
• Use of other investigational drugs before study drug administration 30 days or 5 half-times before study inclusion;
• Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; 2 cycles of intradermal ipilimumab 0.5 mg + nivolumab 1 mg every 3 weeks	Drug: Ipilimumab; intradermal; Drug: Nivolumab; intradermal; Drug: Nivolumab; intravenous
Experimental: B; 6 cycles of intradermal ipilimumab 0.5 mg + nivolumab 1 mg every week	Drug: Ipilimumab; intradermal; Drug: Nivolumab; intradermal; Drug: Nivolumab; intravenous
Experimental: C; 2 cycles of intradermal ipilimumab 10 mg + nivolumab 20 mg every 3 weeks	Drug: Ipilimumab; intradermal; Drug: Nivolumab; intradermal; Drug: Nivolumab; intravenous
Experimental: D; intradermal ipilimumab + nivolumab according to the optimal intradermal regimen plus 2 cycles of intravenous nivolumab 240mg every 3 weeks	Drug: Ipilimumab; intradermal; Drug: Nivolumab; intradermal; Drug: Nivolumab; intravenous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility	Feasibility as measured by the adherence to the timelines in the study protocol. A treatment arm will be declared as not feasible if 2/7 or 5/20 patients cannot adhere to the planned time of surgery due to treatment-related adverse events.	Up to 100 days after treatment
Effectivity	Pathological response as assessed by blinded central review, adapted from the INMC criteria, including pCR, near-pCR, or pPR (0-50% residual viable tumor in resection material), or sentinel node negativity for melanoma.	Up to 5 years after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
treatment-related adverse events	Frequency and duration of all grade and grade 3-5, treatment-related adverse events according to CTCAE 5.0;.	Up to 5 years after randomization
EFS	defined as time from randomization to melanoma progression (irresectable stage II or III, or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first;	Up to 5 years after randomization
DMFS	defined as time between date of surgery (re-excision and SN-procedure) and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first;	Up to 5 years after randomization
OS	defined as time between date of randomization and date of death;	Up to 5 years after randomization

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Investigators: Principal Investigator: Christian Blank, Prof, Medical oncologist/researcher

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2024
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: January 25, 2024
• First Submitted That Met QC Criteria: January 25, 2024
• First Posted (Actual): February 2, 2024

Study Record Updates

• Last Update Posted (Actual): February 2, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: neoadjuvant; immunotherapy; checkpoint inhibitors; intradermal
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: M23MAR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No