Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab

Malignant Melanoma Stage III Clinical Trial

— OpACIN-neo  

Official title:

Multicenter Phase 2 Study to Identify of the Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02977052
• Other study ID #: M16OPN
• Secondary ID: 2016-001984-35CA
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 24, 2016
• Est. completion date: June 2025

Study information

• Verified date: November 2023
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open-label three-arm phase 2 trial (including a Simon stage 2 design) consisting of 90 stage III melanoma patients randomized 1:1:1 to receive either 2 courses 3 mg/kg ipilimumab + 1 mg/kg nivolumab every 3 weeks (Arm A), 2 courses 1 mg/kg ipilimumab + 3 mg/kg nivolumab every 3 weeks (Arm B), or 2 courses ipilimumab 3 mg/kg, directly followed by 2 courses nivolumab 3 mg/kg every 2 weeks (Arm C). All three treatment arms are applied prior to surgery at week 6, 30 patients per arm. Patients will be stratified according to treatment center. An interim analysis will be performed after 13 patients have been included in each arm, thus in total 39 patients have been included.

PRADO extension cohort The trial will enroll in total about 100-110 melanoma patients with macroscopic stage III disease (RECIST measurable disease); inclusion will stop when 50 patients have achieved a pCR or pnCR. All patients will be treated (after marker placement into the largest lymph node metastasis) with the winner combination identified in the first part of the OpACIN-neo study which is 2 courses ipilimumab 1mg/kg + nivolumab 3mg/kg, q3wks. After 6 weeks of treatment, the patients will undergo only surgical resection of the marked index lymph node. Thereafter subsequent surgery and adjuvant therapy will be performed according to the achieved pathologic response.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 186
• Est. completion date: June 2025
• Est. primary completion date: January 3, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adults at least 18 years of age

• World Health Organization (WHO) Performance Status 0 or 1

• Cytologically or histologically confirmed resectable stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months

• No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years

• Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse

• No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1

• No immunosuppressive medications within 6 months prior study inclusion

• Screening laboratory values must meet the following criteria: WBC = 2.0x109/L, Neutrophils =1.5x109/L, Platelets =100 x109/L, Hemoglobin =5.5 mmol/L, Creatinine =1.5x ULN, AST = 1.5 x ULN, ALT = 1.5 x ULN, Bilirubin =1.5 X ULN

• Normal LDH

• Women of childbearing potential (WOCBP) must use appropriate method(s) of contra-ception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug

• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of ipilimumab + nivolumab

• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product

• Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception

• Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.

Exclusion Criteria:

• Distantly metastasized melanoma

• History of in-transit metastases within the last 6 months

• No measurable lesion according to RECIST 1.1

• Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy

• Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy

• Radiotherapy prior or post-surgery

• Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection

• Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

• Allergies and Adverse Drug Reaction

• History of allergy to study drug components

• History of severe hypersensitivity reaction to any monoclonal antibody

• Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;

• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;

• Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion

• Pregnant or nursing

Related Conditions & MeSH terms

• Malignant Melanoma Stage III
• Melanoma

Intervention

Drug:
• Ipilimumab

• Nivolumab

Procedure:
• Surgery
Surgery will be done at 6 weeks
• Blood for PBMCs
Blood will be taken for translational research on PBMCs
• Biopsies
Biopsies will be taken during screening and at relapse.

Locations

Country	Name	City	State
Australia	Melanoma Institute Australia	Sydney	New South Wales
Austria	Medical University of Vienna	Vienna
Netherlands	Netherlands Cancer Institute	Amsterdam	NH
Sweden	Karolinska Institutet	Stockholm

Sponsors (2)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Bristol-Myers Squibb

Countries where clinical trial is conducted

Australia,  Austria,  Netherlands,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	EFS at 2, 3 and 5 years		Up to 5 years after treatment
Other	DMFS at 2, 3 and 5 years		Up to 5 years after treatment
Other	OS at 2, 3 and 5 years		Up to 5 years after treatment
Other	Grade 3/4 immune-related adverse event rate according to CTCAE v4.03 within the first 12 weeks		At 12 weeks
Other	• Surgical complication rates according to Clavien-Dindo surgical classification of only marked index lymph node resection vs. CLND		At 12 weeks
Other	• Description of late adverse event (up to 3 years after treatment initiation) according to CTCAE v4.03		Up to 3 years after treatment
Primary	Safety as measured by the frequency of grade 3/4 immune-related adverse events, using CTCAE 4.03		During the first 12 weeks.
Primary	Response rate according to RECIST 1.1		At 6 weeks
Primary	Pathological response according to central pathological revision, according to pathological response criteria		At 6 weeks
Primary	Pathologic response rate according to central revision of the marked index lymph node		At 6 weeks, prior surgery
Primary	RFS at 24 months in patients achieving pCR or pnCR in their marked index lymph node and did not undergo CLND. RFS will be calculated from date of resection of the marked lymph node.		24 months
Primary	RFS at 24 months in patients with pNR and being subsequently treated with adjuvant nivolumab+optional radiotherapy (or dabrafenib/trametinib if BRAFV600E pos. and treatment is approved). RFS will be calculated from day of resection of marked lymph node.		24 months
Secondary	Recurrence Free Survival		3 years after treatment initiation
Secondary	Description of late adverse events using CTCAE 4.03		Up to 3 years after treatment initiation until new treatment
Secondary	Description of associations of mutational load, RNA tumor signatures, and tumor educated platelet signatures with tumor immune infiltrates and response		At 6 weeks
Secondary	Response rate according to RECIST 1.1 at week 6		At 6 weeks
Secondary	RFS at 2, 3 and 5 years		Up to 5 years after treatment