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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02977052




Registration number
NCT02977052
Ethics application status
Date submitted
21/11/2016
Date registered
30/11/2016
Date last updated
6/11/2018

Titles & IDs
Public title
Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab
Scientific title
Multicenter Phase 2 Study to Identify of the Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo)
Secondary ID [1] 0 0
2016-001984-35
Secondary ID [2] 0 0
M16OPN
Universal Trial Number (UTN)
Trial acronym
OpACIN-neo
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Melanoma Stage III 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ipilimumab
Treatment: Drugs - Nivolumab
Treatment: Surgery - Surgery
Treatment: Surgery - Blood for PBMCs
Treatment: Surgery - Biopsies

Experimental: Arm A: 2 courses ipi 3 + nivo 1 - Patients receive 2 courses standard combination of ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.

Experimental: Arm B: 2 courses ipi 1 + nivo 3 - Patients receive 2 courses ipilimumab 1 mg/kg + nivolumab 3 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.

Experimental: Arm C: 2 courses ipi 3 + 2 courses nivo 3 - Patients receive 2 courses of ipilimumab 3 mg/kg q3wks, directly followed (> 2 hours and < 24 hours) by 2 courses nivolumab 3 mg/kg every 2 weeks prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.

Experimental: PRADO extension cohort - Patients will be treated with 2 courses ipilimumab and nivolumab at the dose level defined as the winner dosing scheme from OpACIN-neo, which is the dosing schedule of arm B.
Surgery and adjuvant therapy
Patients achieving a pCR or pnCR will not undergo CLND and will not receive any adjuvant treatment. Structural follow-up will be perfomed every 12 weeks by CT, ultrasound of regional lymph nodes.
Patients achieving a pPR will undergo CLND and start structural follow-up (including CT and physical examination) every 12 weeks thereafter without any adjuvant treatment.
Patients achieving no response (pNR) will undergo CLND and start at week 12 with adjuvant nivolumab 480mg q4wks for 52 weeks + radiotherapy (according to patient's and physicians' decision). In patients that are BRAF V600E/K mutation positive, adjuvant BRAF+MEK


Treatment: Drugs: Ipilimumab


Treatment: Drugs: Nivolumab


Treatment: Surgery: Surgery
Surgery will be done at 6 weeks

Treatment: Surgery: Blood for PBMCs
Blood will be taken for translational research on PBMCs

Treatment: Surgery: Biopsies
Biopsies will be taken during screening and at relapse.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Safety as measured by the frequency of grade 3/4 immune-related adverse events, using CTCAE 4.03
Timepoint [1] 0 0
During the first 12 weeks.
Primary outcome [2] 0 0
Response rate according to RECIST 1.1
Timepoint [2] 0 0
At 6 weeks
Primary outcome [3] 0 0
Pathological response according to central pathological revision, according to pathological response criteria
Timepoint [3] 0 0
At 6 weeks
Primary outcome [4] 0 0
Pathologic response rate according to central revision of the marked index lymph node
Timepoint [4] 0 0
At 6 weeks, prior surgery
Primary outcome [5] 0 0
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.
Timepoint [5] 0 0
24 months
Primary outcome [6] 0 0
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.
Timepoint [6] 0 0
24 months
Secondary outcome [1] 0 0
Recurrence Free Survival
Timepoint [1] 0 0
3 years after treatment initiation
Secondary outcome [2] 0 0
Description of late adverse events using CTCAE 4.03
Timepoint [2] 0 0
Up to 3 years after treatment initiation until new treatment
Secondary outcome [3] 0 0
Description of associations of mutational load, RNA tumor signatures, and tumor educated platelet signatures with tumor immune infiltrates and response
Timepoint [3] 0 0
At 6 weeks
Secondary outcome [4] 0 0
Response rate according to RECIST 1.1 at week 6
Timepoint [4] 0 0
At 6 weeks
Secondary outcome [5] 0 0
RFS at 2, 3 and 5 years
Timepoint [5] 0 0
Up to 5 years after treatment

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Melanoma Institute Australia - Sydney
Recruitment postcode(s) [1] 0 0
2060 - Sydney
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Vienna
Country [2] 0 0
Netherlands
State/province [2] 0 0
NH
Country [3] 0 0
Sweden
State/province [3] 0 0
Stockholm

Funding & Sponsors
Primary sponsor type
Other
Name
The Netherlands Cancer Institute
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Bristol-Myers Squibb
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/show/NCT02977052
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Christian Blank, Prof.
Address 0 0
Medical oncologist/researcher
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Christian Blank-de Hoop, Prof.
Address 0 0
Country 0 0
Phone 0 0
+31205122951
Fax 0 0
Email 0 0
c.blank@nki.nl
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02977052