## Protocol Section
### Identification Module
**NCT ID:** NCT02437279

**Acronym:** OpACIN

**Brief Title:** Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients

**Official Title:** Feasibility Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Stage III Melanoma Patients

#### Organization Study ID Info
**ID:** N14OPC
#### Organization
**Class:** OTHER
**Full Name:** The Netherlands Cancer Institute
#### Secondary ID Infos
**Domain:** BMS
**ID:** CA209-278
**Type:** OTHER_GRANT
**Domain:** CCMO register
**ID:** NL51280.031.14
**Type:** REGISTRY
### Status Module
#### Completion Date
**Date:** 2025-06

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2022-04-15

**Type:** ACTUAL

**Last Update Submit Date:** 2022-04-14

**Overall Status:** ACTIVE_NOT_RECRUITING

#### Primary Completion Date
**Date:** 2018-06-28

**Type:** ACTUAL

#### Start Date
**Date:** 2016-11-24

**Type:** ACTUAL

**Status Verified Date:** 2022-04

#### Study First Post Date
**Date:** 2015-05-07
**Type:** ESTIMATED
**Study First Submit Date:** 2015-04-13
**Study First Submit QC Date:** 2015-05-04
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Bristol-Myers Squibb

#### Lead Sponsor

**Class:** OTHER

**Name:** The Netherlands Cancer Institute

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** This is a two-arm Phase 1b feasibility trial consisting of 20 patients receiving the combination of ipilimumab+nivolumab, either adjuvant, or split neo-adjuvant and adjuvant.

**Detailed Description:** Patients with stage III melanoma with palpable disease, naïve for CTLA-4/PD-1/PD-L1 immunotherapy, will be treated either post-surgery for 12 weeks with the combination of ipilimumab+nivolumab or in a split design for 6 weeks upfront surgery and for 6 weeks postsurgery. It is a two-arm Phase 1b feasibility trial consisting of 20 patients, 10 in each arm.

At different timepoints tumor biopsies and blood for PBMCs will be taken for translational research. Also scans will be done on specific timepoints.

The study will be held to determine safety, feasibility, and the immune-activating capacity of short-term combined neo-adjuvant and adjuvant ipilimumab + nivolumab. And to determine relapse free survival (RFS), any late adverse events, pharmacokinetics/pharmacodynamics, and the correlation between RFS and changes in neo-antigen specific T cell response.

### Conditions Module

**Conditions:**

- Stage III Skin Melanoma

**Keywords:**

- Palpable

- Stage III

- Skin melanoma

- Ipilimumab

- Nivolumab

- Surgery

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 20

**Type:** ACTUAL

**Phases:**

- PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Post-surgery infusion for 12 weeks with the combination of ipilimumab+nivolumab

**Intervention Names:**

- Procedure: Surgery of the tumor

- Drug: Infusion with ipilimumab 3 mg/kg q3wks

- Drug: Infusion with nivolumab 1 mg/kg q3wks

**Label:** Arm A

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** A split design 6 weeks upfront surgery and 6 weeks post-surgery infusion with the combination of ipilimumab+nivolumab

**Intervention Names:**

- Procedure: Surgery of the tumor

- Drug: Infusion with ipilimumab 3 mg/kg q3wks

- Drug: Infusion with nivolumab 1 mg/kg q3wks

**Label:** Arm B

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Arm A

- Arm B

**Name:** Surgery of the tumor

**Type:** PROCEDURE

#### Intervention 2

**Arm Group Labels:**

- Arm A

- Arm B

**Name:** Infusion with ipilimumab 3 mg/kg q3wks

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Arm A

- Arm B

**Name:** Infusion with nivolumab 1 mg/kg q3wks

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** To this purpose the immunogenic mutational load of each patient's melanoma will be determined by DNA and RNA sequencing from baseline biopsies (3x14g, 5ug tumor DNA). Proteasomal degradation and peptide presentation in HLA will be predicted in silico. MHC-tetramer staining containing the predicted peptides will be done as described before \[2\]. In addition, the effect of therapy on intratumoral T cell responses to obtain better insight into the mode of action of therapy will be analyzed. Identified neo-antigen specific T cells will be analyzed with respect to their phenotype and immunologic function (intracellular cytokine staining, lytic function as determined by CD107 staining, and coculture with APC presenting the cognate antigen).

**Measure:** The alteration in magnitude of the neo-antigen specific T cell response in the time interval pre- to post-adjuvant therapy in peripheral blood

**Time Frame:** 12 weeks from baseline

**Measure:** Safety as measured by SUSARs.

**Time Frame:** 12 weeks from baseline

**Description:** To this purpose the immunogenic mutational load of each patient's melanoma will be determined by DNA and RNA sequencing from baseline biopsies (3x14g, 5ug tumor DNA). Proteasomal degradation and peptide presentation in HLA will be predicted in silico. MHC-tetramer staining containing the predicted peptides will be done as described before \[2\]. In addition, the effect of therapy on intratumoral T cell responses to obtain better insight into the mode of action of therapy will be analyzed. Identified neo-antigen specific T cells will be analyzed with respect to their phenotype and immunologic function (intracellular cytokine staining, lytic function as determined by CD107 staining, and coculture with APC presenting the cognate antigen).

**Measure:** The alteration in breadth of the neo-antigen specific T cell response in the time interval pre- to post-adjuvant therapy in peripheral blood

**Time Frame:** 12 weeks from baseline

**Measure:** Feasibility as measured adherence to the timelines in the study protocol.

**Time Frame:** 12 weeks from baseline

#### Secondary Outcomes

**Measure:** Recurrence Free Survival, as determined according to RECIST 1.1 criteria.

**Time Frame:** Until progression, median 10 months.

**Measure:** Rate of adverse events and late adverse events

**Time Frame:** Until end of follow-up, median 3 years.

**Measure:** Type of adverse events and late adverse events

**Time Frame:** Until end of follow-up, median 3 years.

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Adults at least 18 years of age
* World Health Organization (WHO) Performance Status 0 or 1
* Histologically confirmed stage IIIB metastatic cutaneous melanoma, palpable disease (non-transit only) of the axilla or groin
* Patient willing to undergo triple tumor biopsies during screening and in case of disease progression
* No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
* No immunosuppressive medications within 6 months prior study inclusion
* Presence of at least two of the defined HLA alleles (Table 1, see appendix)
* 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 contraception. 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 (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception

Exclusion Criteria:

* Distantly metastasized melanoma
* 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 within this trial
* Patients will be excluded if they are positive test for hepatitis B virus surface antigen (HBVsAg) 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.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Amsterdam

**Country:** Netherlands

**Facility:** Netherlands Cancer Institute

**State:** NH

**Zip:** 1066CX

#### Overall Officials

**Official 1:**

**Affiliation:** The Netherlands Cancer Institute

**Name:** Christian Blank, MD PhD

**Role:** PRINCIPAL_INVESTIGATOR

### References Module

#### References

**Citation:** Versluis JM, Reijers ILM, Rozeman EA, Menzies AM, van Akkooi ACJ, Wouters MW, Ch'ng S, Saw RPM, Scolyer RA, van de Wiel BA, Schilling B, Long GV, Blank CU. Neoadjuvant ipilimumab plus nivolumab in synchronous clinical stage III melanoma. Eur J Cancer. 2021 May;148:51-57. doi: 10.1016/j.ejca.2021.02.012. Epub 2021 Mar 15.

**PMID:** 33735809

**Citation:** Rozeman EA, Hoefsmit EP, Reijers ILM, Saw RPM, Versluis JM, Krijgsman O, Dimitriadis P, Sikorska K, van de Wiel BA, Eriksson H, Gonzalez M, Torres Acosta A, Grijpink-Ongering LG, Shannon K, Haanen JBAG, Stretch J, Ch'ng S, Nieweg OE, Mallo HA, Adriaansz S, Kerkhoven RM, Cornelissen S, Broeks A, Klop WMC, Zuur CL, van Houdt WJ, Peeper DS, Spillane AJ, van Akkooi ACJ, Scolyer RA, Schumacher TNM, Menzies AM, Long GV, Blank CU. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat Med. 2021 Feb;27(2):256-263. doi: 10.1038/s41591-020-01211-7. Epub 2021 Feb 8.

**PMID:** 33558721

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000018358

- Term: Neuroendocrine Tumors

- ID: D000017599

- Term: Neuroectodermal Tumors

- ID: D000009373

- Term: Neoplasms, Germ Cell and Embryonal

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000009380

- Term: Neoplasms, Nerve Tissue

- ID: D000018326

- Term: Nevi and Melanomas

- ID: D000012878

- Term: Skin Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000012871

- Term: Skin Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M11528

- Name: Melanoma

- Relevance: HIGH

- As Found: Melanoma

- ID: M3212

- Name: Melanoma, Cutaneous Malignant

- Relevance: HIGH

- As Found: Skin Melanoma

- ID: M20495

- Name: Neuroendocrine Tumors

- Relevance: LOW

- As Found: Unknown

- ID: M19845

- Name: Neuroectodermal Tumors

- Relevance: LOW

- As Found: Unknown

- ID: M20388

- Name: Neuroectodermal Tumors, Primitive

- Relevance: LOW

- As Found: Unknown

- ID: M12318

- Name: Neoplasms, Germ Cell and Embryonal

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M12325

- Name: Neoplasms, Nerve Tissue

- Relevance: LOW

- As Found: Unknown

- ID: M12448

- Name: Nevus, Pigmented

- Relevance: LOW

- As Found: Unknown

- ID: M12446

- Name: Nevus

- Relevance: LOW

- As Found: Unknown

- ID: M20470

- Name: Nevi and Melanomas

- Relevance: LOW

- As Found: Unknown

- ID: M15681

- Name: Skin Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M15674

- Name: Skin Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T4091

- Name: Neuroendocrine Tumor

- Relevance: LOW

- As Found: Unknown

- ID: T4092

- Name: Neuroepithelioma

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008545

- Term: Melanoma

- ID: D000096142

- Term: Melanoma, Cutaneous Malignant

### Intervention Browse Module - Ancestors

- ID: D000074322

- Term: Antineoplastic Agents, Immunological

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000082082

- Term: Immune Checkpoint Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M1854

- Name: Nivolumab

- Relevance: HIGH

- As Found: Prospective

- ID: M1348

- Name: Ipilimumab

- Relevance: HIGH

- As Found: While

- ID: M1346

- Name: Antineoplastic Agents, Immunological

- Relevance: LOW

- As Found: Unknown

- ID: M2342

- Name: Immune Checkpoint Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000077594

- Term: Nivolumab

- ID: D000074324

- Term: Ipilimumab

### Misc Info Module

- Version Holder: 2024-05-24
