A Phase II Trial of Ipilimumab and Nivolumab for the Treatment of Rare Cancers

NCT02923934 | Completed Phase 2 DMC

• 1 other identifier: ONJ2016-001
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 5

Brief Summary

The three tumour streams that will be studied in this protocol are: (i) upper GI malignancies (comprising intra-hepatic/extra-hepatic cholangiocarcinomas,gall bladder cancers and duodenal cancers).); (ii) neuroendocrine tumours (inc. Pancreatic, bronchial and intestinal carcinoid tumours) and (iii) rare gynaecological tumours (including but will not be limited to: vaginal or vulval carcinomas, clear cell carcinoma of the ovary, low grade serous ovarian cancer, mixed mullarian tumours (carcinosarcoma), sarcomas of the female genital tract and granulosa cell tumours). The role of immunotherapy is being defined in more common cancer types, however because of their rarity, the efficacy of immunotherapy for these cancers is poorly defined. This protocol provides an important opportunity to establish whether the combination of nivolumab \& ipilimumab has efficacy in these cancers.

Conditions

Gastrointestinal Cancer; Neuroendocrine Tumours; Malignant Female Reproductive System Neoplasm

Outcome Measures

Primary Outcomes (1)

• To determine the clinical efficacy of the combination treatment of ipilimumab with nivolumab in rare cancers.

  Clinical benefit rate for whole population (CR (complete response)+PR (partial response)+SD (stable disease)\>3 months)

  at 12 weeks following randomisation then every 6 weeks until disease progression

Secondary Outcomes (1)

• To identify whether a common predictive biomarker or immune signature can be identified in responding patients that can occur irrespective of tumour type.

  Pre-dose samples will be collected during the first two cycles (6 weeks/cycle)

Study Arms (1)

Ipilimumab and Nivolumab

EXPERIMENTAL

All Subjects will be treated with: Nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg concurrently every 3 weeks for 4 doses followed by nivolumab only at 3mg/kg every 2 weeks until progression (up to 48 total doses of nivolumab)

Drug: Ipilimumab; Drug: Nivolumab

Interventions

Ipilimumab DRUG

CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a key regulator of T cell activity. Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of tumor reactive T effector cells which mobilize to mount a direct T-cell immune attack against tumor cells. CTLA-4 blockade can also reduce T regulatory cell function, which may lead to an increase in anti-tumor immune response.

Also known as: YERVOY ®

Ipilimumab and Nivolumab

Nivolumab DRUG

A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed cell death-1 (PD-1,PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs (antigen presenting cells). This results in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and and plays a key role in in tumor evasion from host immunity.

Also known as: Opdivo

Ipilimumab and Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Written Informed Consent
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
• Target Population
• Histologically confirmed Upper GI malignancies (Cholangiocarcinoma/ duodenal carcinoma - collect MSI (microsatellite instability) status); Neuroendocrine tumours (inc. pancreatic, bronchial and intestinal carcinoid tumours) and Rare Gynaecological tumours (including but will not be limited to: vaginal or vulval carcinomas, clear cell carcinoma of the ovary, low grade serous ovarian cancer, mixed Mullarian tumours (carcinosarcoma), sarcomas of the female genital tract and granulosa cell tumours).
• Eastern Cooperative Oncology Group (ECOG) performance status of 1
• Prior systemic therapy is permitted if it was completed at least 4 weeks prior to enrolment, and all related adverse events have either returned to baseline or stabilized or subjects are not suitable for, or if declining established standard therapies.
• Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration.
• Measurable disease by CT or MRI per RECIST 1.1 criteria
• Tumour tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. If an insufficient amount of tumour tissue from an unresectable or metastatic site is available prior to the start of the screening phase, subjects must consent to allow the acquisition of additional tumour tissue for performance of biomarker analyses.
• Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:
• WBC (white blood cells) \> or = to 2000/μL
• Neutrophils \> or = to 1500/μL
• Platelets \> or = to 100 x103/μL
• Hemoglobin \> 9.0 g/dL
• Serum creatinine \< or = to 1.5 x ULN or creatinine clearance (CrCl) 40 mL/min (using the Cockcroft-Gault formula)

You may not qualify if:

• Target Disease Exceptions
• Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI except where contraindicated in which CT scan is acceptable) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. Cases should be discussed with the medical monitor. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
• Medical History and Concurrent Diseases
• Prior combination treatment directed against the PD-1/PDL1 (Programmed Death Ligand 1) axis (anti PD 1, anti PD-L1, anti PD L2), and anti CTLA 4 antibody. Prior monotherapy with these agents or other immune-stimulating/regulating agents is permitted.
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Physical and Laboratory Test Findings
• Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
• 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.
• Sex and Reproductive Status

Sponsors & Collaborators

• Olivia Newton-John Cancer Research Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (5)

Border Medical Oncology Unit

Albury, New South Wales, 2640, Australia

Location

Blacktown Hospital

Sydney, New South Wales, 2145, Australia

Location

Monash Health

Clayton, Victoria, 3168, Australia

Location

Austin Health

Heidelberg, Victoria, 3078, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Related Publications (1)

• Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, Jackett L, Lum C, Behren A, Palmer J, Tebbutt NC, Carlino MS, Cebon J. Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2020 Sep 1;6(9):1405-1409. doi: 10.1001/jamaoncol.2020.2814.

  PMID: 32729929 DERIVED

MeSH Terms

Conditions

Gastrointestinal Neoplasms; Neuroendocrine Tumors

Interventions

Ipilimumab; Nivolumab

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Oliver Klein, MD

  ONJCRI and Austin Health

  STUDY CHAIR

• Jonathan Cebon, MD

  ONJCRI and Austin Health

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Masking Details: This is an open label study, all patients receive the same treatment as per the protocol.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 2, 2016
• First Posted: October 5, 2016
• Study Start: August 22, 2017
• Primary Completion: April 27, 2020
• Study Completion: December 12, 2023
• Last Updated: July 24, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

AU (5)