Combination Immunotherapy in Rare Cancers Under InvesTigation

NCT04969887 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: ONJ2021-002CA209-6D6
• Study Type: interventional
• Target: 240
• Locations: 2 countries
• Sites: 18

Brief Summary

The four tumour streams that will be studied in this protocol are based on immunotherapy sensitive rare cancers from CA209-538 which will be further investigated under this protocol and divided into four groups:

1. 1.Neuroendocrine cancers: Atypical bronchial carcinoid, neuroendocrine carcinoma and Grade 3 NETs independent of primary site (SCLC excluded)
2. 2.Biliary tract cancers: Intrahepatic cholangiocarcinoma and gallbladder carcinoma
3. 3.Gynaecological malignancies: Ovarian clear cell carcinoma, uterine clear cell carcinoma, uterine/ovarian carcinosarcoma, uterine leiomyosarcoma and vaginal/vulva squamous cell carcinoma
4. 4.Mismatch repair protein deficient (MSI-H) cancers (excluding colorectal carcinoma).

Conditions

Neuroendocrine Tumors; Female Reproductive System Neoplasm; MSI-H Solid Malignant Tumor; Advanced Biliary Tract Cancer

Outcome Measures

Primary Outcomes (2)

• Confirm the clinical efficacy of ipi/nivo in rare cancer histotypes which have demonstrated to be responsive to the regimen in the CA209-538 study.

  Clinical benefit rate for whole population (CR (complete response)+PR (partial response) assessed by radiographic evidence in accordance with RECIST 1.1 criteria

  At 12 weeks following registration then as assessed by standard care until progression.

• Determine the proportion of participants with progression free survival at 6 months

  Progression-free survival based on clinical or radiographic evidence of progressive disease according to RECIST 1.1 criteria at 6 months.

  Enrolment on study until 6 months.

Secondary Outcomes (3)

• To confirm the overall survival of participants receiving ipi/nivo in rare cancer histotypes which have demonstrated to be responsive to the regimen

  From date of enrolment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years.

• To confirm the progression free survival of participants receiving ipi/nivo in rare cancer histotypes which have demonstrated to be responsive to the regimen

  From date of enrolment until the date of first documented progression up to 5 years.

• Quantification of treatment related toxicities to ipi/nivo according to CTCAE V5.0

  From 1st dose until 30 days following last dose [up to max 2 years + 30 days].

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 480mg every 4 weeks until progression (up to 2 years)

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
• a) Histologically confirmed Neuroendocrine cancers: Atypical bronchial carcinoid, neuroendocrine carcinoma and Grade 3 NETs independent of primary site (SCLC excluded); Biliary Tract Cancers: Intrahepatic cholangiocarcinoma, gallbladder carcinoma; Gynaecological malignancies: Ovarian clear cell carcinoma, uterine clear cell carcinoma, uterine/ovarian carcinosarcoma, uterine leiomyosarcoma, vaginal/vulva squamous cell carcinoma; Mismatch repair protein deficient (MSI-H) cancers (excluding colorectal carcinoma)
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤1
• Prior systemic therapy (≤1) for advanced disease 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 participants are not suitable for, or if declining established standard therapies. For MSI-H rare cancers and atypical bronchial carcinoid only, patients will be eligible independent of the number of prior lines of systemic treatment received as long as treatment has been completed at least 4 weeks prior to enrolment.
• 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 available for 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 (18)

Border Medical Oncology Unit

Albury, New South Wales, 2640, Australia

Location

Orange Health Service

Orange, New South Wales, Australia

Location

Blacktown Hospital

Sydney, New South Wales, 2145, Australia

Location

Calvary Mater Newcastle

Waratah, New South Wales, 2298, Australia

Location

Cairns and Hinterland Hospital and Health Service

Cairns, Queensland, 4870, Australia

Location

Townsville Hospital and Health Service

Douglas, Queensland, 4814, Australia

Location

Townville Hospital and Health Service

Townsville, Queensland, 4814, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Location

Royal Hobart Hospital

Hobart, Tasmania, 7000, Australia

Location

Bendigo Health Services

Bendigo, Victoria, Australia

Location

Peninsula Health

Frankston, Victoria, Australia

Location

Barwon Health

Geelong, Victoria, Australia

Location

Austin Health

Heidelberg, Victoria, 3084, Australia

Location

Peter MacCalllum Cancer Centre

Parkville, Victoria, Australia

Location

Goulburn Valley Health

Shepparton, Victoria, 3630, Australia

Location

South West Healthcare

Warrnambool, Victoria, Australia

Location

Fiona Stanley Hospital

Perth, Western Australia, Australia

Location

Auckland City Hospital

Auckland, New Zealand

Location

Related Publications (2)

• Carlino MS, Gao B, Michael M, Marshall H, Gunjur A, Chan H, Zielinski R, So J, Harris SJ, Kee D, Collins IM, Lam WS, Lyle M, Underhill C, Brown MP, Harrup R, Wong SF, Grady J, Ballinger M, Tavancheh E, Thomas DM, Palmer J, Wilkie K, Cebon J, Klein O. Nivolumab and Ipilimumab in Advanced Mismatch Repair-Deficient/Microsatellite Instability-High Noncolorectal Cancers: A Nonrandomized Clinical Trial. JAMA Oncol. 2026 Jan 1;12(1):39-47. doi: 10.1001/jamaoncol.2025.4721.

  PMID: 41231502 DERIVED

• Gao B, Carlino MS, Michael M, Underhill C, Marshall H, Gunjur A, So J, Kee D, Antill Y, Lam WS, Chan H, Harrup R, Hamilton A, Grady J, Ballinger M, Tavancheh E, Yoon WH, Palmer J, Thomas D, Wilkie K, Cebon J, Klein O. Nivolumab and Ipilimumab Combination Treatment in Advanced Ovarian and Endometrial Clear Cell Cancers: A Nonrandomized Clinical Trial. JAMA Oncol. 2025 Sep 1;11(9):982-989. doi: 10.1001/jamaoncol.2025.1916.

  PMID: 40608313 DERIVED

MeSH Terms

Conditions

Neuroendocrine Tumors; Genital Neoplasms, Female

Interventions

Ipilimumab; Nivolumab

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Urogenital Neoplasms; Neoplasms by Site; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

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: July 6, 2021
• First Posted: July 21, 2021
• Study Start: August 3, 2021
• Primary Completion: March 1, 2025
• Study Completion (Estimated): March 1, 2027
• Last Updated: February 27, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

NZ (1); AU (17)