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Advanced Biliary Tract CancerPhase 2MOST-CIRCUITNCT04969887

Combination Immunotherapy in Rare Cancers Under InvesTigation

A Phase 2 study testing Ipilimumab and Nivolumab in people with Advanced Biliary Tract Cancer and Neuroendocrine Tumors, run by Olivia Newton-John Cancer Research Institute at 18 sites in 2 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ipilimumab and Nivolumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
240 participants
Where
18 sitesin 2 countries
Study dates
3 Aug 2021to 1 Mar 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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)
  • AST/ALT (aspartate transaminase/alanine transaminase) < or = to 3 x ULN (in the event of metastatic liver disease, an exception to this upper limit may be accepted in consultation with the study physician).
  • Total Bilirubin < or = to 1.5 x ULN (Upper limit of normal) (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).
  • Subject Re-enrolment: This study permits the re-enrolment of a subject that has discontinued the study as a pre-treatment failure (i.e. subject has not been treated) after obtaining agreement from the medical monitor prior to re enrolling a subject. If re-enrolled, the subject must be re-consented.
  • Age and Reproductive Status
  • Men and women, > or = to 18 years of age
  • Women of childbearing potential (WOCBP) must use method(s) of contraception. WOCBP should therefore 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 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 investigational product.
  • Women must not be breastfeeding
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1 percent per year. Men that are sexually active with WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half lives. The half life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. Given the blinded nature of the study, men who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half lives) after the last dose of investigational drug.
  • Women who are not of childbearing potential (i.e. who are postmenopausal or surgically sterile and azoospermic men do not require contraception.

Who cannot join

  • 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.
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  • 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
  • WOCBP who are pregnant or breastfeeding
  • Women with a positive pregnancy test at enrolment or prior to administration of study medication.
  • Other Exclusion Criteria
  • Prisoners or subjects who are involuntarily incarcerated
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.

Trial locations and contacts

18 sites in 2 countries.

18 sites in 2 countries

Australia17 sites

  • Royal Adelaide Hospital

    Adelaide, South Australia

  • Border Medical Oncology Unit

    Albury, New South Wales, 2640

  • Bendigo Health Services

    Bendigo, Victoria

  • Cairns and Hinterland Hospital and Health Service

    Cairns, Queensland, 4870

  • Townsville Hospital and Health Service

    Douglas, Queensland, 4814

  • Peninsula Health

    Frankston, Victoria

  • Barwon Health

    Geelong, Victoria

  • Austin Health

    Heidelberg, Victoria, 3084

  • Royal Hobart Hospital

    Hobart, Tasmania, 7000

  • Orange Health Service

    Orange, New South Wales

  • Peter MacCalllum Cancer Centre

    Parkville, Victoria

  • Fiona Stanley Hospital

    Perth, Western Australia

  • Goulburn Valley Health

    Shepparton, Victoria, 3630

  • Blacktown Hospital

    Sydney, New South Wales, 2145

  • Townville Hospital and Health Service

    Townsville, Queensland, 4814

  • Calvary Mater Newcastle

    Waratah, New South Wales, 2298

  • South West Healthcare

    Warrnambool, Victoria

Other trials in Australia

New Zealand1 site

  • Auckland City Hospital

    Auckland

Other trials in New Zealand

About this study

Official title: Ipilimumab and Nivolumab Combination Therapy in Patients With Selected Immunotherapy Sensitive Advanced Rare Cancers

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

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.

Read the detailed description

This is a phase 2 clinical trial of nivolumab combined with ipilimumab in immunotherapy sensitive rare cancers. This study will allow an evaluation of the clinical benefit, as measured by progression free survival (PFS) >6 months and overall survival (OS), provided by nivolumab combined with ipilimumab.

Study Rationale Clinically advanced rare cancers pose a significant clinical challenge because evidence based treatments are seldom available for patients suffering from these malignancies. Despite little evidence that shows clinical benefit, these patients are often treated with chemotherapeutic agents that are used in patients with more common malignancies that arise from the same anatomical site. Furthermore, because of small numbers, patients are often excluded from clinical trials with newer agents. CA209-538 examined this treatment combination in three 'baskets' of rare cancers: rare upper gastrointestinal, gynaecological and neuroendocrine cancers. The cancers on study all individually had an incidence of <2/100000/year. The cancer specific survival of patients diagnosed with a rare malignancy is significantly lower than with common cancers highlighting the need to improve management and treatment of rare cancer patients. Given the success of cancer immunotherapy with checkpoint regulators such as ipilimumab and nivolumab in a range of different cancer types, it was postulated that these agents could be beneficial in rare cancers and improve the overall outlook of patients with these conditions. CA209-538 enrolled 120 rare cancer patients on study, clinical benefit rate was >30% across all baskets, long term survival follow-up is underway.

This study will enrol 240 participants, across 4 cohorts with histotypes which demonstrated clinical benefit on CA209-538. All participants will receive ipilimumab and nivolumab as combination immunotherapy.

Being tested
Ipilimumab, Nivolumab
Medical subject headings
Neuroendocrine Tumors, Genital Neoplasms, Female

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IpilimumabDrug

    Also called YERVOY ®

    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.

  • NivolumabDrug

    Also called Opdivo

    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.

Study groups in NCT04969887
Study groupRoleWhat they receive
Ipilimumab and NivolumabExperimentalAll 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)
Receives: Drug: Ipilimumab; Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

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

  2. 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.

    Measured: Enrolment on study until 6 months.

Secondary outcomes (3)

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

    Quantification of OS.

    Measured: 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.

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

    Quantification of PFS

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

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

    Quantification of treatment related toxicities according to CTCAE V5.0.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jul 2021
  2. Study start3 Aug 2021
  3. Primary completion1 Mar 2025
  4. Study completion1 Mar 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
240 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04969887
Sponsor's protocol ID
ONJ2021-002
Other IDs
CA209-6D6
Acronym
MOST-CIRCUIT
Status last verified
Feb 2026
First submitted
6 Jul 2021
Last updated
27 Feb 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: No plan to share individual participant data

Publications

  • 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.

    PubMed 41231502

  • 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.

    PubMed 40608313

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ipilimumab and Nivolumab in people with Advanced Biliary Tract Cancer and Neuroendocrine Tumors, run by Olivia Newton-John Cancer Research Institute at 18 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 27 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 18 sites in Australia, New Zealand. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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. (time frame: At 12 weeks following registration then as assessed by standard care until progression.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04969887, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Feb 2026.

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