NCT04969887

Combination Immunotherapy in Rare Cancers Under InvesTigation

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

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 240 (actual)
• Sponsor: Olivia Newton-John Cancer Research Institute · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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. 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). 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.

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.

Conditions

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

Interventions

Type	Name	Description
DRUG	Ipilimumab	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.
DRUG	Nivolumab	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.

Timeline

• Start date: 2021-08-03
• Primary completion: 2025-03-01
• Completion: 2027-03-01
• First posted: 2021-07-21
• Last updated: 2026-02-27

Locations

18 sites across 2 countries: Australia, New Zealand