Phase IIb Study Evaluating Immunogenic Chemotherapy Combined with Ipilimumab and Nivolumab in Breast Cancer

NCT03409198 | Completed Phase 2

• 1 other identifier: ICON CA209-9FN
• Study Type: interventional
• Target: 82
• Locations: 2 countries
• Sites: 6

Brief Summary

Breast cancer is rarely curable after metastasis, and the therapeutic options are limited. Interestingly, the host immune response is strongly predictive for the effect of chemotherapy in subgroups of patients with breast cancer. The aim is to release the brake on the immune response by use of ipilimumab, which blocks CTLA-4 and may deplete regulatory T cells, combined with nivolumab (anti PD1). Importantly, it is possible that non-responders to nivolumab/ipilimumab (nivo/ipi) can be turned responders by use of immunogenic chemotherapy.

Conditions

Breast Cancer; Hormone Receptor Positive Tumor; Metastatic Breast Cancer

Keywords

Neoplasms

Outcome Measures

Primary Outcomes (2)

• Toxicity: CTCAE v4.0

  Assessment of toxicity of combined treatment with ipilimumab, nivolumab, pegylated liposomal doxorubicin and cyclophosphamide (ipi/nivo/chemo)

  3 years

• Progression-free survival (PFS)

  Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: Progression-free survival (PFS); compare the PFS rates when 95% of patients in the control croup have PD

  We expect to reach the data-driven time point for PFS-analysis (95% PFS in the control group) approximately 3 years after the study opens. If this is not met within 24 months after inclusion of the last patient, the PFS-analysis will be performed at this

Secondary Outcomes (16)

• Duration of Response (DR)

  3 years

• Overall Survival (OS)

  5 years

• Duration of Response (DR) in cross-over arm

  3 years

• Overall Suvival (OS) in cross-over arm

  5 years

• Toxicity, cross-over arm, CTCAE v4.0

  3 years

Other Outcomes (4)

• Immunological response

  3 years

• Biomarkers for clinical response

  3 years

• Biomarkers for toxicity

  3 years

Study Arms (2)

Arm A

ACTIVE COMPARATOR

Chemo only (pegylated liposomal doxorubicin + cyclophosphamide)

Drug: Pegylated liposomal doxorubicin; Drug: Cyclophosphamide

Arm B

EXPERIMENTAL

Chemo + ipilimumab + nivolumab

Drug: Ipilimumab; Drug: Nivolumab; Drug: Pegylated liposomal doxorubicin; Drug: Cyclophosphamide

Interventions

Ipilimumab DRUG

Ipilimumab blocks CTLA-4 and may deplete regulatory T cells

Also known as: Yervoy

Arm B

Nivolumab DRUG

Nivolumab blocks PD-1 and thereby enhances the effector phase of the immune reaction, by enabling T cells to kill tumor cells and engage effectively with other PD-L1 expressing targets.

Also known as: Opdivo

Arm B

Pegylated liposomal doxorubicin DRUG

Chemotherapy

Arm A; Arm B

Cyclophosphamide DRUG

Chemotherapy

Arm A; Arm B

Eligibility Criteria

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

You may qualify if:

• Metastatic hormone receptor positive breast cancer (primary or recurrent), defined as ER+ \>1% in metastatic biopsy (archival material or study biopsy) or cytology and HER2 negative in the last biopsy or cytology evaluable for HER2. HER2-analysis is to be perfomed according to national criteria.
• Adequate core or excisional study biopsy of a tumor lesion. Lesions in previously irradiated areas may only be used for the biopsy if the lesion has appared or progressed after radiation. No anti-tumor treatment is allowed between the time point for biopsy and study entry.
• Measurable metastatic disease according to RECIST
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Signed Informed Consent Form
• Women or men aged ≥ 18 years
• A minimum of 12 months from adjuvant/neoadjuvant chemotherapy with antracyclins to relapse disease
• A maximum of one previous line with chemotherapy in the metastatic setting
• Chemotherapy is considered as preferred treatment
• Previous endocrine and targeted therapy is allowed
• No use of systemic corticosteroids at study entry
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential should agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \< 1% per year, during the treatment period and for at least 5 months after the last dose of study therapy.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy
• Able to swallow and retain orally administered medication

You may not qualify if:

• Malignancies other than breast cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer)
• Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for \> 8 weeks prior to randomization
• Known CNS disease, except for asymptomatic CNS metastases, provided all of the following criteria are met:
• Measurable disease outside the CNS
• Asymptomatic for CNS disease \> 4 weeks
• No ongoing requirement for corticosteroids as therapy for CNS disease
• No radiation of brain lesions within 2 weeks prior to randomization
• No leptomeningeal disease
• Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters (e.g., PleurX®) are allowed
• Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to randomization
• Ionized calcium \> 1.2 x UNL. The use of bisphosphonates is allowed
• Pregnant or breastfeeding
• Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
• Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina Patients with a known left ventricular ejection fraction (LVEF) \< 40% will be excluded. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF \< 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
• Severe infection within 21 days prior to randomization, requiring hospitalization

Sponsors & Collaborators

• Oslo University Hospital: lead
• Bristol-Myers Squibb: collaborator
• Helse Stavanger HF: collaborator
• Helse Sor-Ost: collaborator
• Sorlandet Hospital HF: collaborator
• Jules Bordet Institute: collaborator
• Cliniques universitaires Saint-Luc- Université Catholique de Louvain: collaborator
• Centre Hospitalier Universitaire UCLouvain Namur: collaborator

Study Sites (6)

Institut Jules Bordet

Brussels, Brussels Capital, 1000, Belgium

Location

Cliniques universitaires Saint-Luc

Brussels, Brussels Capital, 1200, Belgium

Location

CHU UCL Namur

Namur, Namur, 5000, Belgium

Location

Soerlandet Hospital HF Kristiansand

Kristiansand, Norway

Location

Oslo University Hospital

Oslo, Norway

Location

Stavanger University Hospital

Stavanger, 4011, Norway

Location

Related Publications (2)

• Andresen NK, Rossevold AH, Quaghebeur C, Gilje B, Boge B, Gombos A, Falk RS, Mathiesen RR, Julsrud L, Garred O, Russnes HG, Lereim RR, Chauhan SK, Lingjaerde OC, Dunn C, Naume B, Kyte JA. Ipilimumab and nivolumab combined with anthracycline-based chemotherapy in metastatic hormone receptor-positive breast cancer: a randomized phase 2b trial. J Immunother Cancer. 2024 Jan 19;12(1):e007990. doi: 10.1136/jitc-2023-007990.

  PMID: 38242720 BACKGROUND

• Kyte JA, Andresen NK, Russnes HG, Fretland SO, Falk RS, Lingjaerde OC, Naume B. ICON: a randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer. J Transl Med. 2020 Jul 3;18(1):269. doi: 10.1186/s12967-020-02421-w.

  PMID: 32620163 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Neoplasms

Interventions

Ipilimumab; Nivolumab; liposomal doxorubicin; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Jon Amund Kyte

  Oslo University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Randomized, open-label

Study Record Dates

• First Submitted: December 4, 2017
• First Posted: January 24, 2018
• Study Start: January 21, 2018
• Primary Completion: May 11, 2022
• Study Completion: May 11, 2022
• Last Updated: October 15, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

BE (3); NO (3)