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Breast CancerPhase 2ICONNCT03409198

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

A Phase 2 study testing Ipilimumab, Nivolumab and Pegylated liposomal doxorubicin in people with Breast Cancer and Hormone Receptor Positive Tumor, run by Oslo University Hospital at 6 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ipilimumab, Nivolumab and Pegylated liposomal doxorubicin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
82 participants
Where
6 sitesin 2 countries
Study dates
21 Jan 2018to 11 May 2022
Phase
Phase 2
Are there results?
None posted in the registry

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

  • 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
Show all 16Show fewer
  • 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
  • Adequate organ function as defined in Table 1

Who cannot join

  • 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
Show all 41Show fewer
  • 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
  • Received oral or IV antibiotics within 1 week prior to Cycle 1, Day 1. Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive pulmonary disease exacerbation or for dental extraction) are eligible
  • Major surgical procedure within 21 days prior to randomization or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis. Placement of central venous access catheter(s) is not considered a major surgical procedure and is therefore permitted
  • A history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Known hypersensitivity to any of the components of the investigational products
  • A history of autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxin, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted provided that they meet all of the following conditions:
  • Rash must cover less than 10% of body surface area.
  • Disease is well controlled at baseline and only requiring low potency topical steroids
  • No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids)
  • Undergone allogeneic stem cell or solid organ transplantation
  • A history of idiopathic pulmonary fibrosis pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • A positive test for HIV
  • Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
  • Active tuberculosis
  • Currently receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Received treatment with immune checkpoint modulators, including anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapeutic antibodies
  • Received treatment with systemic immunostimulatory agents (including but not limited to interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
  • Received treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
  • Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study
  • Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI
  • The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed
  • Received anti-cancer therapy (medical agents or radiation) within 2 weeks prior to study Cycle 1, Day 1. Palliative radiotherapy for bone lesions is allowed up to 7 days before start of therapy.
  • A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator
  • Known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial
  • Received a live vaccine within 30 days of planned start of study therapy, or is expected to receive such a vaccine while on therapy
  • Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  • Any reason why, in the opinion of the investigator, the patient should not participate

Trial locations and contacts

6 sites in 2 countries.

6 sites in 2 countries

Belgium3 sites

  • Institut Jules Bordet

    Brussels, Brussels Capital, 1000

  • Cliniques universitaires Saint-Luc

    Brussels, Brussels Capital, 1200

  • CHU UCL Namur

    Namur, Namur, 5000

Other trials in Belgium

Norway3 sites

  • Soerlandet Hospital HF Kristiansand

    Kristiansand

  • Oslo University Hospital

    Oslo

  • Stavanger University Hospital

    Stavanger, 4011

Other trials in Norway

About this study

Official title: A Randomized Phase IIb Study Evaluating Immunogenic Chemotherapy Combined With Ipilimumab and Nivolumab in Patients With Metastatic Hormone Reseptor Positive Breast Cancer

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.

Read the detailed description

There is compelling evidence from animal studies, supported by data from humans, that some chemotherapeutic agents are immunogenic. Doxorubicin and cyclophosphamide have been shown to be particularly powerful inducers of immunogenic cell death. Both agents fulfil 5/5 criteria established for assessing the immunogenicity of different chemotherapeutic drugs. There is also strong evidence from humans, particularly in breast cancer, indicating that the clinical effect of doxorubicin and cyclophosphamide depends on the host immune response. Further, these agents have been shown to induce a Type I interferon immune response in breast cancer. Taken together, there is a strong rationale for synergy between doxorubicin/cyclophosphamide and PD-1/CTLA-4 blockade. The trial combines nivolumab and ipilimumab with established 1st choice chemotherapy in patients with metastatic hormone reseptor positive breast cancer. Nivolumab/ipilimumab (nivo/ipi) may i) potentiate the patient´s spontaneous anti-tumor immune response ii) synergize with chemotherapeutic agents that induce immunological cell death

Being tested
Ipilimumab, Nivolumab, Pegylated liposomal doxorubicin, Cyclophosphamide
Keywords
Neoplasms
Medical subject headings
Breast Neoplasms, Neoplasms

What participants receive

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

  • IpilimumabDrug

    Also called Yervoy

    Ipilimumab blocks CTLA-4 and may deplete regulatory T cells

  • NivolumabDrug

    Also called Opdivo

    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.

  • Pegylated liposomal doxorubicinDrug

    Chemotherapy

  • CyclophosphamideDrug

    Chemotherapy

Study groups in NCT03409198
Study groupRoleWhat they receive
Arm AActive comparatorChemo only (pegylated liposomal doxorubicin + cyclophosphamide)
Receives: Drug: Pegylated liposomal doxorubicin; Drug: Cyclophosphamide
Arm BExperimentalChemo + ipilimumab + nivolumab
Receives: Drug: Ipilimumab; Drug: Nivolumab; Drug: Pegylated liposomal doxorubicin; Drug: Cyclophosphamide

What is being measured

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

  1. Toxicity: CTCAE v4.0

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

    Measured: 3 years

  2. 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

    Measured: 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)

  1. Duration of Response (DR)

    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: duration of response (DR)

    Measured: 3 years

  2. Overall Survival (OS)

    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: overall survival (OS)

    Measured: 5 years

  3. Duration of Response (DR) in cross-over arm

    Assessment of clinical response in ipi/nivo group: duration of response (DR)

    Measured: 3 years

  4. Overall Suvival (OS) in cross-over arm

    Assessment of clinical response in ipi/nivo group: overall survival (OS)

    Measured: 5 years

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

    Assessment of toxicity of ipi/nivo (without chemotherapy) in cross-over arm

    Measured: 3 years

  6. Objective tumor Response Rate (ORR)

    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: Objective tumor response rate (ORR)

    Measured: 3 years

  7. Durable tumor Response Rate (DRR)

    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: durable tumor response rate (DRR; >6 months)

    Measured: 3 years

  8. Objective tumor Response Rate (ORR) in cross-over arm

    Assessment of clinical response in ipi/nivo group: Objective tumor response rate (ORR)

    Measured: 3 years

  9. Durable tumor Response Rate (DRR) in cross-over arm

    Assessment of clinical response in ipi/nivo group: durable tumor response rate (DRR; >6 months)

    Measured: 3 years

  10. Clinical Benefit Rate (CBR)

    Proportion of patients with an objective tumor response or with stable disease lasting at least 6 months

    Measured: 3 years

  11. Clinical Benefit Rate (CBR) in cross-over arm

    Proportion of patients with an objective tumor response or with stable disease lasting at least 6 months

    Measured: 3 years

  12. PD-L1 expression

    Assessment of PD-L1 expression, mutation load and immune gene expression as biomarkers for clinical response

    Measured: 3 years

  13. Chalder Fatigue Questionnaire (FQ)

    Assessment of patient reported outcomes, as measured by the Chalder Fatigue Questionnaire (FQ)

    Measured: 3 years

  14. Pain intensity

    Assessment of patient reported outcomes, as measured by an 11 point Numerical Rating Scale (NRS) for pain intensity

    Measured: 3 years

  15. EORTC QLQ-C15-PAL

    Assessment of patient reported outcomes, as measured by the EORTC QLQ-C15-PAL

    Measured: 3 years

  16. Biological response in molecular subtypes of breast cancer

    Comparison of clinical and biological response in molecular subtypes of breast cancer

    Measured: 3 years

Timeline

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

  1. First posted24 Jan 2018
  2. Study start21 Jan 2018
  3. Primary completion11 May 2022
  4. Study completion11 May 2022

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
Randomised
Intervention model
Parallel groups
Model description
Randomized, open-label
Masking
None (open label)
Enrolment
82 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03409198
Sponsor's protocol ID
ICON CA209-9FN
Acronym
ICON
Status last verified
Feb 2024
First submitted
4 Dec 2017
Last updated
15 Oct 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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.

    PubMed 38242720

  • 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.

    PubMed 32620163

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ipilimumab, Nivolumab and Pegylated liposomal doxorubicin in people with Breast Cancer and Hormone Receptor Positive Tumor, run by Oslo University Hospital at 6 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 16 inclusion and 41 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: finished, as of the sponsor's last update on 15 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in Belgium, Norway. 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?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Toxicity: CTCAE v4.0 (time frame: 3 years). 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 NCT03409198, 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 15 Oct 2024.

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