Clinical Trials /

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

NCT03409198

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ICON CA209-9FN
  • NCT ID: NCT03409198

Conditions

  • Breast Cancer
  • Hormone Receptor Positive Tumor
  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
IpilimumabYervoyArm B
NivolumabOpdivoArm B
Pegylated liposomal doxorubicinArm A
CyclophosphamideArm A

Purpose

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.

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
    

Trial Arms

NameTypeDescriptionInterventions
Arm AActive ComparatorChemo only (pegylated liposomal doxorubicin + cyclophosphamide)
  • Pegylated liposomal doxorubicin
  • Cyclophosphamide
Arm BExperimentalChemo + ipilimumab + nivolumab
  • Ipilimumab
  • Nivolumab
  • Pegylated liposomal doxorubicin
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          1. 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.

          2. 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.

          3. Measurable metastatic disease according to RECIST

          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          5. Signed Informed Consent Form

          6. Women or men aged ≥ 18 years

          7. A minimum of 12 months from adjuvant/neoadjuvant chemotherapy with antracyclins to
             relapse disease

          8. A maximum of one previous line with chemotherapy in the metastatic setting

          9. Chemotherapy is considered as preferred treatment

         10. Previous endocrine and targeted therapy is allowed

         11. No use of systemic corticosteroids at study entry

         12. 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

         13. 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.

         14. 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

         15. Able to swallow and retain orally administered medication

         16. Adequate organ function as defined in Table 1

        Exclusion Criteria:

          1. 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)

          2. 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

          3. Known CNS disease, except for asymptomatic CNS metastases, provided all of the
             following criteria are met:

               1. Measurable disease outside the CNS

               2. Asymptomatic for CNS disease > 4 weeks

               3. No ongoing requirement for corticosteroids as therapy for CNS disease

               4. No radiation of brain lesions within 2 weeks prior to randomization

               5. No leptomeningeal disease

          4. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with
             indwelling catheters (e.g., PleurX®) are allowed

          5. 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

          6. Ionized calcium > 1.2 x UNL. The use of bisphosphonates is allowed

          7. Pregnant or breastfeeding

          8. 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)

          9. 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

         10. Severe infection within 21 days prior to randomization, requiring hospitalization

         11. 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

         12. 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

         13. A history of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

         14. Known hypersensitivity to any of the components of the investigational products

         15. 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:

               1. Rash must cover less than 10% of body surface area.

               2. Disease is well controlled at baseline and only requiring low potency topical
                  steroids

               3. 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)

         16. Undergone allogeneic stem cell or solid organ transplantation

         17. 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

         18. A positive test for HIV

         19. 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

         20. Active tuberculosis

         21. 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

         22. Received treatment with immune checkpoint modulators, including anti−CTLA-4,
             anti−PD-1, or anti−PD-L1 therapeutic antibodies

         23. 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

         24. 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

               1. 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

               2. Patients with a history of allergic reaction to IV contrast requiring steroid
                  pre-treatment should have baseline and subsequent tumor assessments performed
                  using MRI

               3. 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

         25. 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.

         26. 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

         27. Known psychiatric or substance abuse disorders that would interfere with cooperation
             and the requirements of the trial

         28. Received a live vaccine within 30 days of planned start of study therapy, or is
             expected to receive such a vaccine while on therapy

             a. 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.

         29. Any reason why, in the opinion of the investigator, the patient should not participate
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicity: CTCAE v4.0
Time Frame:3 years
Safety Issue:
Description:Assessment of toxicity of combined treatment with ipilimumab, nivolumab, pegylated liposomal doxorubicin and cyclophosphamide (ipi/nivo/chemo)

Secondary Outcome Measures

Measure:Duration of Response (DR)
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: duration of response (DR)
Measure:Overall Survival (OS)
Time Frame:5 years
Safety Issue:
Description:Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: overall survival (OS)
Measure:Duration of Response (DR) in cross-over arm
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response in ipi/nivo group: duration of response (DR)
Measure:Overall Suvival (OS) in cross-over arm
Time Frame:5 years
Safety Issue:
Description:Assessment of clinical response in ipi/nivo group: overall survival (OS)
Measure:Toxicity, cross-over arm, CTCAE v4.0
Time Frame:3 years
Safety Issue:
Description:Assessment of toxicity of ipi/nivo (without chemotherapy) in cross-over arm
Measure:Objective tumor Response Rate (ORR)
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: Objective tumor response rate (ORR)
Measure:Durable tumor Response Rate (DRR)
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: durable tumor response rate (DRR; >6 months)
Measure:Objective tumor Response Rate (ORR) in cross-over arm
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response in ipi/nivo group: Objective tumor response rate (ORR)
Measure:Durable tumor Response Rate (DRR) in cross-over arm
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response in ipi/nivo group: durable tumor response rate (DRR; >6 months)
Measure:Clinical Benefit Rate (CBR)
Time Frame:3 years
Safety Issue:
Description:Proportion of patients with an objective tumor response or with stable disease lasting at least 6 months
Measure:Clinical Benefit Rate (CBR) in cross-over arm
Time Frame:3 years
Safety Issue:
Description:Proportion of patients with an objective tumor response or with stable disease lasting at least 6 months
Measure:PD-L1 expression
Time Frame:3 years
Safety Issue:
Description:Assessment of PD-L1 expression, mutation load and immune gene expression as biomarkers for clinical response
Measure:Chalder Fatigue Questionnaire (FQ)
Time Frame:3 years
Safety Issue:
Description:Assessment of patient reported outcomes, as measured by the Chalder Fatigue Questionnaire (FQ)
Measure:Pain intensity
Time Frame:3 years
Safety Issue:
Description:Assessment of patient reported outcomes, as measured by an 11 point Numerical Rating Scale (NRS) for pain intensity
Measure:EORTC QLQ-C15-PAL
Time Frame:3 years
Safety Issue:
Description:Assessment of patient reported outcomes, as measured by the EORTC QLQ-C15-PAL
Measure:Biological response in molecular subtypes of breast cancer
Time Frame:3 years
Safety Issue:
Description:Comparison of clinical and biological response in molecular subtypes of breast cancer

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Oslo University Hospital

Trial Keywords

  • Neoplasms

Last Updated

March 4, 2020