Clinical Trials /

Peri-Operative Ipilimumab+Nivolumab and Cryoablation Versus Standard Care in Women With Triple-negative Breast Cancer

NCT03546686

Description:

The purpose of this study is to determine the impact of pre-operative cryoablation, ipilimumab and nivolumab versus standard pre-operative care on on 3-year Event Free Survival (EFS), in women with residual hormone receptor negative, HER2-negative ("triple negative") resectable breast cancer after taxane-based neoadjuvant chemotherapy.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Peri-Operative Ipilimumab+Nivolumab and Cryoablation Versus Standard Care in Women With Triple-negative Breast Cancer
  • Official Title: A Randomized Phase 2 Study of Peri-Operative Ipilimumab, Nivolumab and Cryoablation Versus Standard Peri-Operative Care in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer.

Clinical Trial IDs

  • ORG STUDY ID: IIT2018-01-McArthur-IPI
  • NCT ID: NCT03546686

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
IpilimumabYervoyIntervention Arm
NivolumabOpdivoIntervention Arm

Purpose

The purpose of this study is to determine the impact of peri-operative cryoablation, ipilimumab and nivolumab versus standard pre-operative care on 3-year Distant Disease-Free Survival (DDFS), in women with residual hormone receptor negative, HER2-negative ("triple negative") resectable breast cancer after taxane-based neoadjuvant chemotherapy.

Detailed Description

      The purpose of this study is to determine the impact of peri-operative cryoablation,
      ipilimumab and nivolumab versus standard pre-operative care on 3-year Distant Disease-Free
      Survival (DDFS), in women with residual hormone receptor negative, HER2-negative ("triple
      negative") resectable breast cancer after taxane-based neoadjuvant chemotherapy. Our strategy
      combines two interventions: first we induce activation and maturation of dendritic cells and
      tumor-specific T cells by cross-presentation of tumor antigens via local destruction of tumor
      tissue by cryoablation. Second, we administer ipilimumab, a CTLA4 blocking antibody that
      enhances the magnitude and potency of the tumor specific T cell response, with nivolumab, a
      PD-1 blocking antibody that interferes with PD-1 mediated T-cell regulatory signaling. In
      this study, women with hormone receptor negative, HER2-negative ("triple negative")
      resectable breast cancer after neoadjuvant chemotherapy will be randomized to standard
      peri-operative management versus tumor cryoablation with peri-operative nivolumab and
      ipilimumab. Women undergoing either mastectomy or breast conserving surgery are eligible.
    

Trial Arms

NameTypeDescriptionInterventions
Intervention ArmExperimentalIpilimumab + Nivolumab + Core Biopsy/Cryoablation + Breast Surgery
  • Ipilimumab
  • Nivolumab
Control ArmActive ComparatorBreast Surgery

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Women age 18 years or older
    
              -  Confirmed histologic diagnosis of invasive adenocarcinoma of the breast
    
              -  Cedars Sinai pathology confirmation of invasive adenocarcinoma (reported or requested
                 and pending)
    
              -  ER, PR and HER2 negative on outside or Cedars Sinai biopsy report, where ER and PR
                 negative are defined as staining present in <1% of invasive cancer cells by IHC, and
                 HER2-negative is defined as IHC 0-1+ or FISH <2.0. If ER, PR and HER2 status are not
                 reported the results must be requested and pending.
    
              -  Operable tumor measuring ≥1.0 cm in maximal diameter
    
              -  Any nodal status
    
              -  Multifocal and multicentric disease is permitted.
    
              -  Synchronous bilateral invasive breast cancer is permitted
    
              -  No indication of distant metastases
    
              -  Total mastectomy or lumpectomy planned
    
              -  Tumor amenable to cryoablation as determined by a study radiologist
    
              -  ECOG performance status score of 0 or 1.
    
              -  Screening laboratory values must meet the following criteria:
    
              -  White blood cells (WBCs) ≥ 2000/μL
    
              -  Absolute neutrophil count (ANC) ≥ 1500/μL
    
              -  Platelets ≥ 100 x 103/μL ii. Hemoglobin ≥ 9.0 g/dL iii. Serum creatinine ≤ 1.5 x ULN
                 or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula
                 below): Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine
                 in mg/dL
    
              -  AST/ALT ≤ 3 x upper limit of normal (ULN)
    
              -  Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert's syndrome, who must have total
                 bilirubin < 3.0 mg/dL)
    
              -  Negative HIV screening test
    
              -  Negative screening tests for Hepatitis B and Hepatitis C. Patients with positive
                 results that do not indicate true active or chronic infection may enroll after
                 discussion and consensus agreement by the treating physician and principal
                 investigator.
    
              -  Women of childbearing potential** (WOCBP) must use appropriate method(s) of
                 contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30
                 days plus the time required for nivolumab and ipilimumab to undergo five half-lives)
                 after the last dose of investigational drug
    
              -  Women of childbearing potential 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 nivolumab
    
              -  Women must not be breastfeeding
    
              -  Willing to adhere to the study visit schedule and the prohibitions and restrictions
                 specified in this protocol.
    
                   -  "Women of childbearing potential" is defined as any female who has experienced
                      menarche and who has not undergone surgical sterilization (hysterectomy or
                      bilateral oophorectomy) or who is not postmenopausal. Menopause is defined
                      clinically as 12 months of amenorrhea in a woman over 45 in the absence of other
                      biological or physiological causes. In addition, women under the age of 62 must
                      have a documented serum follicle stimulating hormone (FSH) level less than 40
                      mIU/mL.
    
            Women of childbearing potential (WOCBP) receiving nivolumab and ipilimumab will be
            instructed to adhere to contraception for a period of 23 weeks after the last dose of
            investigational product. Men receiving nivolumab and who are sexually active with WOCBP
            will be instructed to adhere to contraception for a period of 31 weeks after the last dose
            of investigational product. These durations have been calculated using the upper limit of
            the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP
            use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP
            use contraception for 5 half-lives plus 90 days.
    
            Exclusion Criteria:
    
              -  Medical history and concurrent diseases
    
                   -  Autoimmune disease: subjects with a documented history of inflammatory bowel
                      disease, including ulcerative colitis and Crohn's disease are excluded from this
                      study as are subjects with a history of symptomatic disease (e.g., rheumatoid
                      arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus
                      Erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]). Subjects
                      with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre
                      Syndrome) are excluded from this study.
    
                   -  Any underlying medical or psychiatric condition, which in the opinion of the
                      investigator, will make the administration of study drug hazardous or obscure the
                      interpretation of AEs, such as a condition associated with frequent or poorly
                      controlled diarrhea.
    
                   -  Prohibited Treatments and/or Therapies
    
                   -  Chronic use of immunosuppressants and/or systemic corticosteroids (used in the
                      management of cancer or non-cancer-related illnesses). Brief periods of steroid
                      use, for example for the management of chemotherapy-associated toxicities, are
                      allowed. The use of corticosteroids on study is allowed for the treatment of
                      immune related adverse events (irAEs) and other medical conditions including
                      adrenal insufficiency.
    
                   -  Any non-oncology vaccine therapy used for prevention of infectious diseases
                      within 4 weeks prior to first dose of ipilimumab.
    
                   -  Prior treatment with a CTLA4 inhibitor or PD1 inhibitor;
    
                   -  Prior investigational agents within 4 weeks prior to ipilimumab/nivolumab;
    
                   -  Prior therapy with any anti-cancer agents including chemotherapy, adjuvant
                      chemotherapy, immunosuppressive agents, surgery or radiotherapy within 4 weeks
                      prior to first dose of ipilimumab.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Distant Disease-Free Survival
    Time Frame:36 Months
    Safety Issue:
    Description:Time (in months) between randomization and distant recurrence (i.e. evidence of breast cancer in any anatomic site that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer). Time (in months) between randomization and second primary non-breast invasive cancer. Time (in months) between randomization and date of death.

    Secondary Outcome Measures

    Measure:Invasive Disease-Free Survival
    Time Frame:36 Months
    Safety Issue:
    Description:Time (in months) between randomization and ipsilateral invasive breast tumor recurrence (i.e. an invasive breast cancer involving the same breast parenchyma as the original primary lesion); or Time (in months) between randomization and ipsilateral local-regional invasive breast cancer (i.e. an invasive breast cancer in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral breast); or Time (in months) between randomization and distant recurrance (i.e. evidence of breast cancer in any anatomic site - other than the two abovementioned sites - that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); or Time (in months) between randomization and contralateral invasive brease cancer; or Time (in months) between randomization and second primary non-breast invasive cancer; or Time (in months) between randomization and date of death
    Measure:Disease-Free Survival
    Time Frame:36 Months
    Safety Issue:
    Description:-Time (in months) between randomization and the date of the first occurrence of an invasive Disease Free Survival event including second primary non breast cancer events or contralateral or ipsilateral Ductal Carcinoma In Situ.
    Measure:Overall Survival
    Time Frame:36 Months
    Safety Issue:
    Description:-Time (in months) between randomization and death attributable to any cause. Patients who are alive, including lost to follow-up, at the time of the analysis will be censored at the last known alive date.
    Measure:Overall Safety
    Time Frame:36 Months
    Safety Issue:
    Description:Number of related adverse events based on CTCAE v.5.0

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Cedars-Sinai Medical Center

    Trial Keywords

    • Hormone Receptor Negative
    • Her2- Negative
    • Resectable Breast Cancer
    • breast cancer
    • immunotherapy

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