Clinical Trials /

Pembrolizumab in Treating Patients With Triple-Negative Breast Cancer

NCT02954874

Description:

This randomized phase III trial studies how well pembrolizumab works in treating patients with triple-negative breast cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Treating Patients With Triple-Negative Breast Cancer
  • Official Title: A Randomized, Phase III Trial to Evaluate the Efficacy and Safety of MK-3475 (Pembrolizumab) as Adjuvant Therapy for Triple Receptor-Negative Breast Cancer With >/= 1 CM Residual Invasive Cancer or Positive Lymph Nodes (ypN+) After Neoadjuvant Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01595
  • SECONDARY ID: NCI-2016-01595
  • SECONDARY ID: S1418/BR006
  • SECONDARY ID: s16-02231
  • SECONDARY ID: S1418
  • SECONDARY ID: S1418
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT02954874

Conditions

  • Invasive Breast Carcinoma
  • Stage 0 Breast Cancer AJCC v6 and v7
  • Stage I Breast Cancer AJCC v7
  • Stage IA Breast Cancer AJCC v7
  • Stage IB Breast Cancer AJCC v7
  • Stage II Breast Cancer AJCC v6 and v7
  • Stage IIA Breast Cancer AJCC v6 and v7
  • Stage IIB Breast Cancer AJCC v6 and v7
  • Stage III Breast Cancer AJCC v7
  • Stage IIIA Breast Cancer AJCC v7
  • Stage IIIB Breast Cancer AJCC v7
  • Stage IIIC Breast Cancer AJCC v7
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm II (pembrolizumab)

Purpose

This randomized phase III trial studies how well pembrolizumab works in treating patients with triple-negative breast cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare invasive disease-free survival (IDFS) of patients with triple-negative (TNBC)
      or low estrogen receptor (ER)-positive and/or HER2 borderline breast cancer who have >= 1 cm
      residual invasive breast cancer and/or positive lymph nodes (ypN1mi, ypN1, ypN2, ypN3) after
      neoadjuvant chemotherapy randomized to receive 1 year of MK-3475 (pembrolizumab) adjuvant
      therapy compared to no MK-3475 (pembrolizumab), in both the entire study population and also
      in the PD-L1 positive subset.

      SECONDARY OBJECTIVES:

      I. To compare the effects of MK-3475 (pembrolizumab) on overall survival (OS) and distant
      recurrence-free survival (DRFS) between the two randomized arms for the PD-L1 positive
      patients and then all patients.

      II. To assess the toxicity and tolerability of MK-3475 (pembrolizumab) in this patient
      population with or without radiation therapy.

      BEHAVIORAL AND HEALTH OUTCOMES (BAHO) STUDY OBJECTIVES:

      I. To examine the association between biomarkers of inflammation and quality of life and
      patient reported outcomes between the two groups during and at the end of therapy.

      II. To examine the long-term and late effects of treatment on patient-reported outcomes.

      ADDITIONAL OBJECTIVE:

      I. To collect tissue and whole blood for processing and banking in anticipation of future
      correlative studies in this patient population.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I (OBSERVATION): Patients receive no treatment but are monitored at standard clinical
      intervals during first year after randomization. Patients are examined every 12 weeks for 1
      year, and every 6 months for 4 years, then annually for 5 years.

      ARM II (PEMROLIZUMAB): Patients receive pembrolizumab intravenously (IV) over 30 minutes on
      days 1 and 22. Cycles repeat every 42 days for 52 weeks in the absence of disease progression
      or unacceptable toxicity.

      All patients may undergo radiation therapy within 12 weeks of last breast cancer operation or
      after treatment.

      After completion of study treatment, patients are followed up to 10 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (observation)ExperimentalPatients receive no treatment but are monitored at standard clinical intervals during first year after randomization. Patients are examined every 12 weeks for 1 year, every 6 months for 4 years, and then annually for 5 years. Patients may undergo radiation therapy within 12 weeks of last breast cancer operation or after treatment.
    Arm II (pembrolizumab)ExperimentalPatients receive pembrolizumab IV over 30 minutes on days 1 and 22. Cycles repeat every 42 days for 52 weeks in the absence of disease progression or unacceptable toxicity. Patients may undergo radiation therapy within 12 weeks of last breast cancer operation or after treatment.
    • Pembrolizumab

    Eligibility Criteria

            Inclusion Criteria:
    
              -  STEP 1 REGISTRATION
    
              -  Patients must have histologically confirmed estrogen receptor (ER)-, progesterone
                 receptor (PR)- and HER2-negative (triple-negative, TNBC) or ER-, PR- weakly positive,
                 and HER2- equivocal status and must not have received and not be planning to receive
                 adjuvant anti-HER2 or endocrine therapies after completion of neoadjuvant
                 chemotherapy; patients who are HER2 positive by American Society of Clinical Oncology
                 (ASCO) College of American Pathologists (CAP) guidelines are ineligible; HER2-negative
                 and HER2-equivocal cases as per ASCO CAP guidelines that do not receive HER2-targeted
                 therapy are eligible; patients with weakly ER or PR positive disease, defined as ER
                 and/or PR less than or equal to (=<) 5% by immunohistochemistry, are eligible if the
                 treating physician considers the patient not eligible for adjuvant endocrine therapy;
                 residual disease must be >= 1 cm in greatest dimension, and/or have positive lymph
                 nodes (ypN1mi, ypN1, ypN2, ypN3) observed on pathologic exam
    
                   -  NOTE: If the ER and/or HER2 results are discordant between the initial,
                      pre-chemotherapy, and post-chemotherapy surgical tissue, the receptor status of
                      the residual disease has to be used to determine eligibility. IHC-positive
                      isolated tumor cells in the lymph node (N0 [i+]) are not considered node-positive
                      and these patients also must have >= 1 cm residual invasive cancer in the breast
                      to be eligible.
    
              -  Patients must not have metastatic disease (i.e., must be clinically M0; systemic
                 staging studies with imaging should follow routine practice as per National
                 Comprehensive Cancer Network (NCCN) and ASCO guidelines); patients must not have
                 locally recurrent disease
    
              -  It is preferred that axillary lymph node sampling is performed after completion of
                 neoadjuvant chemotherapy to allow more accurate assessment of pathologic response;
                 patients must have a complete axillary lymph node dissection after neoadjuvant
                 chemotherapy in the following situations (except for patients participating in the
                 Alliance A11202 trial):
    
                   -  Patients had documented pathologic involvement of the axillary nodes (fine needle
                      aspiration [FNA] or core biopsy) before neoadjuvant chemotherapy and had sentinel
                      node biopsy after neoadjuvant chemotherapy with positive sentinel node(s)
    
                   -  Patient had documented pathologic involvement of the axillary nodes (FNA or core
                      biopsy) before neoadjuvant chemotherapy and had only 1 sentinel lymph node
                      removed after neoadjuvant chemotherapy
    
                        -  NOTE: Patients who undergo sentinel node biopsy before starting neoadjuvant
                           treatment and do not undergo post neoadjuvant assessment of the axillary
                           nodes or who have negative axillary nodes on post neoadjuvant assessment
                           must have >= 1 cm residual invasive cancer in the breast after completion of
                           neoadjuvant chemotherapy
    
              -  Patients must have a minimum of five, available unstained formalin-fixed
                 paraffin-embedded (FFPE) slides from the residual (post-neoadjuvant) invasive tumor in
                 primary site or lymph node; (these will be submitted to a central laboratory to
                 determine PD-L1 expression); the tumor tissue must be adequate for PD-L1 testing,
                 which typically requires a minimum of 100 cancer cells per slide; local PD-L1 results,
                 even if available, will not substitute for central testing
    
                   -  NOTE: Initial order for specimen kits should be placed at least two weeks prior
                      to registering the first patient at each site
    
              -  Patients must be offered the opportunity to participate in specimen banking
    
              -  English-speaking patients must be willing to participate in the BAHO substudy
    
              -  Patients must have had neoadjuvant chemotherapy followed by surgery; the choice of
                 neoadjuvant chemotherapy is determined by the treating physician; we recommend
                 following the NCCN treatment guidelines for TNBC; patients who cannot complete all
                 planned treatment cycles for any reason are considered high risk and therefore are
                 eligible for the study if they have residual disease; patients must have resolution of
                 adverse event(s) of the most recent prior chemotherapy to grade 1 or less, except
                 alopecia and =< grade 2 neuropathy which are allowed
    
              -  Patients may receive post-operative (adjuvant) chemotherapy for up to 24 weeks of
                 duration (e.g. 8 cycles of capecitabine as in the CREATE-X trial) after completion of
                 surgery at the discretion of the treating physician; co-enrollment to EA1131 is
                 allowed, provided that patients complete or discontinue adjuvant chemotherapy prior to
                 step registration; at the time of step 1 registration, patients must have resolution
                 of adverse event(s) of the most recent prior chemotherapy to grade 1 or less, except
                 alopecia and =< grade 2 neuropathy which are allowed; patients that have received
                 adjuvant chemotherapy (including via co-enrollment to EA1131) must be registered to
                 screening within 35 days after final dose of adjuvant chemotherapy
    
              -  Patients must have completed their final breast surgery (rendering them free from
                 disease) with clear resection margins for invasive cancer and DCIS within the
                 following timelines:
    
                   -  90 days prior to screening registration for patients not receiving post-operative
                      (adjuvant) chemotherapy OR
    
                   -  270 days prior to step 1 screening registration for patients who have received
                      post-operative (adjuvant) chemotherapy Positive margins are allowed only if the
                      surgical team of the patient deems further resection impossible
    
              -  Patients for whom radiation therapy (RT) to the affected breast or chest wall and
                 regional nodal areas is clinically indicated as per NCCN treatment guidelines, should
                 receive routine RT after randomization when possible, and receive MK-3475
                 (pembrolizumab) concurrent with RT, if randomized to the experimental arm; however,
                 routine RT administered, or initiated, prior to registration is also allowed; MK-3475
                 (pembrolizumab) may be added to ongoing radiation, or started after its completion, if
                 randomized to the experimental arm, provided there are no > grade 1 radiation-related
                 skin toxicities and provided that no radiosensitizing chemotherapy is being
                 administered; co-enrollment in the Alliance A221505 (NCT03414970) and A011202
                 (NCT01901094) trials or in the NSABP-B51 (NCT01872975) trial is allowed, but patients
                 must not be planning to receive radiation therapy given on these trials concurrently
                 with MK-3475 (pembrolizumab) treatment on S1418; whether or not patient will receive
                 RT and the extent of intended RT must be specified at time of registration; NOTE:
                 Patients who receive post-operative chemotherapy may receive radiation therapy before
                 or after the chemotherapy; a short course of reduced dose chemotherapy or other agents
                 concomitant with radiation for radiation sensitization is not considered to be
                 adjuvant chemotherapy
    
              -  Patients must not have had prior immunotherapy with anti-PD-L1, anti-PD-1, anti-CTLA4
                 or similar drugs; patients must not be planning to receive any of the prohibited
                 therapies during the screening or treatment phases of the study
    
              -  Patients must not be planning to receive concomitantly other biologic therapy,
                 hormonal therapy, other chemotherapy, surgery or other anti-cancer therapy except
                 radiation therapy while receiving treatment on this protocol; however, patients
                 receiving extended adjuvant endocrine therapy for an earlier ER positive breast cancer
                 treated with curative intent and without recurrence for at least 5 years may continue
                 with their endocrine therapy
    
              -  Patients must have Zubrod performance status =< 2
    
              -  Patients must not have a history of (non-infectious) pneumonitis that required
                 steroids or evidence of active pneumonitis within 2 years prior to registration
    
              -  Patients must not have active autoimmune disease that has required systemic treatment
                 in past 2 years (i.e., with use of disease modifying agents, corticosteroids or
                 immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or
                 physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
                 etc.) is not considered a form of systemic treatment
    
              -  Patients must not have received live vaccines within 30 days prior to registration;
                 examples of live vaccines include, but are not limited to, the following: measles,
                 mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin
                 (BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are
                 generally killed virus vaccines and are allowed; however, intranasal influenza
                 vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
    
              -  Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV)
                 infection prior to registration; patients who have completed curative therapy for HCV
                 are eligible; patients with known human immunodeficiency virus (HIV) infection are
                 eligible if they meet each of the following 3 criteria:
    
                   -  CD4 counts >= 350 mm^3
    
                   -  Serum HIV viral load of < 25,000 IU/ml and
    
                   -  Treated on a stable antiretroviral regimen
    
              -  No other prior invasive malignancy is allowed except for the following: adequately
                 treated basal (or squamous cell) skin cancer, in situ breast or cervical cancer; stage
                 I or II invasive cancer treated with a curative intent without evidence of disease
                 recurrence for at least five years
    
              -  Patients must have complete history and physical examination within 28 days prior to
                 registration
    
              -  Patients must be informed of the investigational nature of this study and must sign
                 and give written informed consent for this protocol in accordance with institutional
                 and federal guidelines
    
              -  As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
                 treating institution's identity is provided in order to ensure that the current
                 (within 365 days) date of institutional review board approval for this study has been
                 entered in the system
    
              -  STEP 2 REGISTRATION
    
              -  Patients must not be registered to step 2 until receiving confirmation from the
                 Southwest Oncology Group (SWOG) Statistical Center that the patient's tissue specimen
                 was adequate for PD-L1 testing; patients must be registered within 14 days of
                 receiving the e-mail notification confirming submission was evaluable for PD-L1 status
    
              -  Absolute neutrophil count (ANC) >= 1,500 microliter (mcL), obtained within 28 days
                 prior to step 2 registration
    
              -  Platelets >= 100,000/mcL, obtained within 28 days prior to step 2 registration
    
              -  Hemoglobin >= 9 g/dL, obtained within 28 days prior to step 2 registration
    
              -  A serum thyroid-stimulating hormone (TSH) and/or free T4 must be obtained within 28
                 days prior to step 2 registration to obtain a baseline value
    
              -  Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except Gilbert's
                 syndrome, who must have a total bilirubin < 3.0 mg/dL), obtained within 28 days prior
                 to step 2 registration
    
              -  Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
                 serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
                 IULN, obtained within 28 days prior to step 2 registration
    
              -  Alkaline phosphatase =< 2.5 x IULN, obtained within 28 days prior to step 2
                 registration
    
              -  Serum creatinine =< IULN OR measured or calculated creatinine clearance >= 60 mL/min,
                 obtained within 28 days prior to step 2 registration
    
              -  Women of childbearing potential must have a negative urine or serum pregnancy test
                 within 28 day prior to registration; women/men of reproductive potential must have
                 agreed to use an effective contraceptive method for the course of the study through
                 120 days after the last dose of study medication; should a woman become pregnant or
                 suspect she is pregnant while she or her partner is participating in this study, she
                 should inform her treating physician immediately; a woman is considered to be of
                 "reproductive potential" if she has had menses at any time in the preceding 12
                 consecutive months; in addition to routine contraceptive methods, "effective
                 contraception" also includes heterosexual celibacy and surgery intended to prevent
                 pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
                 bilateral oophorectomy, bilateral tubal ligation, or vasectomy; however, if at any
                 point a previously celibate patient chooses to become heterosexually active during the
                 time period for use of contraceptive measures outlined in the protocol, he/she is
                 responsible for beginning contraceptive measures; patients must not be pregnant or
                 nursing; women of childbearing potential must plan to have a urine or serum pregnancy
                 test within 72 hours prior to receiving the first dose of study medication; if the
                 urine test is positive or cannot be confirmed as negative, a negative serum pregnancy
                 test will be required
    
              -  Patients must not have an active infection requiring systemic therapy at the time of
                 starting therapy
    
              -  Site must verify that there is no known change in the step 1 eligibility since initial
                 registration
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Invasive disease-free survival (IDFS)
    Time Frame:From date of randomization to date of first invasive recurrence, second invasive primary cancer (breast or not), or death due to any cause, assessed up to 10 years
    Safety Issue:
    Description:The distributions of IDFS will be estimated using the Kaplan-Meier method, with 95% confidence intervals (CI) calculated using Greenwood's formula. Comparisons between the two treatment arms will be performed using the stratified log-rank test. The hazard ratios and 95% CIs will be based on the stratified Cox proportional hazard model with treatment as the only covariate. Secondary analyses of IDFS will be performed to describe consistency or divergence across subgroups. This will include a forest plot of treatment hazard ratios and associated 95% confidence intervals for each level of the stratification factors and major prognostic covariates (such as use of radiation therapy). The statistical significance of the interaction between treatment and each stratification factor or prognostic variable will be assessed.

    Secondary Outcome Measures

    Measure:Overall survival (OS)
    Time Frame:From date of randomization to date of death due to any cause, assessed up to 10 years
    Safety Issue:
    Description:The distributions of OS will be estimated using the Kaplan-Meier method, with 95% CI calculated using Greenwood's formula. Comparisons between the two treatment arms will be performed using the stratified log-rank test. The hazard ratios and 95% CIs will be based on the stratified Cox proportional hazard model with treatment as the only covariate.
    Measure:Distant recurrence-free survival (DRFS)
    Time Frame:From date of randomization to date of invasive distant disease recurrence, second invasive primary cancer (breast or not) or death due to any cause, assessed up to 10 years
    Safety Issue:
    Description:The distributions of DRFS will be estimated using the Kaplan-Meier method, with 95% CI calculated using Greenwood's formula. Comparisons between the two treatment arms will be performed using the stratified log-rank test. The hazard ratios and 95% CIs will be based on the stratified Cox proportional hazard model with treatment as the only covariate.
    Measure:Incidence of adverse events
    Time Frame:Up to 10 years
    Safety Issue:
    Description:Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Toxicity analysis will be conducted in all patients receiving at least one dose of MK-3475 (pembrolizumab). The incidence of adverse events will be reported.
    Measure:Severity and frequency of treatment-related symptoms (diarrhea, nausea, rash, cough, and shortness of breath, musculoskeletal pain) over time of patients receiving pembrolizumab
    Time Frame:Up to 10 years
    Safety Issue:
    Description:Compared without treatment. The distributions of the corresponding Patient Reported Outcomes version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) items will be compared between the two treatment groups using a mixed ordinal logistic regression model for repeated measures. The model will also include the corresponding baseline measurement and time. Presence of treatment-by-time interaction will be tested for each of these endpoints. Similar analyses will be performed for disease related symptoms. The descriptive and graphical methods suggested in Basch, et. al. will be used to summarize the distributions of different symptoms by treatment group over time.
    Measure:Emotional function and disease-related symptoms in patients receiving pembrolizumab
    Time Frame:Up to 10 years
    Safety Issue:
    Description:Assessed by PROMIS global mental health scale score. Will be compared between the two treatment groups using a mixed model for repeated measures analysis with adjustment for the baseline score and time. Presence of treatment-by-time interaction will be investigated.
    Measure:Impact of treatment and treatment-related symptoms on physical function in patients without therapy
    Time Frame:55 weeks after randomization
    Safety Issue:
    Description:Compared to patients receiving pembrolizumab. A multiple linear regression model will be performed with physical health scale score as an outcome and treatment and treatment related symptoms as covariates. Presence of treatment by each individual symptom item interactions will be investigated.
    Measure:Relationship between treatment-related symptoms and adherence to the study medication
    Time Frame:Up to 10 years
    Safety Issue:
    Description:Will be investigated among patients randomized to pembrolizumab treatment group by means of multiple logistic regression. Patients who have been on study therapy for 70% or more of their expected time on therapy will be considered adherent.
    Measure:Resolution of treatment-related symptoms in patients receiving pembrolizumab
    Time Frame:18 months after randomization
    Safety Issue:
    Description:Compared to patients without treatment. A change in severity of the particular symptom will be compared between the two treatment groups by means of multiple linear regression with adjustment for the corresponding measurement at the 55 week assessment point.
    Measure:Long-term quality of life and symptoms between the two treatment groups
    Time Frame:Up to 60 months after randomization
    Safety Issue:
    Description:Mixed models for repeated measures analysis will be used with adjustment for scores at 18 months to examine changes in physical and emotional domain scores, fatigue and other persistent symptoms over the course
    Measure:Role of pro-inflammatory cytokines in the development of pembrolizumab associated symptoms
    Time Frame:Up to 55 weeks
    Safety Issue:
    Description:Specifically focused on treatment-associated fatigue. This will be compared to patients in the observation group.
    Measure:Single nucleotide polymorphisms (SNPs) in the promotor region of pro-inflammatory cytokine genes and the risk for development and severity of treatment-associated fatigue and other symptoms
    Time Frame:Up to 10 years
    Safety Issue:
    Description:The role of these SNPs in the persistence of long-term fatigue in all patients will also be explored using treatment assignment as a covariate.

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated