Pembrolizumab vs. Observation in People With Triple-negative Breast Cancer Who Had a Pathologic Complete Response After Chemotherapy Plus Pembrolizumab

• ClinicalTrials.gov Identifier: NCT05812807
• Recruitment Status: Recruiting
• First Posted: April 14, 2023
• Last Update Posted: April 9, 2024
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: March 23, 2023
• First Posted Date: April 14, 2023
• Last Update Posted Date: April 9, 2024
• Actual Study Start Date: May 10, 2023
• Estimated Primary Completion Date: May 31, 2033 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 12, 2023)

Recurrence-free survival (RFS) [ Time Frame: Up to 10 years. ]

Defined as the time from randomization to first invasive local, regional, or distant recurrence or death due to any cause. RFS will be compared between treatment arms using the hazard ratio (with 90% confidence interval and stratified log-rank test) from a stratified Cox model.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 12, 2023)

• Incidence of adverse events (AEs) [ Time Frame: Up to 27 weeks after registration ]
  Adverse events will be determined using the latest version of the Common Terminology Criteria for Adverse Events (CTCAE). The proportions of patients with a grade 3 or higher AE will be compared between the arms using a chi-square test. A similar analysis will be done to compare the grade 3 or higher irAE rates
• Overall survival [ Time Frame: Up to 10 years. ]
  Defined as the time from randomization to death due to any cause. OS will be compared between treatment arms using the hazard ratio (and stratified log-rank test) from a stratified Cox model
• Locoregional recurrence incidence [ Time Frame: Up to 10 years. ]
  Defined as the time from randomization to first invasive local or regional recurrence. The cumulative incidence of LRR will be compared between treatment arms using a log-rank test (and estimated using Kaplan-Meier curves).
• Radiation adverse events [ Time Frame: Up to 27 weeks after registration ]
  Radiation adverse events include pneumonitis, hypothyroidism and dermatitis. Radiation AE event rates will be determined for patients who received radiation. The numerator is the number of patients with the radiation AE and the denominator is the number of patients who received radiation. The analysis of the radiation related adverse event rates will only include patients who received radiation treatment. The radiation AE rates will be compared between the two arms using a chi-square test.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pembrolizumab vs. Observation in People With Triple-negative Breast Cancer Who Had a Pathologic Complete Response After Chemotherapy Plus Pembrolizumab
• Official Title: OptimICE-PCR: De-Escalation of Therapy in Early-Stage TNBC Patients Who Achieve pCR After Neoadjuvant Chemotherapy With Checkpoint Inhibitor Therapy
• Brief Summary: The phase III trial compares the effect of pembrolizumab to observation for the treatment of patients with early-stage triple-negative breast cancer who achieved a pathologic complete response after preoperative chemotherapy in combination with pembrolizumab. 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. This trial may help researchers determine if observation will result in the same risk of cancer coming back as pembrolizumab after surgery in triple-negative breast cancer patients who achieve pathologic complete response after preoperative chemotherapy with pembrolizumab.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate whether observation results in a non-inferior recurrence-free survival (RFS) compared to adjuvant pembrolizumab in early-stage triple-negative breast cancer (TNBC) patients who achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy with pembrolizumab.

II. To compare quality of life (QOL) at approximately 27 weeks as assessed by the Functional Assessment of Cancer Therapy-Breast (FACT-B) Trial Outcome Index between patients randomized to adjuvant pembrolizumab versus observation. (Quality of Life) III. To assess the social value of de-escalation of adjuvant breast cancer immunotherapy at approximately 27 weeks and, by modeling, over a lifetime. (Value of Care)

SECONDARY OBJECTIVES:

I. To evaluate whether observation compared to adjuvant pembrolizumab impacts the following:

Ia. RFS by stage at presentation and by receipt of prior anthracycline therapy; Ib. Adverse event rate: difference in Grade 3 or higher adverse event rates overall and Grade 3 or higher immune-related adverse events (irAEs) rates; Ic. Overall Survival (OS); Id. Locoregional recurrence (LRR both isolated LRR as first events and LRR events simultaneous with DM); Ie. RFS, LRR, OS, adverse events, and QOL by age (=< 45, 46-65, and > 65), race, and ethnicity; If. Adverse events related to receipt of radiotherapy. II. To assess the value of de-escalation of breast cancer immunotherapy from the payer perspective at approximately 27 weeks and, by modelling, over a lifetime. (Value of Care) III. To compare patient out-of-pocket costs at approximately 27 weeks between patients randomized to adjuvant pembrolizumab versus observation. (Value of Care) IV. To compare financial toxicity at approximately 27 weeks between patients randomized to adjuvant pembrolizumab versus observation. (Value of Care) V. To compare work/productivity impairment at approximately 27 weeks between patients randomized to adjuvant pembrolizumab versus observation. (Value of Care)

EXPLORATORY OBJECTIVES:

I. To describe trajectories of QOL over time among patients randomized to adjuvant pembrolizumab versus (vs.) observation. (Quality of Life) II. To compare various QOL domains after approximately 27 weeks as assessed by the 5 subscales of the FACT-B Index between patients randomized to adjuvant pembrolizumab versus observation. (Quality of Life) III. To compare self-reported symptomatic adverse events at approximately 27 weeks assessed by the patient reported outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE) between patients randomized to adjuvant pembrolizumab versus observation. (Quality of Life) IV. To describe trajectories of financial toxicity and work/productivity impairment over time from baseline to approximately 27 weeks among patients randomized to adjuvant pembrolizumab versus observation. (Value of Care) V. To develop and assess a measure of value from the patient perspective at approximately 27 weeks. (Value of Care)

OUTLINE: Patients are randomized to 1 of 2 arms after completing neoadjuvant chemotherapy in combination with pembrolizumab, followed by definitive breast surgery.

ARM I (PEMBROLIZUMAB): Patients receive pembrolizumab intravenously (IV) on study. Patients also undergo tumor biopsy on study, and collection of blood on study and during follow-up.

ARM II (OBSERVATION): Patients undergo observation on study. Patients also undergo tumor biopsy on study, and collection of blood on study and during follow-up.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Anatomic Stage I Breast Cancer AJCC v8
• Anatomic Stage II Breast Cancer AJCC v8
• Anatomic Stage III Breast Cancer AJCC v8
• Early Stage Triple-Negative Breast Carcinoma

Intervention

• Biological: Pembrolizumab
  Given IV
  Other Name: Keytruda
• Other: Patient Observation
  Undergo observation
  Other Names:

  • Active surveillance
  • watchful waiting
  • observation
• Procedure: Biopsy
  Undergo biopsy
• Procedure: Biospecimen Collection
  Undergo collection of blood
• Other: Questionnaire Administration
  Ancillary studies
• Other: Quality-of-Life Assessment
  Ancillary studies

Study Arms

• Active Comparator: Arm I (pembrolizumab)
  Patients receive pembrolizumab IV on study. Patients also undergo tumor biopsy on study, and collection of blood on study and during follow-up.
  Interventions:

  • Biological: Pembrolizumab
  • Procedure: Biopsy
  • Procedure: Biospecimen Collection
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Arm II (observation)
  Patients undergo observation on study. Patients also undergo tumor biopsy on study, and collection of blood on study and during follow-up.
  Interventions:

  • Other: Patient Observation
  • Procedure: Biopsy
  • Procedure: Biospecimen Collection
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 12, 2023): 1295
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 31, 2033
• Estimated Primary Completion Date: May 31, 2033 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

• Triple Negative Breast Cancer:

  • Patients with a history of stage T1cN1-2 or T2-4N0-2 breast cancer according to the primary tumor-regional lymph node anatomic staging criteria of the American Joint Committee on Cancer (AJCC), 8th edition as determined by the investigator in radiologic assessment, clinical assessment or both
  • Patients must have no residual invasive disease in the breast or lymph nodes after the completion of neoadjuvant therapy. Residual ductal carcinoma in situ (DCIS) is allowed. Isolated tumor cells are considered node-negative
  • Estrogen (ER) and progesterone (PR) =< 10%; HER2-negative by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (immunohistochemistry [IHC] and fluorescence in situ hybridization [FISH])
  • If invasive disease was present in both breasts, participation in the study is permitted as long as the eligibility criteria are met for both tumors/breasts
• Patients must have received neoadjuvant chemotherapy in combination with pembrolizumab for a minimum of 6 cycles. All systemic chemotherapy and ICI therapy should have been completed preoperatively

• An interval of no more than 12 weeks between the completion date of the final surgery and the date of randomization

  * Note: Adjuvant radiation can be given on study. If given, it is encouraged to be given concurrently with pembrolizumab, per investigator discretion. Treatment with adjuvant pembrolizumab is strongly discouraged prior to participation in this trial, but if administered (e.g., if patients are awaiting pathology results), pembrolizumab may be administered for up to 6 weeks post-surgery and must be completed prior to registration

• Use of investigational anti-cancer agents must be discontinued at time of registration

• Adequate excision: Surgical removal of all clinically evident disease in the breast and lymph nodes as follows:

  • Breast surgery: Total mastectomy or breast-conserving surgery with histologically negative margins, including no ink on tumor for DCIS, at the time of excision

    ** For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of ductal carcinoma in-situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates DCIS at the line of resection, additional operative procedures may be performed to obtain clear margins. If DCIS is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for classic lobular carcinoma in situ (LCIS) are eligible without additional resection

  • Lymph node surgery:

    • For a patient with clinically N0 disease, a sentinel lymph node biopsy should have been performed at time of surgical evaluation, and if pathologically node positive, the patient is no longer eligible. Isolated tumor cells are considered node-negative

    • For a patient with clinically N1 disease at diagnosis (with positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy performed prior to preoperative therapy) additional surgical evaluation of the axilla following preoperative therapy is required

      *** If they become cN0 (no palpable adenopathy), then a sentinel lymph node biopsy could have been performed at time of surgery (axillary dissection would also be permitted); if the sentinel lymph node biopsy is positive, the patient is no longer eligible

    • If sentinel node biopsy performed before preoperative therapy was negative, no additional surgical evaluation of the axilla is required after preoperative therapy. If sentinel node biopsy performed before preoperative therapy was positive, an ALND is required after preoperative therapy
    • If the only sentinel node identified by isotope scan is in the internal mammary chain, surgical evaluation of the axilla is still required
    • If sentinel node evaluation after preoperative therapy is negative, no further additional surgical evaluation of the axilla is required
    • Axillary dissection without sentinel node evaluation is permitted as the initial or sole axillary evaluation after preoperative therapy
• If breast-conserving surgery was performed but patient will not be receiving breast radiation, the patient is not eligible
• Not pregnant and not nursing, because this study involves an agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 7 days prior to randomization is required
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet Count >= 100,000/mm^3
• Estimated glomerular filtration rate (eGFR) >= 15 mL/min/1.73m^2

• Total Bilirubin =<1.5 x upper limit of normal (ULN)

  * Patients with Gilbert's disease with a total bilirubin =< 2.5 x ULN and direct bilirubin within normal limits are permitted

• Aspartate aminotransferase (AST) serum aspartate aminotransferase [SGOT] / alanine aminotransferase (ALT) serum glutamic pyruvic transaminase [SGPT] =< 3 x institutional ULN
• Patients must be willing to provide tumor tissue from the diagnostic core biopsy. If inadequate tumor tissue is available, patients are still eligible to participate in the trial
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial

Exclusion Criteria:

• No stage IV (metastatic) breast cancer
• No history of any prior (ipsi- or contralateral) invasive breast cancer. Prior DCIS is allowed
• No evidence of recurrent disease following preoperative therapy and surgery
• No known active liver disease, e.g. due to hepatitis B virus (HBV), hepatitis C virus (HCV), autoimmune hepatic disorders, or sclerosing cholangitis

• No history of intolerance, including Grade 3 or 4 infusion reaction or hypersensitivity to pembrolizumab or murine proteins or any components of the product

  * Note: Prior immune-related adverse events (irAEs) are allowed if they resolved and the patient tolerated subsequent therapy without requiring chronic steroids for the irAE

• No medical conditions that require chronic systemic steroids (>10 mg prednisone daily or equivalent) or any other form of immunosuppressive medications and has required such therapy in the last two years. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic therapy
• Patients who are unable or unwilling to comply with the requirements of the protocol per investigator assessment are not eligible

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Sara Tolaney, MD; 617-632-2335; Sara_Tolaney@dfci.harvard.edu

Contact: Laura Hoffman; 773-834-2546; lhoffman22@bsd.uchicago.edu

• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT05812807
• Other Study ID Numbers: A012103; NCI-2022-07859 ( Other Identifier: NCI Clinical Trial Reporting Program )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)
• Investigators: Not Provided
• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: April 2024