Clinical Trials /

Breast Cancer Study of Preoperative Pembrolizumab + Radiation

NCT03366844

Description:

This study is being done to assess the feasibility of pembrolizumab (study drug) combined with standard radiation to the tumor (tumor boost) before patients undergo standard treatment that can consist of one or more of the following: breast-conserving surgery, radiation to the entire breast/chest wall after surgery, and chemotherapy. Study participants will receive two doses of the study drug intravenously (through the vein) before their planned breast surgery or chemotherapy. The study drug will be administered three weeks apart. At the time of the second dose, radiation to the tumor in the affected breast will be given. This type of radiation treatment is called a "tumor boost", which is a standard part of radiation therapy for breast cancer that may occur either before or after planned breast-conserving surgery. Patients will receive breast surgery or begin chemotherapy approximately six weeks after your first dose of the study drug.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Breast Cancer Study of Preoperative Pembrolizumab + Radiation
  • Official Title: Preoperative Combination of Pembrolizumab and Radiation Therapy in Patients With Operable Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: IIT2017-07-HO-PembroRT
  • NCT ID: NCT03366844

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, MK-3475Pembrolizumab with RT Boost

Purpose

This study is being done to assess the feasibility of pembrolizumab (study drug) combined with standard radiation to the tumor (tumor boost) before patients undergo standard treatment that can consist of one or more of the following: breast-conserving surgery, radiation to the entire breast/chest wall after surgery, and chemotherapy. Study participants will receive two doses of the study drug intravenously (through the vein) before their planned breast surgery or chemotherapy. The study drug will be administered three weeks apart. At the time of the second dose, radiation to the tumor in the affected breast will be given. This type of radiation treatment is called a "tumor boost", which is a standard part of radiation therapy for breast cancer that may occur either before or after planned breast-conserving surgery. Patients will receive breast surgery or begin chemotherapy approximately six weeks after your first dose of the study drug.

Detailed Description

      With more than 1 million new cases diagnosed yearly worldwide, breast cancer is a global
      public health burden. Over the past decade, molecular subtyping of breast cancer has
      identified intrinsic subtypes that may be at enhanced risk for both local and distant
      recurrence. This study focuses on the immunogenicity of high-risk breast cancer subtypes that
      are likely to display a dense lymphocytic infiltration including including TNBC and HR+/HER2-
      tumors.

      Immune build up via immune co-stimulatory molecules permits the ensuing immune response to
      strengthen and destroy cancer systemically. Thus, the effect of the anti-tumor immune
      response initiated by the radiation to an intact tumor by combination with checkpoint
      blockade is increased.

      Pembrolizumab is an optimal immunotherapy agent to study, as this agent has recently been FDA
      approved for use in multiple tumor types. It is therefore ready to be tested for efficacy in
      other disease sites and in combination with other treatments.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab with RT BoostExperimentalStudy drug plus "tumor boost" before standard of care treatment
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Confirmed histologic diagnosis of invasive adenocarcinoma of the breast, and

          -  ER, PR and HER2 testing (on outside or Cedars-Sinai biopsy report), and

               -  High-risk, ER-positive and HER2-negative breast cancer patients. ER-positive
                  disease is defined as ER>10%, any PR and HER2-negative by ASCO CAP guidelines.
                  High-risk disease will be defined by the presence of at least 2 of the following
                  3 criteria: histologic grade II-III, Ki-67 > 20%, ER expression < 75% by IHC)

               -  TNBC patients (defined as ER<10%, PR<10%, HER2-neu 0-1+ by IHC or FISH-negative;
                  or as per MD discretion)

          -  Operable tumor measuring ≥2 cm in maximal diameter as measured by any available
             standard of care imaging (mammogram, breast ultrasound, breast MRI)

          -  Any nodal status

          -  Multifocal disease is permitted; largest focus must measure ≥2 cm

          -  Synchronous bilateral invasive breast cancer is permitted

          -  No indication of distant metastases

          -  Breast-conserving therapy is planned

          -  Tumor amenable to preoperative radiation therapy boost as determined by radiation
             oncologist

          -  ECOG performance status score of 0 or 1

          -  Screening laboratory values must meet the following criteria:

             i. White blood cells (WBCs) ≥ 2000/μL ii. Absolute neutrophil count (ANC) ≥ 1500/μL
             iii. Platelets ≥ 100 x 103/μL iv. Hemoglobin ≥ 11.0 g/dL v. Serum creatinine ≤ 2 mg/dL
             (or glomerular filtration rate ≥ 40 ml/min) vi. AST ≤ 2.5 x upper limit of normal
             (ULN) vii. ALT ≤ 2.5 x ULN viii. Total bilirubin within normal limits (except subjects
             with Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL) ix. INR ≤ 1.5 x
             ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is
             within therapeutic range of intended use of anticoagulant(s) x. Negative HIV screening
             test xi. 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 be using an acceptable method of
             contraception to avoid pregnancy throughout the study and for at least 4 months after
             the last dose of pembrolizumab in such a manner that the risk of pregnancy is
             minimized.

          -  WOCBP must have a negative serum pregnancy test within 14 days prior to the first dose
             of pembrolizumab.

          -  Women must not be breastfeeding.

          -  Willingness to adhere to the study visit schedule and the prohibitions and
             restrictions specified in this protocol.

          -  Willingness to undergo mandatory Week 4 research biopsy

          -  Written informed consent obtained from subject and ability for subject to comply with
             the requirements of the study.

        Exclusion Criteria:

          -  HER2-positive breast cancer defined as IHC3+ or IHC2+ with FISH>2 AND copy number >4
             OR FISH <2 AND copy number >6

          -  Inflammatory breast cancer

          -  Contraindication(s) to breast-conserving therapy

          -  Contraindication to radiation therapy or planned partial breast irradiation

          -  Patients with cosmetic breast augmentations, specifically sub glandular implants with
             altered breast tissue, at the time of diagnosis

          -  Evidence of metastatic disease.

          -  Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
             dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.

          -  Known additional malignancy that is progressing or has required active treatment
             within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer in situ) that have undergone potentially curative therapy are not
             excluded.

          -  Medical history and concurrent diseases

               -  Active 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 (eg., thyroxine, insulin, or
                  physiologic corticosteroid replacement therapy for adrenal or pituitary
                  insufficiency, etc.) is not considered a form of systemic treatment.

               -  History of (non-infectious) pneumonitis that required steroids or has current
                  pneumonitis.

               -  Active infection requiring systemic therapy.

               -  Any serious or uncontrolled medical disorder that, in the opinion of the
                  investigator, may increase the risk associated with study participation or study
                  drug administration, impair the ability of the subject to receive protocol
                  therapy, or interfere with the interpretation of study results.

               -  Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

               -  Known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C
                  (e.g., HCV RNA [qualitative] is detected).

          -  Prohibited Treatments and/or Therapies

               -  Chronic use of immunosuppressants and/or systemic corticosteroids (used in the
                  management of cancer or non-cancer-related illnesses). However, use of
                  corticosteroids is allowed for the treatment of immune related Adverse Events
                  (irAEs), or adrenal insufficiency.

               -  Live vaccines within 30 days prior to the first dose of study treatment and while
                  participating in the study. Examples of live vaccines include, but are not
                  limited to, the following: measles, mumps, rubella, varicella/zoster, yellow
                  fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for
                  injection are generally killed virus vaccines and are allowed; however,
                  intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are
                  not allowed.

               -  Prior treatment with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an
                  agent directed to another stimulatory or co-inhibitory T-cell receptor (eg,
                  CTLA-4, OX 40, CD137)

               -  Prior systemic anti-cancer therapy including investigational agents within 4
                  weeks prior to study start. Note: Participants must have recovered from all AEs
                  due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2
                  neuropathy may be eligible. Note: If participant received major surgery, they
                  must have recovered adequately from the toxicity and/or complications from the
                  intervention prior to starting study treatment.

               -  Prior radiotherapy within 2 weeks of start of study treatment to sites outside
                  the breast. Participants must have recovered from all radiation-related
                  toxicities, not require corticosteroids, and not have had radiation pneumonitis.

               -  Currently participating in or has participated in a study of an investigational
                  agent or has used an investigational device within 4 weeks prior to the first
                  dose of study treatment. Note: Participants who have entered the follow-up phase
                  of an investigational study may participate as long as it has been 4 weeks after
                  the last dose of the previous investigational agent.

          -  For subjects who agree to the research breast MRI sub-study: Four or more previous
             gadolinium contrast scans due to the risk of brain deposits following repeated use of
             gadolinium-based contrast agents.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients who do not necessitate a delay in standard of care treatment after receiving the investigational combination of preoperative Pembrolizumab and radiation
Time Frame:8 weeks after trial initiation
Safety Issue:
Description:Feasibility of preoperative radiation and Pembrolizumab in newly diagnosed, non-metastatic patients with triple negative breast cancer.

Secondary Outcome Measures

Measure:Pembrolizumab-related adverse events
Time Frame:15 weeks after trial initiation
Safety Issue:
Description:Treatment toxicities
Measure:Immune-related adverse events
Time Frame:One year post treatment
Safety Issue:
Description:Treatment toxicities
Measure:Invasive disease-free survival after preoperative radiation and Pembrolizumab
Time Frame:From treatment start date until date of documented recurrence or death from breast cancer, assessed up to 19 weeks after start of treatment
Safety Issue:
Description:Disease-free survival, as described from time from occurrence of surgery to time from first recurrence from or death from breast cancer
Measure:Pathological complete response rate
Time Frame:From treatment start date until the time of curative-intent surgery, approximately 8 weeks.
Safety Issue:
Description:Absence of invasive disease in the breast and lymph nodes at the time of curative-intent surgery.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Stephen Shiao

Trial Keywords

  • invasive adenocarcinoma of the breast
  • ER-positive and HER2-negative breast cancer
  • Triple negative breast cancer (TNBC)
  • immunotherapy
  • checkpoint inhibitor
  • HR-positive

Last Updated

April 21, 2021