Clinical Trials /

Pre-op Pembro + Radiation Therapy in Breast Cancer

NCT04443348

Description:

This research trial is studying a combination of neoadjuvant radiotherapy (RT), immunotherapy (pembrolizumab) and chemotherapy for lymph node-positive, triple negative (TN) or hormone receptor positive/HER2-negative breast cancer. The names of the study interventions involved in this study are: - Radiation Therapy (RT) - Immunotherapy: Pembrolizumab (MK-3475) - Chemotherapies: - Paclitaxel - Doxorubicin (also called Adriamycin) - Cyclophosphamide - Carboplatin (optional, and in TN only) - Capecitabine (optional, and in TN only)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pre-op Pembro + Radiation Therapy in Breast Cancer
  • Official Title: P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 20-157
  • NCT ID: NCT04443348

Conditions

  • Triple Negative Breast Cancer
  • Hormone Receptor Positive (HR+), HER2-negative Breast Cancer
  • Biopsy-proven, Positive Lymph Node(s)

Interventions

DrugSynonymsArms
PembrolizumabKeytruda®.Group A (No RT Boost)
PaclitaxelTaxolGroup A (No RT Boost)
CarboplatinParaplatinGroup A (No RT Boost)
CyclophosphamideCytophosphaneGroup A (No RT Boost)
DoxorubicinAdriamycinGroup A (No RT Boost)

Purpose

This research trial is studying a combination of neoadjuvant radiotherapy (RT), immunotherapy (pembrolizumab) and chemotherapy for lymph node-positive, triple negative (TN) or hormone receptor positive/HER2-negative breast cancer. The names of the study interventions involved in this study are: - Radiation Therapy (RT) - Immunotherapy: Pembrolizumab (MK-3475) - Chemotherapies: - Paclitaxel - Doxorubicin (also called Adriamycin) - Cyclophosphamide - Carboplatin (optional, and in TN only)

Detailed Description

      The main purpose of this study is to find out what is the best dose of preoperative RT when
      combined with pembrolizumab and chemotherapy. The study will assess if combining the RT with
      the immunotherapy agent, pembrolizumab, will increase the ability of the immune system to
      destroy cancer cells.

      The research study procedures include: screening for eligibility and study treatment,
      including evaluations and follow-up visits.

      The study aims to assess the effectiveness of pembrolizumab (study drug) with or without RT
      directed to the breast tumor. Participants will then undergo neoadjuvant chemotherapy with
      pembrolizumab, followed by standard of-care treatment that can consist of one or more of the
      following:

        -  Breast surgery (lumpectomy or mastectomy) and axillary surgery

        -  Adjuvant radiation to the entire breast or chest wall, plus or minus the lymph nodes
           after surgery

        -  Adjuvant chemotherapy

        -  Hormone therapy

      Participants will be randomized to 1 of 3 groups. Neither the participant not the research
      doctor will choose the group that the participant is assigned to. However, the participant
      will be notified of the group prior to the start of study treatment. Participants will
      receive study treatment for up to 7 months. Participants will be followed for 2 years after
      the end of the study treatment.

      It is expected that a total of 120 people will be participating in total.

      This research study is a randomized, phase II study. The U.S. Food and Drug Administration
      (FDA) has not approved pembrolizumab for your specific disease, but it has been approved for
      other uses. The U.S. Food and Drug Administration (FDA) has approved the chemotherapies being
      used in this study (Paclitaxel, Doxorubicin,
    

Trial Arms

NameTypeDescriptionInterventions
Group A (No RT Boost)ExperimentalNo RT plus pembrolizumab for 1 cycle, followed by pembrolizumab plus paclitaxel+/- carboplatin, doxorubicin and cyclophosphamide chemotherapy for 8 cycles. There will be a total of 9 cycles of pembrolizumab.
  • Pembrolizumab
  • Paclitaxel
  • Carboplatin
  • Cyclophosphamide
  • Doxorubicin
Group B (Low Dose RT Boost)ExperimentalLow-dose RT plus pembrolizumab for 1 cycle, followed by pembrolizumab plus paclitaxel+/- carboplatin, doxorubicin and cyclophosphamide chemotherapy for 8 cycles. There will be a total of 9 cycles of pembrolizumab pre-operatively.
  • Pembrolizumab
  • Paclitaxel
  • Carboplatin
  • Cyclophosphamide
  • Doxorubicin
Group C (High Dose RT Boost)ExperimentalHigh-dose RT plus pembrolizumab for 1 cycle, followed by pembrolizumab plus paclitaxel+/- carboplatin, doxorubicin and cyclophosphamide chemotherapy for 8 cycles. There will be a total of 9 cycles of pembrolizumab.
  • Pembrolizumab
  • Paclitaxel
  • Carboplatin
  • Cyclophosphamide
  • Doxorubicin

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥18 years old

          -  Participant has non-metastatic, T1*-T2 and N1-3 and one of the following
             histologically confirmed disease subtypes:

               -  Triple negative breast cancer is defined as ER-negative (<1% cells), PR-negative
                  (<1% cells) and HER2-negative (<2+ HER2 IHC or <2.2 HER2/CEP17 ratio by FISH), as
                  per testing at local institution

               -  High-risk HR+/HER2-negative breast cancer is defined as ER≥1%, HER2-negative (<2+
                  Her2 IHC or <2.2 HER2/CEP17 ratio by FISH) and either histologic grade II-III or
                  a high-risk genomic assay score (Oncotype RS>25, high risk Mammaprint, PAM-50,
                  EndoPredict or ProSigna score).

               -  Note: Eligibility requires primary tumor size ≥1.5 cm in maximum diameter and
                  axillary node-positive breast cancer

          -  Primary breast tumor measuring ≥1.5 cm in maximal diameter as measured by any
             available standard of care imaging (mammogram, breast ultrasound, breast MRI).

          -  Biopsy-proven, axillary lymph node-positive breast cancer at diagnosis. Note:
             Clinically node-positive disease is classified as cN1-3. cN1: without matted nodes,
             even if several/multiple appear matted on ultrasound or MRI; cN2: clinically fixed or
             matted nodes on examination or clinically or imaging-detected internal mammary node
             involvement.

          -  Clips or fiducial placement within the biopsy-proven axillary lymph node and breast
             primary tumor are required.

          -  Multifocal and multicentric disease is permitted; however only one breast tumor may be
             preoperatively boosted.

          -  Synchronous bilateral invasive breast cancer is permitted; however only one breast
             tumor may be preoperatively boosted.

          -  No indication of distant metastases. Staging scans are not required and are per the
             discretion of the treating physician.

          -  Neoadjuvant chemotherapy (NAC) with paclitaxel, dose-dense doxorubicin and
             cyclophosphamide (dd AC) is planned. Note: For TNBC patients, administration of
             carboplatin is optional, as per MD choice. For HR+ patients, carboplatin will not be
             administered.

          -  The boost volume is determined to be able to meet study dose constraints by the
             treating radiation oncologist.

          -  Breast-conserving surgery or mastectomy +/- reconstruction is planned following NAC.

          -  ECOG performance status score of 0 or 1.

          -  Have adequate organ function as defined in the following table. Bloodwork must be
             collected within 10 days prior to the start of study treatment.

               -  Hematological

                    -  Absolute neutrophil count (ANC) ≥1500/µL

                    -  Platelets ≥100 000/µL

                    -  Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

               -  Renal

                  --- Creatinine ≤1.5 × ULN OR Measured or calculated b creatinine clearance (GFR
                  can also be used in place of creatinine or CrCl) OR ≥30 mL/min for participant
                  with creatinine levels >1.5 × institutional ULN

               -  Hepatic

                    -  Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with
                       total bilirubin levels >1.5 × ULN

                    -  AST (SGOT) and ALT (SGPT) ≤2.5 × ULN

               -  Coagulation

                    -  International normalized ratio (INR) OR prothrombin time (PT) Activated
                       partial thromboplastin time (aPTT)

                    -  ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as
                       PT or aPTT is within therapeutic range of intended use of anticoagulants

                    -  ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);
                       AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic
                       transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

                    -  Criteria must be met without erythropoietin dependency and without packed
                       red blood cell (pRBC) transfusion within last 2 weeks.

                    -  Creatinine clearance (CrCl) should be calculated per institutional standard.

               -  Note: This table includes eligibility-defining laboratory value requirements for
                  treatment; laboratory value requirements should be adapted according to local
                  regulations and guidelines for the administration of specific chemotherapies.

          -  A female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and at least one of the following conditions applies:

             -- a) Not a woman of childbearing potential (WOCBP) OR b) A WOCBP who agrees to follow
             the contraceptive guidance 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.

          -  A male participant must agree to use a contraception as detailed in Appendix A of this
             protocol during the treatment period and for at least 4 months after the last dose of
             after the last dose of study treatment and refrain from donating sperm during this
             period.

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

          -  Willingness to undergo mandatory research biopsy of the breast tumor between weeks 2-3
             of Cycle 1.

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

          -  Patients unable to read/write English are eligible to participate in the overall
             study, but will not be required to participate in the Patient-Reported Outcome
             questionnaires.

        Exclusion Criteria:

          -  HER2-positive breast cancer by ASCO/CAP guidelines (HER2 IHC 3+ or ≥ 2.2 HER2/CEP17
             ratio by FISH)

          -  Inflammatory (cT4d) breast cancer

          -  Metastatic breast cancer (M1)

          -  Contraindication(s) to breast-conserving therapy or mastectomy

          -  Contraindication to radiation therapy

          -  Prior ipsilateral breast, chest wall or thoracic radiotherapy

          -  Prior ipsilateral invasive breast cancer, contralateral breast cancer or a known
             additional, invasive malignancy that is progressing or required active treatment in
             the last 5 years.

        Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the
        skin or cervical carcinoma in situ that has undergone potentially curative therapy and a
        previous diagnosis of ductal carcinoma in situ are not excluded.

          -  Has a known history of active tuberculosis (Bacillus tuberculosis

          -  Has received prior therapy 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).

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to randomization.

        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. If participant
        received major surgery, she/he must have recovered adequately from the toxicity and/or
        complications from the intervention prior to starting study treatment.

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  Participants with active, known or suspected autoimmune disease. Participants with
             vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
             condition only requiring hormone replacement, psoriasis not requiring systemic
             treatment, or conditions not expected to recur in the absence of an external trigger
             are permitted to enroll.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Known history of Human Immunodeficiency Virus (HIV).Note: No HIV testing is required
             unless mandated by local health authorities.

          -  Known active Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or
             known active hepatitis C virus (defined as HCV RNA [qualitative] is detected)
             infection. (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is
             detected). Note: Testing for hepatitis B or hepatitis C is not required, unless
             mandated by local health authorities or institutional guidelines.

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.

          -  A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose
             of study treatment (see Appendix A). If the urine test cannot be confirmed as
             negative, a serum pregnancy test is required. In such cases, the participant must be
             excluded from participation if the serum pregnancy result is positive.

          -  Prohibited Treatments and/or Therapies:Use of immunosuppressants and/or systemic
             corticosteroids is exclusionary, except the following in the absence of active
             autoimmune disease:

               -  As premedication for chemotherapy

               -  For the prevention of nausea in the three days following chemotherapy

               -  Participants are permitted the use of corticosteroids with minimal systemic
                  absorption (e.g. topical, ocular, intra-articular, intranasal and inhaled)

               -  Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
                  equivalent permitted

               -  Adrenal replacement steroid doses including doses >10 mg daily prednisone is
                  permitted

               -  A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT
                  scan premedication against contrast dye allergy) or for treatment of
                  non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by
                  a contact allergen is permitted (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.

               -  Any non-oncology vaccine therapy used for prevention of infectious diseases
                  within 4 weeks prior to first dose of pembrolizumab.

               -  Prior treatment with pembrolizumab or other anti-PD-1 and anti-PD-L1 antibodies
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tumor Infiltrating Lymphocytes (TILs; CD3+/CD8+ T-cell Breast Immunoscore)
Time Frame:14 through 21 Days
Safety Issue:
Description:Quantitative immunofluorescence in post-treatment tumor biopsy samples collected on day 14-21 of C1 of Pembrolizumab.

Secondary Outcome Measures

Measure:Residual Cancer Burden (RCB) score
Time Frame:24 Weeks
Safety Issue:
Description:RCB is a measure of residual cancer burden in the breast and regional lymph nodes at the time of definitive surgery following completion of neoadjuvant systemic therapy.
Measure:Pathologic response rate
Time Frame:24 Weeks
Safety Issue:
Description:Pathologic response rate is measured by the presence or absence of residual cancer cells in all sampled regional lymph nodes. RCB measures residual disease in the breast and lymph nodes at the time of definitive surgery. CD3+/CD8+ T cell Breast Immunoscore greater than 75% versus patients with Post-treatment CD3+/CD8+ T cell Breast Immunoscore less than or equal to 75%.
Measure:Percent change in pre- versus post-treatment intra-tumoral TILs
Time Frame:24 Weeks
Safety Issue:
Description:Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
Measure:Percent changes in pre- versus post-treatment peri-tumoral
Time Frame:24 Weeks
Safety Issue:
Description:Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
Measure:Percent changes in pre- versus post-treatment stromal CD3+ or CD8+ T cell
Time Frame:24 Weeks
Safety Issue:
Description:Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
Measure:Change in TIL counts by H&E in pre-treatment versus post-RT boost tumor biopsy
Time Frame:24 Weeks
Safety Issue:
Description:TIL counts by H&E in pre-treatment versus post-RT boost tumor biopsy specimens in each RT dose and breast cancer subtype cohort. H&E will be performed according to Salgado Criteria [1].
Measure:Changes in PD-L1 expression
Time Frame:24 Weeks
Safety Issue:
Description:To quantify changes in PD-L1 expression levels after treatment with Pembro + no, low or high RT boost (at the time of the time of interval biopsy). QIF for PD-L1 will be performed in pre- and post-treatment FFPE tumor biopsy samples.
Measure:Changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities
Time Frame:24 Weeks
Safety Issue:
Description:To quantify changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities in response to treatment with preoperative Pembro + no, low, or high dose RT boost (at the time of interval biopsy). QIF for CD4 and Foxp3 will be performed in pre- and post-treatment FFPE tumor biopsy samples. Pan-cytokeratin staining will be used to identify tumor regions
Measure:Number of Participants with Treatment Related Adverse Events as Assessed NCI CTCAE version 5.0
Time Frame:Baseline up 6 months post surgery up to 13 months
Safety Issue:
Description:NCI CTCAE version 5.0
Measure:Invasive disease-free survival
Time Frame:time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer up to 31 months
Safety Issue:
Description:iDFS is defined as time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer.
Measure:Symptomatic Improvement
Time Frame:baseline to 21 Weeks
Safety Issue:
Description:PROMIS Global Health Measure Quality of life (e.g., global, physical, mental, and social health) outcomes will be measured by two PROMIS (Patient-Reported Outcomes Measurement Information System) short forms consisting of 4 questions total. This instrument has demonstrated content-validity, cross-sectional validity, and responsiveness to change in numerous publications[93].
Measure:Change in Symptoms and Satisfaction with Treatment
Time Frame:baseline to Week 3
Safety Issue:
Description:(Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life
Measure:Change in Symptoms and Satisfaction with Treatment
Time Frame:baseline to week 21
Safety Issue:
Description:(Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life
Measure:Change Patient Reported Outcomes
Time Frame:3 years
Safety Issue:
Description:PRO-CTCAE will evaluate symptom burden in the previous week using a Likert scale to assess presence/absence, frequency, severity and/or interference for different symptoms. Each symptom will be presented descriptively, using summary statistics and graphical representations across time points.
Measure:Financial Burden
Time Frame:3 to 6 wks after last dose in the Neoadjuvant Period up to 8 Months
Safety Issue:
Description:recently coined term used to describe the potential financial burden patients experience while receiving medical care. Two questions were adapted from the National Health Interview Survey[95] and a survey administered to caregivers of participants of the Cancer Car Outcomes Research and Surveillance (CanCORS) study[96] to assess financial burden and impact on employment-related metrics (e.g., sick leave, unpaid time off work). Financial burden will be assessed at the post-surgery visit.
Measure:Trial Satisfaction
Time Frame:3 to 6 wks after last dose in the Neoadjuvant Period up to 8 Months
Safety Issue:
Description:The Was It Worth It (WIWI) instrument, also called the "Trial Satisfaction" survey, was developed to investigate the patient experience on clinical trials. Multiple cooperative group studies have utilized this instrument at the completion of treatment to measure patient satisfaction relating to clinical trial enrollment, although formal validity and reliability data is not yet available[

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Alice Ho

Trial Keywords

  • Triple Negative Breast Cancer
  • Hormone Receptor Positive breast cancer
  • Estrogen Receptor Positive breast cancer

Last Updated

June 19, 2020