Pre-op Pembro + Radiation Therapy in Breast Cancer (P-RAD)

  • STATUS
    Recruiting
  • End date
    Dec 1, 2023
  • participants needed
    120
  • sponsor
    Alice Ho
Updated on 25 March 2022
paclitaxel
cyclophosphamide
doxorubicin
carboplatin
capecitabine
HER2
triple negative breast cancer
erbb2
invasive breast cancer
mastectomy
breast-conserving surgery
mammogram
magnetic resonance imaging of breast
her2/neu-negative breast cancer
adriamycin

Summary

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)

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 treatment that can consist of one or more of the following:

  • Pembrolizumab (optional, per MD discretion)
  • Standard of Care Treatment
  • 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 (optional Capecitabine for TNBC patients)
  • 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 13 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, Cyclophosphamide, Carboplatin, Capecitabine).

Details
Condition Triple Negative Breast Cancer, Hormone Receptor Positive (HR+), HER2-negative Breast Cancer, Biopsy-proven, Positive Lymph Node(s)
Treatment Capecitabine, cyclophosphamide, carboplatin, Paclitaxel, Pembrolizumab, doxorubicin, Radiation Therapy Boost, Radiation Therapy Boost
Clinical Study IdentifierNCT04443348
SponsorAlice Ho
Last Modified on25 March 2022

Eligibility

Yes No Not Sure

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 ≥1.0 cm in maximum diameter and axillary node-positive breast cancer
Primary breast tumor measuring ≥1.5 cm in maximal diameter as measured by any
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
available standard of care imaging (mammogram, breast ultrasound, breast MRI)
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
\--Note: For patients with multifocal disease and are randomized to receive a
preoperative RT boost, all sites of multifocal disease should be contained
within the pre-operative boost volume. Subsequently, these patients will not
need a post-op boost
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
Renal
Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
\--- 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
Hepatic
participant with creatinine levels >1.5 × institutional ULN
Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
Coagulation
AST (SGOT) and ALT (SGPT) ≤2.5 × ULN
International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT)
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
≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
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
\-- a) Not a woman of childbearing potential (WOCBP) OR b) A WOCBP who agrees
treatment; laboratory value requirements should be adapted according to local
to follow the contraceptive guidance throughout the study and for at least 4
regulations and guidelines for the administration of specific chemotherapies
months after the last dose of pembrolizumab in such a manner that the risk of
A female participant is eligible to participate if she is not pregnant, not
pregnancy is minimized
breastfeeding, and at least one of the following conditions applies
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

Inflammatory (cT4d) breast cancer
Metastatic breast cancer (M1)
Contraindication(s) to breast-conserving therapy or mastectomy
Contraindication to radiation therapy including: prior ipsilateral breast or mantle RT, active scleroderma, systemic lupus erythematosis and pregnancy
HER2-positive breast cancer by ASCO/CAP guidelines (HER2 IHC 3+ or ≥ 2.2 HER2/CEP17 ratio by FISH)
\--Note: All cardiac implantable electronic devices are permitted, provided
that methods to assess radiation doses and minimize damage to the devices
during RT is planned, per institutional guidelines
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
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
therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may
be eligible. If participant received major surgery, she/he must have recovered
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). Note: Testing for hepatitis B or hepatitis C is not required, unless mandated by local health authorities or institutional guidelines
Has known severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
Has had an allogenic tissue/solid organ transplant
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
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
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)
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
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent permitted
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