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A Randomized Phase II Study of Pembrolizumab, an Anti-PD (Programmed Cell Death)-1 Antibody, in Combination With Carboplatin Compared to Carboplatin Alone in Breast Cancer Patients With Chest Wall Disease

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ClinicalTrials.gov Identifier: NCT03095352
Recruitment Status : Recruiting
First Posted : March 29, 2017
Last Update Posted : November 22, 2018
Sponsor:
Collaborators:
Mayo Clinic
Johns Hopkins University
Translational Breast Cancer Research Consortium
Massachusetts General Hospital
Information provided by (Responsible Party):
Hope Rugo, MD, University of California, San Francisco

Brief Summary:
This is a phase II multicenter study including breast cancer patients with chest wall disease that is hormone resistant (estrogen receptor (ER) positive/progesterone receptor (PR) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer with progressive disease on 2 prior lines of hormonal therapy) or triple negative (ER negative/PR negative/HER2 negative, TNBC). Eighty-four patients will be enrolled at Translational Breast Cancer Research Consortium (TBCRC) sites and will be randomized 2:1 to receive treatment with pembrolizumab and carboplatin (n=56, Arm A) or carboplatin alone (n=28, Arm B) until documented disease progression. Patients randomized to Arm B may cross-over following progression to pembrolizumab alone (Arm Bx). Patients may have received any number of prior lines of chemotherapy. Patients in Arm A will be treated with pembrolizumab 200 mg IV and carboplatin area under curve (AUC) 5 IV every 3 weeks for at least 6 cycles followed by maintenance pembrolizumab 200 mg IV every 3 weeks if stable or responding disease. Patients in Arm B will be treated with carboplatin AUC 5 IV every 3 weeks until progression, whereupon they may cross-over to pembrolizumab 200 mg IV every 3 weeks alone (Arm Bx). An interim analysis for futility will be performed after 18 patients are enrolled into Arm B to allow early stopping of that trial arm for lack of efficacy. The primary endpoint is to compare disease control rates at 18 weeks of treatment. Secondary endpoints include progression free survival, toxicity, and overall response rate.

Condition or disease Intervention/treatment Phase
Breast Cancer Chest Wall Disease Biological: Pembrolizumab Drug: Carboplatin Biological: Trastuzumab Phase 2

Detailed Description:
There will be a companion translational study operating concurrently with the study described above. In this study, biomarker research to be performed on tumor biopsies and peripheral blood samples will be performed to explore the immunologic and genomic mechanism of action underlying treatment with pembrolizumab and carboplatin versus carboplatin alone. This protocol includes tissue and blood correlative exploratory endpoints including changes in tumor PD-L1 (programmed death ligand 1) gene expression, tumor and peripheral blood immune composition and cytokine expression, plasma tumor DNA, circulating tumor cells, and tumor myelocytomatosis (MYC) oncogene expression using tumor biopsy and peripheral blood testing before and after treatment; correlations with these markers and disease control rate will be assessed.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Pembrolizumab, an Anti-PD (Programmed Cell Death)-1 Antibody, in Combination With Carboplatin Compared to Carboplatin Alone in Breast Cancer Patients With Chest Wall Disease
Actual Study Start Date : September 9, 2017
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : September 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Arm A
Arm A: Patients receive carboplatin intravenously (IV) and pembrolizumab IV over 30 minutes on day 1. Patients who are HER2+ also receive trastuzumab IV every 3 weeks. Treatment repeats every 3 weeks for a least 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 cycles of carboplatin and pembrolizumab, patients then receive pembrolizumab alone on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity
Biological: Pembrolizumab
200 mg Given IV

Drug: Carboplatin
Arm A: AUC 5 IV every 3 weeks Arm B: AUC 5 IV every 3 weeks
Other Name: Ribocarbo

Biological: Trastuzumab
For HER2+ patients: IV every 3 weeks using standard approved dosing

Experimental: Arm B
Arm B: Patients receive carboplatin IV on day 1. Patients who are HER2+ also receive trastuzumab IV every 3 weeks. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with disease progression then receive pembrolizumab IV over 30 minutes on day 1 in the cross over (Arm Bx). Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Carboplatin
Arm A: AUC 5 IV every 3 weeks Arm B: AUC 5 IV every 3 weeks
Other Name: Ribocarbo

Biological: Trastuzumab
For HER2+ patients: IV every 3 weeks using standard approved dosing




Primary Outcome Measures :
  1. Disease control rate [ Time Frame: From the baseline until the chest wall disease progression or death from any cause, assessed at 18 months ]
    Disease control will also be based on PD-L1 expression via immunohistochemistry

  2. Objective response rate (ORR) defined as complete response (CR)/partial response (PR) assessed by RECIST [ Time Frame: Up to 18 months ]
    Will be summarized by treatment arms using the Kaplan-Meier method


Secondary Outcome Measures :
  1. Progression free survival [ Time Frame: Up to 18 months ]
    Will be summarized by treatment arms using the Kaplan-Meier method

  2. ORR defined as CR/PR assessed by immune-related (ir)RECIST [ Time Frame: Up to 18 months ]
    Will be summarized by treatment arms using the Kaplan-Meier method



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Advanced breast cancer with locally recurrent chest wall disease not amenable to surgical excision.

    1. Distant sites of disease are allowed
    2. Prior radiation to the chest wall is not required
  2. The following disease subtypes are eligible:

    1. Triple negative disease (defined as ER < 10%, PR < 10%, HER2 negative)
    2. Hormone receptor positive, HER2 negative disease with evidence of progression on at least two prior lines of hormone therapy. HER2 positive disease with c. evidence of disease progression on trastuzumab, pertuzumab, ado trastuzumab emtansine (T-DM1) and oral tyrosine kinase inhibitor unless contraindicated with no other HER2 targeted therapy options available (patients in this category will be classified by ER status).

    i. Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH) or fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) methodology using standard criteria.

    ii. Cardiac function must be determined within 4 weeks of study entry to be >= institutional lower limit of normal (LLN) using echo or multiple gated acquisition scan (MUGA)

  3. Any number of prior lines of therapy are allowed

    a. Prior platinum based therapy is allowed in the following settings: i. Treatment in the neoadjuvant and/or adjuvant setting without clear progression of disease ii. Treatment in the metastatic setting without clear progression of disease.

  4. At least two weeks from last systemic therapy for breast cancer, with recovery of all treatment related toxicity to grade 1 or less. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion.
  5. At least two weeks from last radiation therapy, with recovery of all treatment related toxicity to grade 1 or less (excluding alopecia).
  6. Prior CNS disease is allowed if stable for at least one month since whole brain radiation therapy, and 2 weeks since stereotactic radiotherapy, and not requiring steroids. Patients whose CNS disease was surgically treated may be enrolled if stable for at least one month, and not requiring steroids.
  7. Able to provide tissue from a newly obtained core or excisional biopsy of a chest wall tumor lesion. Newly-obtained is defined as a specimen any time after the last systemic or local therapy utilized to treat the disease. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor
  8. Willing and able to provide written informed consent.
  9. Greater than or equal to18 years of age on day of signing informed consent.
  10. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2
  11. Adequate organ function as defined in Table 1 within 10 days of treatment initiation.

    Table 1 Adequate Organ Function Laboratory Values

    Hematological Absolute neutrophil count (ANC) ≥1,000 /microliter (mcL)

    Platelets ≥100,000 / mcL

    Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

    Renal Serum creatinine OR Measured or calculated* creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN

    Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

    Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

    Albumin >2.5 mg/dL

    Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

    Activated Partial Thromboplastin Time (aPTT)

    ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

    *Creatinine clearance should be calculated per institutional standard.

  12. Female subjects of childbearing potential should have a negative urine or serum pregnancy 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 serum pregnancy test will be required.
  13. Female subjects of childbearing potential should be willing to use an acceptable form of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  14. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

  1. Treatment with an investigational agent within 4 weeks of the first dose of treatment.
  2. A diagnosis of immunodeficiency or is currently receiving systemic steroid therapy at any dose or is receiving any other form of immunosuppressive therapy. Steroid therapy is not allowed within 7 days prior to the first dose of trial treatment. However, topical and intranasal corticosteroids are allowed, and not an exclusion for participation.
  3. Known active TB (Bacillus Tuberculosis). Patients with a distant history of tuberculosis that was appropriately treated and have no evidence of active infection are eligible to participate. Patients with a history of latent tuberculosis that was appropriately treated are also eligible to participate.
  4. Hypersensitivity to pembrolizumab or any of its excipients.
  5. Hypersensitivity to carboplatin or cisplatin
  6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

    • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion.
    • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
  9. Has 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  10. Have history of/active pneumonitis requiring treatment with steroids or history of/active interstitial lung disease.
  11. Has an active infection requiring systemic therapy.
  12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has been on any prior Merck MK-3475 (pembrolizumab) studies.
  16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  17. Has known active Hepatitis B virus (e.g., HBsAg reactive) or Hepatitis C virus (e.g., HCV RNA [qualitative] is detected).
  18. Has received a live vaccine within 30 days of planned start of study therapy.

Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03095352


Contacts
Contact: Christina Chun 415-885-7820 christina.chun@ucsf.edu
Contact: Amy DeLuca 415-353-7288 Amy.Deluca@ucsf.edu

Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94143
Contact: Ivy Wong    415-353-7873    Ivy.Wong@ucsf.edu   
Principal Investigator: Hope Rugo, M.D.         
United States, District of Columbia
Georgetown University Hospital Not yet recruiting
Washington, District of Columbia, United States, 20007
Contact: Paula Pohlmann, M.D., M.Sc., Ph.D.       Paula.R.Pohlmann@gunet.georgetown.edu   
Principal Investigator: Paula Pohlman, M.D., M.Sc., Ph.D.         
United States, Illinois
University of Chicago Comprehensive Cancer Center Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Rita Nanda, M.D.       rnanda@medicine.bsd.uchicago.edu   
Principal Investigator: Rita Nanda, M.D.         
United States, Indiana
Indiana University/Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Anna M Storniolo, M.D.       astornio@iu.edu   
Principal Investigator: Anna M Storniolo, M.D.         
United States, Maryland
Johns Hopkins University Not yet recruiting
Baltimore, Maryland, United States, 21218
Contact: Ben Ho Park, M.D., Ph.D       bpark@jhmi.edu   
Principal Investigator: Ben Park, M.D., Ph.D         
United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Neelima Vidula, M.D.       nvidula@mgh.harvard.edu   
Principal Investigator: Neelima Vidula, M.D.         
United States, Michigan
University of Michigan Comprehensive Cancer Center Not yet recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Catherine Van Poznak, M.D.       cvanpoz@med.umich.edu   
Principal Investigator: Catherine Van Poznak, M.D.         
United States, Minnesota
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Minetta Lu, M.D.       liu.minetta@mayo.edu   
Principal Investigator: Minetta Lu, M.D.         
United States, Pennsylvania
University of Pittsburgh Cancer Institute Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Rachel Jankowitz, M.D.       jankowitzr@upmc.edu   
Principal Investigator: Rachel Jankowitz, M.D.         
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Vandana Abramson, M.D.       Vandana.Abramson@vanderbilt.edu   
Principal Investigator: Vandana Abramson, M.D.         
Sponsors and Collaborators
University of California, San Francisco
Mayo Clinic
Johns Hopkins University
Translational Breast Cancer Research Consortium
Massachusetts General Hospital
Investigators
Principal Investigator: Hope Rugo University of California, San Francisco
Principal Investigator: Neelima Vidula Massachusetts General Hospital

Publications:

Responsible Party: Hope Rugo, MD, Professor of Medicine; Director, Breast Oncology and Clinical Trials Education, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03095352     History of Changes
Other Study ID Numbers: CC#157521+167513
TBCRC 044 ( Other Identifier: Translational Breast Cancer Research Consortium )
First Posted: March 29, 2017    Key Record Dates
Last Update Posted: November 22, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Pembrolizumab
Carboplatin
Trastuzumab
Antibodies
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs