Clinical Trials /

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

NCT03095352

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: CC#157521+167513
  • SECONDARY ID: TBCRC 044
  • NCT ID: NCT03095352

Conditions

  • Breast Cancer
  • Chest Wall Disease

Interventions

DrugSynonymsArms
PembrolizumabArm A
CarboplatinRibocarboArm A
TrastuzumabArm A

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalArm 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
  • Pembrolizumab
  • Carboplatin
  • Trastuzumab
Arm BExperimentalArm 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.
  • Carboplatin
  • Trastuzumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease control rate
Time Frame:From the baseline until the chest wall disease progression or death from any cause, assessed at 18 months
Safety Issue:
Description:Disease control will also be based on PD-L1 expression via immunohistochemistry

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:Up to 18 months
Safety Issue:
Description:Will be summarized by treatment arms using the Kaplan-Meier method
Measure:ORR defined as CR/PR assessed by immune-related (ir)RECIST
Time Frame:Up to 18 months
Safety Issue:
Description:Will be summarized by treatment arms using the Kaplan-Meier method

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

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