Pembrolizumab With Carboplatin Compared to Carboplatin Alone in Breast Cancer Patients With Chest Wall Disease

• ClinicalTrials.gov Identifier: NCT03095352
• Recruitment Status: Recruiting
• First Posted: March 29, 2017
• Last Update Posted: August 10, 2022
• Sponsor: Hope Rugo, MD
• Collaborators: Mayo Clinic; Johns Hopkins University; Translational Breast Cancer Research Consortium; Massachusetts General Hospital; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Hope Rugo, MD, University of California, San Francisco

Study Description

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 with or without carboplatin at investigator's discretion (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 with or without carboplatin at investigator's discretion (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 Design

• 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-Programmed Cell Death (PD)-1 Antibody, in Combination With Carboplatin Compared to Carboplatin Alone in Breast Cancer Patients With Chest Wall Disease
• Actual Study Start Date: September 2, 2017
• Estimated Primary Completion Date: September 30, 2023
• Estimated Study Completion Date: September 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A: Pembrolizumab + Carboplatin; 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: Carboplatin Monotherapy, then Pembrolizumab for participants who progress only; 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). Carboplatin may be continued or added back into the treatment regimen at the investigator's discretion. 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

Outcome Measures

Primary Outcome Measures :

1. Disease Control Rate (DCR) [ Time Frame: Up to 18 weeks ]
   Complete response (CR), Partial Response (PR), and stable disease (SD)as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at 18 weeks of treatment in breast cancer patients with chest wall disease treated with pembrolizumab and carboplatin or carboplatin alone
2. Median Progression Free Survival (PFS) [ Time Frame: Up to 18 weeks ]
   PFS defined as the time from observed objective response to disease progression and will be summarized by treatment arms using the Kaplan-Meier method

Secondary Outcome Measures :

1. Objective Response Rate (ORR) [ Time Frame: Up to 18 weeks ]
   Complete response (CR) and Partial Response (PR),defined by Immune related Response Evaluation Criteria in Solid Tumors (irRECIST) at 18 weeks of treatment
2. DCR by immune-related (ir) RECIST [ Time Frame: Up to 18 weeks ]
   Complete response (CR), Partial Response (PR), and stable disease (SD)as defined by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) at 18 weeks of treatment in breast cancer patients with chest wall disease treated with pembrolizumab and carboplatin or carboplatin alone also based on PD-L1 expression
3. Number of participants with treatment-related adverse events (AEs) [ Time Frame: Up to 24 weeks ]
   Adverse events will be graded and recorded according to NCI CTCAE Version 4.0 and characterized in terms regarding up to 30 days after the last treatment or end of treatment. Grade 1 laboratory abnormalities and white blood cell differential abnormalities excluding neutrophils (i.e., lymphocytes, monocytes, basophils, etc.) do not need to be recorded as AEs.

Eligibility Criteria

• 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 with curative intent.

   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, unless, per treating investigator's judgement, is not considered a candidate for further endocrine therapy

   3. HER2 positive disease with evidence of disease progression on trastuzumab, pertuzumab, 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

      • 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.
      • 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:

   • Treatment in the neoadjuvant and/or adjuvant setting without clear progression of disease.
   • Treatment in the metastatic setting without clear progression of disease. b Neo/adjuvant treatment with a checkpoint inhibitor is allowed if the last treatment was at least 12 months from the diagnosis of metastatic 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 to 18 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 below within 10 business days of treatment initiation:

    • 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)
    • 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. Creatinine clearance should be calculated per institutional standard.
    • 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 g/dL
    • 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
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. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/ 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. Prior checkpoint inhibitor therapy in the metastatic setting.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B virus (HBV) [e.g., hepatitis B surface antigen (HBsAg) reactive] or Hepatitis C virus (HCV) [e.g., HCV ribonucleic acid (RNA), [qualitative] is detected].
18. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.

Contacts and Locations

Contacts

Contact: Ivy Wong; 415-353-7873; Ivy.Wong@ucsf.edu

Contact: Amy DeLuca; 415-353-7288; Amy.Deluca@ucsf.edu

Locations

United States, California

University of California, San Francisco; 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; 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; 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, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Neelima Vidula, M.D. nvidula@mgh.harvard.edu

Principal Investigator: Neelima Vidula, M.D.

United States, Pennsylvania

University of Pittsburgh Cancer Institute; 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

Hope Rugo, MD

Mayo Clinic

Johns Hopkins University

Translational Breast Cancer Research Consortium

Massachusetts General Hospital

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Hope Rugo; University of California, San Francisco
• Principal Investigator: Neelima Vidula; Massachusetts General Hospital

More Information

Publications:

Disis ML. Immune regulation of cancer. J Clin Oncol. 2010 Oct 10;28(29):4531-8. doi: 10.1200/JCO.2009.27.2146. Epub 2010 Jun 1.

Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005 Apr 1;23(10):2346-57. doi: 10.1200/JCO.2005.00.240.

Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008 Jun 19;358(25):2698-703. doi: 10.1056/NEJMoa0800251.

Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-48. doi: 10.1146/annurev.immunol.23.021704.115611.

Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13866-71. doi: 10.1073/pnas.231486598. Epub 2001 Nov 6.

Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, Cammer M, Chen L, Zhang ZY, Edidin MA, Nathenson SG, Almo SC. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004 Mar;20(3):337-47. doi: 10.1016/s1074-7613(04)00051-2. Erratum In: Immunity. 2004 May;20(5):651.

Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004 Jul 15;173(2):945-54. doi: 10.4049/jimmunol.173.2.945.

Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004 Sep 10;574(1-3):37-41. doi: 10.1016/j.febslet.2004.07.083.

Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009 May;229(1):114-25. doi: 10.1111/j.1600-065X.2009.00767.x.

• Responsible Party: Hope Rugo, MD, Professor of Medicine; Director, Breast Oncology and Clinical Trials Education, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT03095352
• Other Study ID Numbers: CC#157521+167513; TBCRC 044 ( Other Identifier: Translational Breast Cancer Research Consortium ); NCI-2018-00010 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
• First Posted: March 29, 2017
• Last Update Posted: August 10, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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; Carboplatin; Pembrolizumab; Trastuzumab; Antineoplastic Agents; Antineoplastic Agents, Immunological