Pembrolizumab and Capecitabine in Treating Patients With Locally Advanced or Metastatic Triple Negative or Hormone-Refractory Breast Cancer That Cannot Be Removed by Surgery

• Sponsor: Northwestern University (Other)
• Overall Status: Unknown status
• CT.gov ID: NCT03044730
• Collaborator: Merck Sharp & Dohme LLC (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 30
• Locations: 2
• Arm: 1
• Anticipated Duration (Months): 47.2
• Patients Per Site: 15
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to see whether a combination of two different drugs - pembrolizumab and capecitabine - is safe, and if it might be effective in treating triple negative and hormone-refractory breast cancer. Pembrolizumab is a type of drug that contains an antibody. Antibodies are the part of your immune system that finds things that don't belong in your body, such as bacteria or viruses. The antibody in pembrolizumab finds and blocks a protein, which allows your immune system to target and destroy cancer cells. Pembrolizumab is Food and Drug Administration (FDA) approved for other types of cancer. It is not approved for breast cancer, meaning that it is an "experimental" or "investigational" treatment. Capecitabine is a type of chemotherapy pill that is a standard treatment and FDA-approved for breast cancer. It stops the cancer cells from being able to multiply.

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma	Drug: Capecitabine; Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the median progression-free survival (median PFS) for participants receiving pembrolizumab with capecitabine for the treatment of locally advanced or metastatic triple negative breast cancer (TNBC) and hormone-refractory metastatic breast cancer (MBC).

SECONDARY OBJECTIVES:

1. To describe the objective response rate (ORR) for participants receiving pembrolizumab with capecitabine for the treatment of locally advanced or metastatic TNBC and hormone-refractory MBC.

2. To describe the safety and tolerability of the combination of pembrolizumab and capecitabine for the treatment of locally advanced or metastatic TNBC and hormone-refractory MBC.

TERTIARY OBJECTIVES:

1. Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) through immunohistochemical (IHC) analysis.

2. To assess circulating tumor DNA (ctDNA). III. To evaluate ORR and median-PFS using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

OUTLINE:

Patients receive pembrolizumab intravenously (IV) on day 1 and capecitabine orally (PO) twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Pembrolizumab and Capecitabine for Advanced Triple Negative and Hormone-Refractory Breast Cancer
• Actual Study Start Date: May 25, 2017
• Actual Primary Completion Date: Apr 24, 2019
• Anticipated Study Completion Date: May 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (pembrolizumab, capecitabine) Patients receive pembrolizumab IV on day 1 and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: Capecitabine; Given PO; Other Names: Ro 09-1978/000 Xeloda ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda Lambrolizumab MK-3475 SCH 900475

Outcome Measures

Primary Outcome Measures

1. Median PFS (Median Progression-Free Survival) [Approximately 20 months]

   To evaluate the median Progression-Free Survival (PFS) for participants receiving pembrolizumab with capecitabine for the treatment of locally advanced or metastatic TNBC and hormone-refractory MBC. PFS is defined as the length of time during and after the treatment that a patient does not experience progression. Progressive Disease (PD) as defined per RECIST 1.1 is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). PFS was analyzed using a Kaplan-Meier curve. For PFS, assumptions were that the addition of pembrolizumab would increase PFS to 5 months compared to historical control of 3 months.

Secondary Outcome Measures

1. Objective Response Rate (ORR) [Up to 9 Cycles (1 cycle = 21 days)]

   The ORR is the percentage of patients whose cancer shrinks or disappears after treatment. Objective response rate was calculated based on the number of patients who had a Complete Response (CR) or a Partial Response (PR). CR and PR were measured according to RECIST v. 1.1 guidelines: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

2. Incidence of Adverse Events [Up to 2 years]

   Determine the safety and tolerability of the combination of pembrolizumab and Capecitabine by evaluating the incidence of adverse events. All adverse events will be assessed using the National Cancer Institute Common Terminology Criteria 4.03 criteria (NCI CTCAE 4.03 criteria).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically-confirmed unresectable, locally advanced or metastatic breast cancer that meets one of the following:

• Triple negative, defined as estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor receptor 2 (HER2) negative; HER2 negative defined as immunohistochemistry (IHC) 0 or 1+ or fluorescence in situ hybridization (FISH) negative

• Hormone-refractory breast cancer which denotes progression to endocrine therapy (e.g., tamoxifen, aromatase inhibitors, fulvestrant) unless contraindicated

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Patients must have a life expectancy of >= 90 days

• Patients must have baseline laboratory tests within the following parameters at least 4 weeks (28 days) prior to registration:

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency

• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN

• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases

• Albumin >= 2.5 mg/dL

• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (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

• Females of child-bearing potential (FOCBP) must have a negative serum or urine pregnancy test within 7 days prior to registration and must be at least within 3 days prior to first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• (Note: a FOCBP is any woman [regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice] who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy

• Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)

• Female subjects of childbearing potential (FOCBP) must be willing to use an adequate method of contraception; contraception must be used for the course of the study through 120 days after the last dose of study medication

• Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

• Male subjects of childbearing potential must agree to use an adequate method of contraception; contraception must be used starting with the first dose of study therapy through 120 days after the last dose of study therapy

• Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

• Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study

• Patients must be willing and able to comply with scheduled visits, treatment plan and laboratory tests

• Patient must be able to swallow and retain oral medication

Exclusion Criteria:

• Patients with documented HER2-positive metastatic disease are not eligible, even if their primary breast cancer was HER2-negative

• Patients who have received prior anti-cancer therapy (e.g., biologic or other targeted therapy, chemotherapy) within 2 weeks prior to registration; hormone therapy is permitted until registration

• Note: patients who received prior anti-PD-1, PD-L1 or PD-L2 agents are still eligible

• Patients who have not recovered from adverse events to grade 1 severity or lower due to agents administered more than 2 weeks earlier than registration, are not eligible, except for stable sensory neuropathy (=< grade 2) and alopecia

• Patients who have received radiotherapy =< 4 weeks prior to registration, with the exception of palliative radiotherapy, who have not recovered from side effects of such therapy to baseline or grade =< 1 are not eligible for participation

• Patients with central nervous system (CNS) involvement may participate if they meet all the following criteria:

• At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment,

• Clinically stable with respect to the CNS tumor at the time of screening

• Patients who have undergone major surgery =< 4 weeks prior to registration or have not recovered from side effects of such procedure are not eligible for participation

• Patients may not be receiving any other investigational agents

• Patients who have a history of allergic reactions or hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab and/or humanized antibodies are not eligible

• Known hypersensitivity to capecitabine, fluorouracil, or any component of the formulation

• Note: prior capecitabine is permitted

• History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis

• Patients with history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study

• Patients with controlled type I diabetes mellitus on a stable dose of insulin regimen for more than a month may be eligible for this study

• Patients who have evidence of active, noninfectious pneumonitis or have a history of severe pneumonitis that required treatment with steroids are not eligible for this study; (Note: replacement physiologic dose of steroids [prednisone 10 mg daily or equivalent] are allowed)

• Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:

• Hypertension that is not controlled on medication (defined as >= 140/100 at rest, average of 3 consecutive readings)

• Ongoing or active infection requiring systemic treatment

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Cardiac arrhythmia

• Clinically significant electrocardiogram (ECG) abnormality, e.g., a repeated demonstration of a QTc interval > 500 ms

• Psychiatric illness/social situations that would limit compliance with study requirements

• Known positive test for human immunodeficiency virus (HIV)

• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

• Active tuberculosis

• Prior allogeneic bone marrow transplantation or solid organ transplant

• Administration of a live, attenuated vaccine within 4 weeks before starting the study treatment or anticipation that a live attenuated vaccine will be required during the study

• Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints

• Female patients who are pregnant or nursing (lactating) are not eligible

• Patients exhibiting any other condition that would, in the Investigator's judgment, preclude patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures are not eligible for participation; this might include, but is not limited to, infection/inflammation, intestinal obstruction, and/or social/psychological complications

• Patients with impaired gastrointestinal (GI) function or GI disease that may significantly alter absorption of oral capecitabine (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) are not eligible for participation

• Patients with a history of another malignancy that progressed or required treatment within 5 years prior to registration are not eligible for participation; Note: the exceptions to this include non-melanoma skin cancer or excised carcinoma in situ of the cervix

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	Northwestern Lake Forest Hospital	Lake Forest	Illinois	United States	60045

Sponsors and Collaborators

• Northwestern University
• Merck Sharp & Dohme LLC
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Sarika Jain, MD, Northwestern University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 16, 2019

More Information

Publications

None provided.

• Responsible Party: William Gradishar, Principal Investigator, Northwestern University
• ClinicalTrials.gov Identifier: NCT03044730
• Other Study ID Numbers: NU 16B08; STU00203215; NU 16B08; P30CA060553; NCI-2017-00152
• First Posted: Feb 7, 2017
• Last Update Posted: Jul 13, 2020
• Last Verified: Jun 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Carcinoma; Breast Neoplasms; Pembrolizumab; Capecitabine

Study Results

Participant Flow

Recruitment Details	The study opened for enrollment on May 25th, 2017 with an accrual goal of 30 patients. The first patient started treatment on May 30th, 2017. The study closed permanently to further enrollment on March 12th, 2018 as the accrual goal was met.

Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 2 years for PFS, with visits and/or phone calls.
Period Title: 3 Cycles of Pembro + Capecitab
STARTED	30
Attempted Cycle 1	30
Attempted Cycle 2	28
Attempted Cycle 3	26
COMPLETED	26
NOT COMPLETED	4
Period Title: 3 Cycles of Pembro + Capecitab
STARTED	26
Assessed for Cycle 4	26
Started Cycle 4	20
Went on to Cycle 5 and Beyond	16
COMPLETED	16
NOT COMPLETED	10
Period Title: 3 Cycles of Pembro + Capecitab
STARTED	29
COMPLETED	4
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 2 years for PFS, with visits and/or phone calls.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	28 93.3%
>=65 years	2 6.7%
Sex: Female, Male (Count of Participants)
Female	30 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.3%
Not Hispanic or Latino	28 93.3%
Unknown or Not Reported	1 3.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 10%
White	25 83.3%
More than one race	0 0%
Unknown or Not Reported	2 6.7%
Region of Enrollment (participants) [Number]
United States	30 100%
Triple Negative vs Hormone Receptor Positive MBC (Count of Participants)
Triple Negative MBC	16 53.3%
Hormone Receptor Positive MBC	14 46.7%

Outcome Measures

1. Primary Outcome

Title	Median PFS (Median Progression-Free Survival)
Description	To evaluate the median Progression-Free Survival (PFS) for participants receiving pembrolizumab with capecitabine for the treatment of locally advanced or metastatic TNBC and hormone-refractory MBC. PFS is defined as the length of time during and after the treatment that a patient does not experience progression. Progressive Disease (PD) as defined per RECIST 1.1 is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). PFS was analyzed using a Kaplan-Meier curve. For PFS, assumptions were that the addition of pembrolizumab would increase PFS to 5 months compared to historical control of 3 months.
Time Frame	Approximately 20 months

Outcome Measure Data

Analysis Population Description

One patient was not evaluable due to non-compliance with capecitabine. Three patients were not evaluable because they did not reach 3 cycles of treatment (per Protocol).

Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 1 year for PFS, with visits and/or phone calls.
Measure Participants	26
Median (95% Confidence Interval) [months]	4.13

2. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	The ORR is the percentage of patients whose cancer shrinks or disappears after treatment. Objective response rate was calculated based on the number of patients who had a Complete Response (CR) or a Partial Response (PR). CR and PR were measured according to RECIST v. 1.1 guidelines: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Up to 9 Cycles (1 cycle = 21 days)

Outcome Measure Data

Analysis Population Description

One patient was not evaluable due to non-compliance with capecitabine. Three patients were not evaluable because they did not have 3 cycles of treatment (as required per protocol to be evaluable for efficacy endpoints).

Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 1 year for PFS, with visits and/or phone calls.
Measure Participants	26
Complete Response	0 0%
Partial Response	4 13.3%

3. Secondary Outcome

Title	Incidence of Adverse Events
Description	Determine the safety and tolerability of the combination of pembrolizumab and Capecitabine by evaluating the incidence of adverse events. All adverse events will be assessed using the National Cancer Institute Common Terminology Criteria 4.03 criteria (NCI CTCAE 4.03 criteria).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Post-Hoc Outcome

Title	Clinical Benefit Rate (CBR)
Description	To evaluate the clinical benefit rate (CBR) per RECIST v. 1.1. CBR is the rate of participants with complete response (CR), partial response (PR) or stable disease (SD) > 6 months. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Time Frame	Up to 14 cycles (1 cycle= 21 days)

Outcome Measure Data

Analysis Population Description

One patient was not evaluable due to non-compliance with capecitabine. Patients who received at least one dose of capecitabine and pembrolizumab were included in the analysis.

Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 2 years for PFS, with visits and/or phone calls.
Measure Participants	29
Number [percentage of participants]	28 93.3%

5. Post-Hoc Outcome

Title	1-year Progression Free Survival (PFS) Rate
Description	To evaluate the 1-year progression free survival (PFS) rate per RECIST v. 1.1. PFS is defined as the length of time during and after the treatment that a patient does not experience progression. Progressive Disease (PD) as defined per RECIST 1.1 is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). PFS was analyzed using a Kaplan-Meier curve.
Time Frame	Up to 1 year after starting treatment

Outcome Measure Data

Analysis Population Description

One patient was excluded from the analysis due to patient non-compliance with capecitabine. Patients who received at least 1 dose of pembrolizumab and capecitabine were included in the analysis.

Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 2 years for PFS, with visits and/or phone calls.
Measure Participants	29
Number [percentage of participants]	20.7 69%

6. Post-Hoc Outcome

Title	Median PFS (Median Progression-Free Survival)
Description	To evaluate the median Progression-Free Survival (PFS) for participants receiving pembrolizumab with capecitabine for the treatment of locally advanced or metastatic TNBC and hormone-refractory MBC. PFS is defined as the length of time during and after the treatment that a patient does not experience progression. Progressive Disease (PD) as defined per RECIST 1.1 is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). PFS was analyzed using a Kaplan-Meier curve. For PFS, assumptions were that the addition of pembrolizumab would increase PFS to 5 months compared to historical control of 3 months.
Time Frame	Approximately 20 months

Outcome Measure Data

Analysis Population Description

One patient was not evaluable due to non-compliance with capecitabine. Patients who received at least one dose of pembrolizumab with capecitabine were included in the analysis.

Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 2 years for PFS, with visits and/or phone calls.
Measure Participants	29
Median (95% Confidence Interval) [months]	4.0

7. Post-Hoc Outcome

Title	Objective Response Rate (ORR)
Description	The ORR is the percentage of patients whose cancer shrinks or disappears after treatment. Objective response rate was calculated based on percentage of patients who had a Complete Response (CR) or a Partial Response (PR). CR and PR were measured according to RECIST v. 1.1 guidelines: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Up to 9 Cycles (1 cycle = 21 days)

Outcome Measure Data

Analysis Population Description

One patient was not evaluable due to non-compliance with capecitabine. The analysis included all patients who received at least one dose of capecitabine and pembrolizumab.

Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 2 years for PFS, with visits and/or phone calls.
Measure Participants	29
Number [percentage of participants]	14 46.7%

Adverse Events

Time Frame	Patients on study may continue treatment until progression or unacceptable toxicity. AEs currently collected for up to 27 cycles for any patient where one cycle equals 21 days.
Adverse Event Reporting Description	Adverse event data shown below includes all events collected and available up until March 30, 2020 for the study. Data collected includes the highest grade of the event experienced for each participant, and thus includes some serious adverse event data.
Arm/Group Title	Treatment: Pembrolizumab + Capecitabine
Arm/Group Description	This is a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) metastatic breast cancer (MBC) who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. Patients continued treatment until disease progression or unacceptable toxicity. After discontinuation of study drugs, patients were assessed every 3 months up to 2 years for PFS, with visits and/or phone calls.
All Cause Mortality
	Treatment: Pembrolizumab + Capecitabine
	Affected / at Risk (%)	# Events
Total	17/30 (56.7%)
Serious Adverse Events
	Treatment: Pembrolizumab + Capecitabine
	Affected / at Risk (%)	# Events
Total	19/30 (63.3%)
Gastrointestinal disorders
Abdominal Pain	1/30 (3.3%)
Investigations
Blood bilirubin increased	1/30 (3.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Disease Progression	10/30 (33.3%)
Neoplasms benign, malignant and unspecified	1/30 (3.3%)
Nervous system disorders
Seizure	1/30 (3.3%)
Psychiatric disorders
Delerium	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/30 (3.3%)
Pneumonistis	1/30 (3.3%)
Pleural effusion	1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Treatment: Pembrolizumab + Capecitabine
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
Anemia	5/30 (16.7%)
Cardiac disorders
Atrial fibrillation	1/30 (3.3%)
Palpitations	1/30 (3.3%)
Sinus tachycardia	3/30 (10%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	1/30 (3.3%)
Endocrine disorders
Endocrine disorders - Other, specify	4/30 (13.3%)
Hypothyroidism	2/30 (6.7%)
Eye disorders
Blurred vision	4/30 (13.3%)
Dry eye	2/30 (6.7%)
Eye disorders - Other, specify	2/30 (6.7%)
Photophobia	1/30 (3.3%)
Watering eyes	1/30 (3.3%)
Gastrointestinal disorders
Abdominal distension	2/30 (6.7%)
Abdominal pain	9/30 (30%)
Ascites	1/30 (3.3%)
Bloating	3/30 (10%)
Colitis	2/30 (6.7%)
Constipation	10/30 (33.3%)
Diarrhea	15/30 (50%)
Dry mouth	1/30 (3.3%)
Esophagitis	1/30 (3.3%)
Gastroesophageal reflux disease	3/30 (10%)
Gastrointestinal disorders - Other, specify	2/30 (6.7%)
Lip pain	1/30 (3.3%)
Mucositis oral	1/30 (3.3%)
Nausea	13/30 (43.3%)
Rectal pain	1/30 (3.3%)
Stomach pain	2/30 (6.7%)
Vomiting	8/30 (26.7%)
General disorders
Chills	3/30 (10%)
Edema limbs	6/30 (20%)
Fatigue	13/30 (43.3%)
Fever	2/30 (6.7%)
Flu like symptoms	1/30 (3.3%)
Gait disturbance	1/30 (3.3%)
General disorders and administration site conditions - Other, specify	1/30 (3.3%)
Non-cardiac chest pain	1/30 (3.3%)
Pain	1/30 (3.3%)
Hepatobiliary disorders
Gallbladder obstruction	1/30 (3.3%)
Hepatic failure	1/30 (3.3%)
Infections and infestations
Bronchial infection	1/30 (3.3%)
Lip infection	2/30 (6.7%)
Papulopustular rash	1/30 (3.3%)
Sinusitis	3/30 (10%)
Upper respiratory infection	1/30 (3.3%)
Urinary tract infection	1/30 (3.3%)
Vaginal infection	1/30 (3.3%)
Wound infection	1/30 (3.3%)
Injury, poisoning and procedural complications
Fall	1/30 (3.3%)
Spinal fracture	1/30 (3.3%)
Investigations
Activated partial thromboplastin time prolonged	2/30 (6.7%)
Alanine aminotransferase increased	7/30 (23.3%)
Alkaline phosphatase increased	7/30 (23.3%)
Aspartate aminotransferase increased	10/30 (33.3%)
Blood bilirubin increased	6/30 (20%)
Creatinine increased	1/30 (3.3%)
Fibrinogen decreased	1/30 (3.3%)
INR increased	1/30 (3.3%)
Investigations - Other, specify	1/30 (3.3%)
Lymphocyte count decreased	8/30 (26.7%)
Neutrophil count decreased	5/30 (16.7%)
Platelet count decreased	7/30 (23.3%)
Weight loss	2/30 (6.7%)
White blood cell decreased	5/30 (16.7%)
Metabolism and nutrition disorders
Anorexia	4/30 (13.3%)
Dehydration	2/30 (6.7%)
Hypercalcemia	1/30 (3.3%)
Hyperglycemia	11/30 (36.7%)
Hyperkalemia	1/30 (3.3%)
Hypermagnesemia	1/30 (3.3%)
Hypoalbuminemia	7/30 (23.3%)
Hypocalcemia	6/30 (20%)
Hypoglycemia	1/30 (3.3%)
Hypokalemia	11/30 (36.7%)
Hypomagnesemia	1/30 (3.3%)
Hyponatremia	3/30 (10%)
Hypophosphatemia	2/30 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/30 (10%)
Back pain	5/30 (16.7%)
Bone pain	1/30 (3.3%)
Generalized muscle weakness	1/30 (3.3%)
Musculoskeletal and connective tissue disorder - Other, specify	3/30 (10%)
Pain in extremity	8/30 (26.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	7/30 (23.3%)
Nervous system disorders
Dizziness	3/30 (10%)
Headache	9/30 (30%)
Intracranial hemorrhage	1/30 (3.3%)
Nervous system disorders - Other, specify	2/30 (6.7%)
Neuralgia	1/30 (3.3%)
Paresthesia	2/30 (6.7%)
Peripheral sensory neuropathy	2/30 (6.7%)
Seizure	1/30 (3.3%)
Tremor	1/30 (3.3%)
Psychiatric disorders
Anxiety	4/30 (13.3%)
Confusion	4/30 (13.3%)
Delirium	1/30 (3.3%)
Hallucinations	1/30 (3.3%)
Insomnia	5/30 (16.7%)
Renal and urinary disorders
Acute kidney injury	1/30 (3.3%)
Renal and urinary disorders - Other, specify	1/30 (3.3%)
Urinary urgency	1/30 (3.3%)
Reproductive system and breast disorders
Pelvic pain	2/30 (6.7%)
Vaginal discharge	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders
Cough	7/30 (23.3%)
Dyspnea	4/30 (13.3%)
Hypoxia	1/30 (3.3%)
Nasal congestion	2/30 (6.7%)
Pleural effusion	1/30 (3.3%)
Pneumonitis	1/30 (3.3%)
Productive cough	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/30 (3.3%)
Sneezing	1/30 (3.3%)
Sore throat	1/30 (3.3%)
Skin and subcutaneous tissue disorders
Dry skin	2/30 (6.7%)
Erythema multiforme	1/30 (3.3%)
Palmar-plantar erythrodysesthesia syndrome	14/30 (46.7%)
Pruritus	1/30 (3.3%)
Rash acneiform	1/30 (3.3%)
Rash maculo-papular	4/30 (13.3%)
Skin and subcutaneous tissue disorders - Other, specify	6/30 (20%)
Skin ulceration	1/30 (3.3%)
Vascular disorders
Hematoma	0/30 (0%)
Hot flashes	1/30 (3.3%)
Hypertension	3/30 (10%)
Hypotension	2/30 (6.7%)
Thromboembolic event	1/30 (3.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.