Study to Evaluate the Efficacy and Safety of Eribulin Mesylate in Combination With Pembrolizumab in Participants With Metastatic Triple-Negative Breast Cancer (mTNBC) (ENHANCE-1)

• ClinicalTrials.gov Identifier: NCT02513472
• Recruitment Status: Completed
• First Posted: July 31, 2015
• Results First Posted: August 14, 2020
• Last Update Posted: May 5, 2022
• Sponsor: Eisai Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Eisai Inc.

Study Description

Brief Summary:

This is an open-label, single-arm, multicenter, Phase 1b/2 study of eribulin mesylate in combination with pembrolizumab in participants with mTNBC previously treated with 0 (stratum 1) or 1 to 2 (stratum 2) lines of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic setting.

Condition or disease	Intervention/treatment	Phase
Breast Neoplasm	Drug: Eribulin Mesylate; Drug: Pembrolizumab	Phase 1; Phase 2

Detailed Description:

The Phase 1b part will evaluate the safety and tolerability of eribulin mesylate in combination with pembrolizumab. Approximately 6 participants may be enrolled in the Phase 1b part of the study. The Phase 2 part will evaluate the tumor objective response rate (ORR) when treated with eribulin mesylate in combination with pembrolizumab in all participants and will also evaluate ORR in stratum 2 participants and compare with the historical response rate of pembrolizumab monotherapy 10 percent (%) in participants with mTNBC previously treated with >=1 line of prior chemotherapy in the metastatic setting. Approximately 170 mTNBC participants (including participants in Phase 1b who are on RP2D level) will be enrolled in Phase 2.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 258 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Single-Arm Multicenter Phase 1b/2 Study to Evaluate the Efficacy and Safety of Eribulin Mesylate in Combination With Pembrolizumab in Subjects With Metastatic Triple-Negative Breast Cancer (mTNBC)
• Actual Study Start Date: August 28, 2015
• Actual Primary Completion Date: July 31, 2019
• Actual Study Completion Date: April 6, 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Eribulin Mesylate + Pembrolizumab; Participants with mTNBC previously treated with 0 (stratum 1) or 1 to 2 (stratum 2) lines of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic setting.

Drug: Eribulin Mesylate; Eribulin Mesylate will be administered as a 1.4 milligram per square meter (mg/m^2) IV (intravenous) infusion on Day 1 and Day 8 of each 21-day cycle in the presence of clinical benefit until intercurrent illness, unacceptable toxicity, or disease progression occurs, or until the participant withdraws consent.; Other Name: Halaven, E7389; Drug: Pembrolizumab; Pembrolizumab will be administered as a 200 milligram (mg) IV infusion on Day 1 of each 21-day cycle in the presence of clinical benefit until intercurrent illness, unacceptable toxicity, or disease progression occurs, or until the participant withdraws consent.; Other Name: Keytruda, MK-3475

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) [ Time Frame: From date of first dose of study drug administration to date of first documentation of disease progression or death, whichever occurred first (up to 3 years 11 months) ]
   ORR was defined as percentage of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR) using independent imaging review (IIR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. BOR of CR and PR was confirmed by a subsequent CR assessment and CR or PR assessment, respectively at least 4 weeks later. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: at least a 30 percent (%) decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD and there are no unequivocal new lesions, and no progression of non-target disease. The 2-sided 95% confidence interval (CI) calculated by Clopper-Pearson method. As planned, data up to the primary completion date only were analyzed.

Secondary Outcome Measures :

1. Progression-free Survival (PFS) [ Time Frame: From date of first dose of study drug administration to date of first documentation of disease progression or death, whichever occurred first (up to 3 years 11 months) ]
   PFS was assessed by IIR based on RECIST 1.1. PFS was defined as the time from the date of the first dose of study drug to the date of the first documentation of disease progression or death, whichever occurred first. Progressive disease (PD) for target lesion, a minimum 20% increase and a minimum 5 mm absolute increase in SOD compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir: Lowest measure SOD of target lesion at any time point from baseline onward. The median was calculated by Kaplan-Meier (K-M) method and 95% CI were based on a generalized Brookmeyer and Crowley method. As planned, data up to the primary completion date only were analyzed.
2. Overall Survival (OS) [ Time Frame: From date of first dose of study drug administration until date of death from any cause (up to 3 years 11 months) ]
   OS was defined as the time from the date of the first dose of study drug until the date of death from any cause. Median was estimated by K-M method, and the 95% CIs were based on a generalized Brookmeyer and Crowley method. As planned, data up to the primary completion date only were analyzed.
3. Duration of Response (DOR) [ Time Frame: From the date that a confirmed objective response (OR) was first documented to the date of PD or death due to any cause for those participants with a confirmed PR or CR (up to 3 years 11 months) ]
   DOR:time from date of confirmed OR was first documented to date of PD/death due to any cause with confirmed PR/CR using IIR as per RECIST 1.1.BOR of CR and PR was confirmed by subsequent CR assessment and CR or PR assessment, respectively at least 4 weeks later.CR:disappearance of all measurable, non-measurable lesions and no unequivocal new lesions.Any pathological lymph nodes had to be reduced in short axis to <10 mm.PR:at least 30%decrease in SOD of target lesions,taking as reference the baseline SOD, there are no unequivocal new lesions, and no progression of non-target disease.PD for target lesion, a minimum 20% increase and a minimum 5mm absolute increase in SOD compared to nadir, or PD for non-target lesions or unequivocal new lesions. Nadir:Lowest measure SOD of target lesions at any time point from baseline onward.Median calculated by K-M, 95% CI using Brookmeyer, Crowley method. As planned, data up to the primary completion date only were analyzed.
4. Clinical Benefit Rate (CBR) [ Time Frame: From date of first dose of study drug administration to date of first documentation of disease progression or death, whichever occurred first (up to 3 years 11 months) ]
   CBR was defined as the percentage of participant, who had BOR of CR, PR, or durable stable disease (dSD) (>=24 weeks). CBR was assessed by IIR based on RECIST 1.1. BOR of CR and PR was confirmed by a subsequent CR assessment and CR or PR assessment, respectively at least 4 weeks later. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target or non-target) to be reduced in short axis to <10 mm. PR: at least a 30% decrease in SOD of target lesions, as reference the baseline SOD and no unequivocal new lesions, and no progression of non-target disease. Stable disease (SD) must be >=8 weeks after first dose date to be considered best overall response. Durable SD: subset of SD with a duration of >=24 weeks after first dose date. The 2-sided 95% CI is computed by the method of Clopper-Pearson. As planned, data up to the primary completion date only were analyzed.
5. ORR in the Programmed Death Receptor-Ligand 1 (PD-L1) Positive Set [ Time Frame: From date of first dose of study drug administration to date of first documentation of disease progression or death, whichever occurred first (up to 3 years 11 months) ]
   ORR was defined as the percentage of participant with confirmed BOR of CR or PR. ORR in the PD-L1 positive set was assessed by IIR based on RECIST 1.1. BOR of CR and PR was confirmed by a subsequent CR assessment and CR or PR assessment, respectively at least 4 weeks later. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target/non-target) to be reduced in short axis to <10 mm. PR: at least a 30% decrease in SOD of target lesions, as reference the baseline SOD and no unequivocal new lesions, and no progression of non-target disease. PD L1 status was 'Positive' if combined positive score (CPS) >=1 and 'Negative' if CPS ˂1. The 2-sided 95% CI was calculated by the method of Clopper-Pearson. As planned, data up to the primary completion date only were analyzed.
6. PFS in the PD-L1 Positive Set [ Time Frame: From date of first dose of study drug administration to date of first documentation of disease progression or death, whichever occurs first (up to 3 years 11 months) ]
   PFS was defined as the time from the date of the first dose of study drug to the date of the first documentation of disease progression or death, whichever occurred first. PFS in PD-L1 positive set was assessed by IIR based on RECIST 1.1. PD for target lesion, a minimum 20% increase and a minimum 5 mm absolute increase in SOD compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir: Lowest measure SOD of target legions at any time point from baseline onward. The median was calculated by K-M method and 95% CI are based on a generalized Brookmeyer and Crowley method. PD L1 status was 'Positive' if CPS >=1 and 'Negative' if CPS ˂1. As planned, data up to the primary completion date only were analyzed.
7. OS in the PD-L1 Positive Set [ Time Frame: From date of first dose of study drug administration until date of death from any cause (up to 3 years 11 months) ]
   OS in the PD-L1 positive set was defined as the time from the date of the first dose of study drug until the date of death from any cause. The median was estimated by KM method, and the 95% CIs were based on a generalized Brookmeyer and Crowley method. PD L1 status was 'Positive' if CPS >=1 and 'Negative' if CPS ˂1. As planned, data up to the primary completion date only were analyzed.
8. DOR in the PD-L1 Positive Set [ Time Frame: From the date that a confirmed objective response is first documented to the date of PD or death due to any cause for those participants with a confirmed PR or CR (up to 3 years 11 months) ]
   DOR: time from date of confirmed OR was first documented to date of PD or death due to any cause with confirmed PR or CR. DOR in PD-L1 positive set was assessed by using IIR as per RECIST 1.1. BOR of CR and PR was confirmed by a subsequent CR assessment and CR or PR assessment, respectively at least 4 weeks later. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least 30%decrease in SOD of target lesions, taking as reference the baseline SOD, there are no unequivocal new lesions, and no progression of non-target disease. PD for target lesion, a minimum 20% increase and a minimum 5 mm absolute increase in SOD compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir: Lowest measure SOD of target lesions at any time point from baseline onward. Median calculated by K-M and 95% CI using Brookmeyer, Crowley method.

Other Outcome Measures:

1. CBR in the PD-L1 Positive Set [ Time Frame: From date of first dose of study drug administration to date of first documentation of disease progression or death, whichever occurred first (up to 3 years 11 months) ]
   CBR was defined as percentage of participant, had BOR of CR, PR, or dSD (>=24 weeks). CBR in PD-L1 positive set was assessed by IIR based on RECIST 1.1. BOR of CR and PR was confirmed by a subsequent CR assessment and CR or PR assessment, respectively at least 4 weeks later. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target or non-target) to be reduced in short axis to<10 mm. PR: at least 30 % decrease in SOD of target lesions, as reference the baseline SOD and no unequivocal new lesions, no progression of non-target disease.SD must be >=8 weeks after first dose date considered best overall response. Durable SD: subset of SD with duration of >=24 weeks after first dose date. The 2 -sided 95% CI is computed by method of Clopper-Pearson. PD L1 status was 'Positive' if CPS>=1, 'Negative' if CPS˂1. As planned, data up to the primary completion date only were analyzed.

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. Females or males, aged >=18 years at the time of signing the informed consent form (ICF).

2. mTNBC (confirmed from most recent tissue sample) meeting the following criteria:

   1. Estrogen receptor (ER) and progesterone receptor negative (a tumor is ER and/or progesterone receptor positive if at least 1 percent (%) of the cells examined have estrogen and/or progesterone receptors) and human epidermal growth factor receptor 2 (HER2) negative (defined as immunohistochemistry [IHC] less than (<) 2+ or fluorescence in situ hybridization [FISH] negative).
   2. Previously treated with 0 to 2 lines of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic setting. Hormonal therapy and bone metastases treatment (example, bisphosphonates, denosumab, etc) are not considered forms of systemic anticancer therapy.

3. Presence of measurable disease meeting the following criteria:

   1. At least 1 lesion of >=10 millimeter (mm) in long axis diameter for nonlymph nodes or >=15 mm in short axis diameter for lymph nodes that is serially measurable according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) using computerized tomography (CT) or magnetic resonance imaging (MRI) or panoramic and close-up color photography.
   2. Lesions that have had radiotherapy must show subsequent radiographic evidence of increased size to be deemed a target lesion.
4. Life expectancy of >=3 months.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
6. Adequate renal function as evidenced by serum creatinine less than or equal to (<=) 1.5 milligram per deciliter (mg/dL) or calculated creatinine clearance >=50 millimeter per minute (mL/min) according to the Cockcroft and Gault formula.

7. Adequate bone marrow function, defined as:

   1. Absolute neutrophil count (ANC) >=1.5*10^9/L.
   2. Hemoglobin (Hb) >=10.0 gram per deciliter (g/dL) (can be corrected by growth factor or transfusion).
   3. Platelet count >=100*10^9/L.

8. Adequate liver function, defined as:

   1. Total bilirubin <=1.5*upper limit of normal (ULN).
   2. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3*ULN unless there are bone metastases, in which case liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase. ALT and AST <= 5*ULN if participant has liver metastases.
9. Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (<= Grade 2) and alopecia.
10. Archived tissue sample or new biopsy sample.
11. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [B-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 International units per litre (IU/L) or equivalent units of B-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
12. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (that is, bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dosing).
13. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (example, total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, a combination oral contraceptive (estrogen/progesterone), or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 120 days after study drug discontinuation. If currently abstinent, the participant must agree to use a double barrier method as described above if she becomes sexually active during the study period or for 120 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 28 days before dosing and must continue to use the same contraceptive during the study and for 120 days after study drug discontinuation.
14. Males who have had a successful vasectomy (confirmed azoospermia) or they and their female partners meet the criteria above (that is, not of childbearing potential or practicing highly effective contraception throughout the study period or for 120 days after study drug discontinuation). No sperm donation is allowed during the study period or for 120 days after study drug discontinuation.
15. Willing and able to comply with all aspects of the treatment protocol.
16. Provide written informed consent.

Exclusion Criteria:

1. Previous treatment with eribulin mesylate or any anti-programmed death receptor-1 (anti-PD-1), programmed death receptor ligand-1 (PD-L1), or PD-L2 agent.
2. Active autoimmune disease that has required systemic treatment in the past 2 years (that is, with use of disease modifying agents, corticosteroids, or immunosuppresive drugs). Replacement therapy (example, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
3. Less than 6 months since prior adjuvant chemotherapy.
4. Current enrollment in another interventional clinical study or used any investigational drug or device within the past 28 days preceding informed consent.
5. Treatment with chemotherapy or biological therapy within the previous 3 weeks, radiation or small molecule targeted therapy within the previous 2 weeks.
6. Known central nervous system (CNS) disease, except for those participants with treated brain metastasis who are stable for at least 1 month, having no evidence of progression or hemorrhage after treatment and no ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.
7. Known history of human immunodeficiency virus (HIV) positive.
8. Known active hepatitis B (example, HBsAg reactive) or hepatitis C (example, hepatitis C virus ribonucleic acid (HCV RNA) detected).
9. Existing anticancer treatment-related toxicities of Grades >= 2 (except for alopecia and Grade 2 sensory neuropathy) according to Common Terminology Criteria for Adverse Events (CTCAE v4.03).
10. Any other malignancy that required treatment or has shown evidence of recurrence (except for nonmelanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ) during the 5 years prior to enrollment in this study.

11. History of significant cardiovascular disease, defined as:

    1. congestive heart failure greater than New York Heart Association (NYHA) Class II according to the NYHA Functional Classification.
    2. unstable angina or myocardial infarction within 6 months of enrollment.
    3. serious cardiac arrhythmia.
12. Clinically significant electrocardiogram (ECG) abnormality, including a marked Baseline prolonged QT interval/corrected QT interval ([QT/QTc], example, a repeated demonstration of a QTc interval >500 millisecond [ms]).
13. History of concomitant medical conditions or infectious diseases that, in the opinion of the investigator, would compromise the participant's ability to safely complete the study.
14. Hypersensitivity to the active substance or any other excipients of the eribulin mesylate drug product, or severe hypersensitivity (>=Grade 3) to pembrolizumab and/or any of its excipients.
15. Scheduled for major surgery during the study.
16. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor.
17. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
18. Has a history of interstitial lung disease.
19. Has an active infection requiring systemic therapy.
20. Has received a live-virus vaccination within 30 days of planned start of study therapy. Seasonal flu vaccines that do not contain live virus are permitted.
21. The investigator's belief that the participant is medically unfit to receive eribulin mesylate and pembrolizumab or unsuitable for any other reason.

Contacts and Locations

Locations

United States, California

Facility #1

Duarte, California, United States, 91010

Facility #1

Santa Barbara, California, United States, 93105

United States, Colorado

Facility #1

Denver, Colorado, United States, 80218

United States, Florida

Facility #1

Miami, Florida, United States, 33176

Facility #1

West Palm Beach, Florida, United States, 33401

United States, Massachusetts

Facility #1

Boston, Massachusetts, United States, 02115

Facility #2

Boston, Massachusetts, United States, 02115

United States, Minnesota

Facility #1

Minneapolis, Minnesota, United States, 55407

United States, Missouri

Facility #1

Saint Louis, Missouri, United States, 63110

United States, New Hampshire

Facility #1

Lebanon, New Hampshire, United States, 03756

United States, New York

Facility #1

New York, New York, United States, 10032

Facility #2

New York, New York, United States, 10065

United States, Tennessee

Facility #1

Chattanooga, Tennessee, United States, 37404

Facility #1

Nashville, Tennessee, United States, 37203

United States, Texas

Facility #1

Austin, Texas, United States, 78731

Facility #1

Fort Worth, Texas, United States, 76104

Facility #1

San Antonio, Texas, United States, 78217

Facility #2

San Antonio, Texas, United States, 78229

Facility #1

Sherman, Texas, United States, 75090

United States, Virginia

Facility #1

Salem, Virginia, United States, 24153

Facility #1

Winchester, Virginia, United States, 22601

United States, Wisconsin

Facility #1

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

Eisai Inc.

Merck Sharp & Dohme LLC

Investigators

• Study Director: Dr. Claudio Savulsky; Eisai Inc.

  Study Documents (Full-Text)

Documents provided by Eisai Inc.:

Study Protocol  [PDF] June 26, 2020

Statistical Analysis Plan  [PDF] October 8, 2019

More Information

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT02513472
• Other Study ID Numbers: E7389-M001-218; KEYNOTE-150 ( Other Identifier: Merck Sharp and Dohme Corp )
• First Posted: July 31, 2015
• Results First Posted: August 14, 2020
• Last Update Posted: May 5, 2022
• Last Verified: April 2022

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

Keywords provided by Eisai Inc.:

Eribulin Mesylate; Pembrolizumab; Metastatic Triple-Negative Breast Cancer; mTNBC

Additional relevant MeSH terms:

Breast Neoplasms; Triple Negative Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action