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.
Completed
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Eribulin Mesylate | Halaven, E7389 | Eribulin Mesylate + Pembrolizumab |
| Pembrolizumab | Keytruda, MK-3475 | Eribulin Mesylate + Pembrolizumab |
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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Eribulin Mesylate + Pembrolizumab | Experimental | 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. |
|
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | 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 or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Overall Survival (OS) |
| Time Frame: | From date of first dose of study drug administration until date of death from any cause or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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 (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, 95% CI using Brookmeyer, Crowley method. |
| Measure: | 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 or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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 were 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. |
| Measure: | 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 or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 or up to data cutoff date of 31 July 2019 (up to approximately 3 years 11 months) |
| Safety Issue: | |
| Description: | 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. |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Eisai Inc. |
August 24, 2021
