The Phase 1b part of this study is conducted to assess the safety and tolerability of E7386 in combination with pembrolizumab in participants with previously treated selected solid tumors, and to determine the recommended Phase 2 dose (RP2D) of E7386 in combination with pembrolizumab. The Phase 2 part of this study is conducted to assess the objective response rate (ORR) of E7386 in combination with pembrolizumab (melanoma, colorectal cancer \[CRC\], hepatocellular carcinoma \[HCC\]) or of E7386 in combination with pembrolizumab plus lenvatinib (HCC) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
89
E7386 tablet.
Pembrolizumab IV infusion.
Lenvatinib capsule.
University of California, Los Angeles
Los Angeles, California, United States
University of California, Irvine Health
Orange, California, United States
Florida Cancer Specialists
Fort Myers, Florida, United States
SCRI Florida Cancer Specialists East
West Palm Beach, Florida, United States
Winship Cancer Institute
Atlanta, Georgia, United States
Phase 1b Part: Number of Participants With Dose-limiting Toxicities (DLTs)
DLT was graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 based on investigator assessment. DLT was defined as any of the hematological or non-hematological toxicities events that: - Failure to administer greater than or equal to (\>=) 75 percentage (%) of the planned dosage of E7386 as a result of treatment-related toxicity; - Any treatment-related toxicity that causes the participant to discontinue treatment, even if the toxicity does not meet DLT criteria; - Prolonged delay (greater than \[\>\] 2 weeks) in initiating Cycle 2 due to treatment-related toxicities; - Any Grade 5 event or any death not clearly due to the underlying disease or extraneous causes.
Time frame: Cycle 1 (Cycle length=21 days)
Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
A TEAE was defined as an adverse event (AE) that emerged during treatment, having been absent at pretreatment (Baseline) or reemerged during treatment, or up to 30 days following last dose of study drug, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment or up to 30 days following last dose of study drug, relative to the pretreatment state, when the AE was continuous.
Time frame: Up to 30 days after last dose of study drug (up to 12.73 months)
Phase 1b Part: Number of Participants With Serious TEAEs
An SAE was any untoward medical occurrence that at any dose: Resulted in death; Was life-threatening (i.e., the participant was at immediate risk of death from the AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). An SAE was also counted as a TEAE if it emerged up to 90 days after the participant's last dose of study drug, or up to 30 days following cessation of study drug if the participant initiated new anticancer therapy, whichever was earlier.
Time frame: Up to 90 days after last dose of study drug (up to 14.73 months)
Phase 2 Part: Objective Response Rate (ORR)
ORR was defined as the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to less than \[\<\] 10 millimeters \[mm\]). PR: At least a 30 percent (%) decrease in sum of the diameters (SOD) of target lesions, taking as reference the screening SOD. Additionally, progression of target lesions must not be present.
Time frame: Up to 20.40 months
Phase 1b Part: Percentage of Participants With Best Overall Response (BOR)
BOR was defined as CR, PR, stable disease (SD), progressive disease (PD), and not applicable (NA)/not evaluable (NE) as per RECIST version 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to \<10 mm). PR: At least a 30% decrease in SOD of target lesions, taking as reference screening SOD. Additionally, progression of target lesions must not be present. SD: Neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD. PD: At least a 20% increase in the SOD of target lesions, taking as reference nadir SOD (or the screening, if screening is nadir value). In addition to relative increase of 20% in SOD, the SOD must also demonstrate an absolute increase of \>=5 mm. NA: No target lesions were identified at Screening.
Time frame: Up to 11.73 months
Phase 1b and Phase 2 Parts: Duration of Response (DOR)
DOR was defined as the time from the first documentation of CR or PR to the first documentation of PD or death due to any cause (whichever occurs first), in participants with confirmed CR or PR per RECIST 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to \<10 mm). PR: At least a 30% decrease in SOD of target lesions, taking as reference screening SOD. Additionally, progression of target lesions must not be present. SD: Neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD. PD: At least a 20% increase in the SOD of target lesions, taking as reference nadir SOD (or the screening, if screening is nadir value). In addition to relative increase of 20% in SOD, the SOD must also demonstrate an absolute increase of \>=5 mm.
Time frame: Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months
Phase 1b and Phase 2 Parts: Disease Control Rate (DCR)
DCR was defined as the percentage of participants who had a best overall response of confirmed CR or PR, or SD (after \>=5 weeks from the first dose) as per RECIST 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to \<10 mm). PR: At least a 30% decrease in SOD of target lesions, taking as reference screening SOD. Additionally, progression of target lesions must not be present. SD: Neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD. PD: At least a 20% increase in the SOD of target lesions, taking as reference nadir SOD (or the screening, if screening is nadir value). In addition to relative increase of 20% in SOD, the SOD must also demonstrate an absolute increase of \>=5 mm.
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Barbara Ann Karmanos Cancer Center
Detroit, Michigan, United States
Rutgers cancer Institute of NJ
New Brunswick, New Jersey, United States
Icahn School of Medicine at Mount Sinai
New York, New York, United States
Providence Medical Center Institute Franz Clinic
Portland, Oregon, United States
Tennessee Oncology PPLC
Nashville, Tennessee, United States
...and 22 more locations
Time frame: Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months
Phase 1b and Phase 2 Parts: Clinical Benefit Rate (CBR)
CBR was defined as the percentage of participants who had a best overall response of confirmed CR or PR, or durable SD (duration of SD \>=23 weeks) per RECIST 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to \<10 mm). PR: At least a 30% decrease in SOD of target lesions, taking as reference screening SOD. Additionally, progression of target lesions must not be present. SD: Neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD.
Time frame: Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months
Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs
A TEAE was defined as an AE that emerged during treatment, having been absent at pretreatment (Baseline) or reemerged during treatment, or up to 30 days following last dose of study drug, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment or up to 30 days following last dose of study drug, relative to the pretreatment state, when the AE was continuous. Related TEAEs was defined as AE for which a causal relationship between the study drug and the AE was a reasonable possibility.
Time frame: Up to 30 days after last dose of study drug (up to 21.40 months)
Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab
Cmax was defined as the maximum plasma concentration for E7386 when co-administered with Pembrolizumab. PK parameters were derived by noncompartmental analysis.
Time frame: Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days)
Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab
Tmax was defined as the time to reach maximum observed plasma concentration for E7386 when co-administered with Pembrolizumab. PK parameters were derived by noncompartmental analysis.
Time frame: Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days)
Phase 1b Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for E7386 When Co-administered With Pembrolizumab
AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 (pre-dose) to time of last quantifiable concentration for E7386 when co-administered with Pembrolizumab. PK parameters were derived by noncompartmental analysis.
Time frame: Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days)
Phase 1b Part, CLss/F: Apparent Clearance From Plasma at Steady State for E7386 When Co-administered With Pembrolizumab
CLss/F for E7386 when co-administered with Pembrolizumab was reported. PK parameters were derived by noncompartmental analysis.
Time frame: Cycle 1 Day 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days)