Melanoma, Carcinoma, Hepatocellular, Colorectal Neoplasms
Conditions
Keywords
metastatic or unresectable melanoma, metastatic or unresectable hepatocellular carcinoma, metastatic or unresectable colorectal cancer, Solid tumors, E7386
Brief summary
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.
Interventions
Sponsors
Merck Sharp & Dohme LLC
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, age \>=18 years at the time of informed consent 2. Have a histologically or cytologically-documented, advanced (metastatic and/or unresectable) selected solid tumor for which prior standard systemic therapy has failed. Selected tumor types: melanoma (excluding uveal melanoma), CRC, HCC 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 4. Must have disease progression on current or since the last anticancer treatment 5. At least one measurable lesion by computer tomography (CT) or magnetic imaging resonance (MRI) based on RECIST 1.1 6. Adequate organ function and serum mineral level per blood work as confirmed by the investigator 1. Calcium (albumin-corrected) within normal range 2. Potassium within normal reference range 3. Magnesium less than or equal to (\>=) 1.2 milligram per deciliter (mg/dL) or 0.5 millimoles per litre (mmol/L). 7. Melanoma cohort (Phase 2), participants must have: * Unresectable Stage III or Stage IV melanoma, not amenable to local therapy. * Received only 1 or, if BRAF mut +ve, 2 lines of therapies locally advanced or metastatic setting prior to study enrolment. Note: Adjuvant anti-PD-1/PD-L1 mAb/ BRAF inhibitor treatment will be counted as prior line of treatment if relapse occurred during active treatment or within 12 weeks of treatment discontinuation. 8. CRC cohort (Phase 2), participants must have received at least 2 prior systemic therapies in adjuvant and/or metastatic setting (not exceeding 4 lines of therapies in the metastatic setting, progressed on at least 1 prior regimen in the metastatic setting or could not tolerate standard treatment) 9. Participants with HCC cohort (Phase 2) must have: * Stage B (not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment) or stage C based on Barcelona Clinic Liver Cancer \[BCLC\] staging System and Child-Pugh class A only. * Have received only 1 prior line of systemic therapy in the locally advanced or metastatic setting, and must have progressed on treatment with an anti-PD-1/L1 monoclonal antibodies (mAb) administered either as monotherapy, or in combination 10. Must agree to take Vitamin D continuous supplementation as per local institutional guideline/ investigator's clinical discretion if their 25-hydroxyvitamin D levels are less than 10 nanogram per milliliter (ng/mL). 11. Triplet treatment cohorts only: Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP \<=150/90 millimeter of mercury (mmHg) at Screening/Baseline and no change in antihypertensive medications within 1 week before starting treatment in this study.
Exclusion criteria
1. Have present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to study drug administration. The participant can receive diuretic drugs as needed per the treating physician. Consult with the sponsor if the participant has more than trivial/trace fluid accumulation. 2. Prior treatment with E7386 or prior therapy with anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (example, CTLA-4, OX 40, CD137) that was discontinued due to a Grade 3 or higher immune-related (ir)AE 3. Participants with central nervous system (CNS) metastases are not eligible unless they are previously treated are radiologically stable, that is, without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), and are clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment 4. Any active infection requiring systemic treatment 5. Have severe hypersensitivity to study drugs and/or any of its excipients 6. Have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 7. Have an active autoimmune disease that has required systemic treatment in the past 2 years 8. Have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis 9. Any bone disease/conditions as follows: * Osteoporosis with T-score \<-2.5 by DXA scan * Metabolic bone disease, such as hyperparathyroidism, Paget's disease or osteomalacia * Symptomatic hypercalcemia requiring bisphosphonate therapy * History of any fracture within 6 months prior to starting study drug * History of symptomatic vertebral fragility fracture or any fragility fracture * Moderate or severe morphometric vertebral fracture at baseline. * Any condition requiring orthopedic intervention. * Bone metastases not being treated with a bisphosphonate or denosumab 10. Active viral hepatitis (B or C) as demonstrated by positive serology for participants with melanoma and CRC. Dual active hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection at study entry for participants with HCC 11. Known to be human immunodeficiency virus (HIV) positive 12. Received blood/platelet transfusion or G-CSF within 4 weeks before study entry 13. For Melanoma only, participants with ocular melanoma are excluded. Note: Participants with mucosal melanoma will not exceed 20% of the enrolled participants in melanoma cohort in Phase 2. 14. For CRC only, participants are excluded if: \- have a tumor that is microsatellite instability high (MSI H)/ DNA mismatch repair-deficient (dMMR) positive 15. For HCC only, participants are excluded if: * Clear invasion to bile duct * Have had esophageal or gastric variceal bleeding within the last 6 months. Participants in triplet treatment cohorts will be screened for esophageal or gastric varices unless such screening has been performed in the past 3 months before first dose of treatment. If varices are present, they should be treated according to institutional standards before starting study intervention; esophageal or gastric varices that require interventional treatment within 28 days prior to first dose of study drug are excluded * History of hepatic encephalopathy within 6 months prior to starting study drug unresponsive to therapy within 3 days. Participants on rifaximin or lactulose during screening to control their hepatic encephalopathy are not allowed 16. For participants in the triplet treatment cohorts only: * Proteinuria greater than (\>) 1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein \>=1 gram per 24 hours (g/24 hours) will be ineligible * Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR monitoring (example, warfarin or similar agents). Treatment with low molecular weight heparin and factor X inhibitors is permitted * Clinically significant hemoptysis from any source or tumor bleeding within 3 weeks prior to the first dose of study drug * Pre-existing \>=Grade 3 gastrointestinal or non-gastrointestinal fistula
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b Part: Number of Participants With Dose-limiting Toxicities (DLTs) | Cycle 1 (Cycle length=21 days) | 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. |
| Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Up to 30 days after last dose of study drug (up to 12.73 months) | 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. |
| Phase 1b Part: Number of Participants With Serious TEAEs | Up to 90 days after last dose of study drug (up to 14.73 months) | 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. |
| Phase 2 Part: Objective Response Rate (ORR) | Up to 20.40 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs | Up to 30 days after last dose of study drug (up to 21.40 months) | 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. |
| Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days) | Cmax was defined as the maximum plasma concentration for E7386 when co-administered with Pembrolizumab. PK parameters were derived by noncompartmental analysis. |
| Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | Up to 11.73 months | 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. |
| 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 | Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days) | 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. |
| Phase 1b Part, CLss/F: Apparent Clearance From Plasma at Steady State for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days) | CLss/F for E7386 when co-administered with Pembrolizumab was reported. PK parameters were derived by noncompartmental analysis. |
| Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days) | 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. |
| Phase 1b and Phase 2 Parts: Duration of Response (DOR) | Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months | 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. |
| Phase 1b and Phase 2 Parts: Disease Control Rate (DCR) | Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months | 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. |
| Phase 1b and Phase 2 Parts: Clinical Benefit Rate (CBR) | Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months | 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. |
Countries
Japan, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 25 investigative sites in Japan, United States, Spain, and United Kingdom from 27 October 2021 to 15 October 2024.
Pre-assignment details
A total of 152 participants were screened, of which 63 were screen failures and 89 received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg Participants received E7386 100 mg, tablets, orally, BID, plus pembrolizumab 200 mg, IV infusion, Q3W continuously in 21-day cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice, or discontinuation of the study program. | 6 |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg Participants received E7386 120 mg, tablets, orally, BID, plus pembrolizumab 200 mg, IV infusion, Q3W continuously in 21-day cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice, or discontinuation of the study program. | 6 |
| Phase 2, Dose Expansion, HCC: E7386 120 mg + Pembrolizumab 200 mg Participants with HCC received E7386 120 mg, tablets, orally, BID, plus pembrolizumab 200 mg, IV infusion, Q3W continuously in 21-day cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice, or discontinuation of the study program. | 17 |
| Phase 2, Dose Expansion, Melanoma: E7386 120 mg + Pembrolizumab 200 mg Participants with melanoma received E7386 120 mg, tablets, orally, BID, plus pembrolizumab 200 mg, IV infusion, Q3W continuously in 21-day cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice, or discontinuation of the study program. | 29 |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg Participants with CRC received E7386 120 mg, tablets, orally, BID, plus pembrolizumab 200 mg, IV infusion, Q3W continuously in 21-day cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice, or discontinuation of the study program. | 31 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 6 | 5 | 8 | 16 | 26 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Survival follow-up ceased/discontinued by sponsor | 0 | 0 | 7 | 10 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 2, Dose Expansion, HCC: E7386 120 mg + Pembrolizumab 200 mg | Phase 2, Dose Expansion, Melanoma: E7386 120 mg + Pembrolizumab 200 mg | Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 64.8 years STANDARD_DEVIATION 8.38 | 63.3 years STANDARD_DEVIATION 14 | 66.4 years STANDARD_DEVIATION 12.52 | 60.8 years STANDARD_DEVIATION 11.16 | 55.5 years STANDARD_DEVIATION 11.2 | 60.5 years STANDARD_DEVIATION 11.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 16 Participants | 27 Participants | 29 Participants | 84 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 6 Participants | 5 Participants | 5 Participants | 12 Participants | 34 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 10 Participants | 23 Participants | 14 Participants | 47 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 6 Participants | 10 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 11 Participants | 19 Participants | 19 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 5 / 6 | 8 / 17 | 16 / 29 | 26 / 31 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 17 / 17 | 28 / 29 | 30 / 31 |
| serious Total, serious adverse events | 0 / 6 | 2 / 6 | 7 / 17 | 5 / 29 | 10 / 31 |
Outcome results
Primary
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)
Population: The DLT Analysis Set included all participants in Phase 1b part who had received study drug as planned (that is \[i.e.\], complete at least 75% of the planned E7386) in Cycle 1, or who experienced a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
Primary
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)
Population: Safety Analysis Set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part: Number of Participants With Serious TEAEs | 0 Participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part: Number of Participants With Serious TEAEs | 2 Participants |
Primary
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)
Population: Safety Analysis Set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
Primary
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
Population: Efficacy Analysis Set included all participants with measurable disease at Baseline who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 2 Part: Objective Response Rate (ORR) | 0.0 percentage of participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 2 Part: Objective Response Rate (ORR) | 6.9 percentage of participants |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Phase 2 Part: Objective Response Rate (ORR) | 3.2 percentage of participants |
Secondary
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
Population: Efficacy Analysis Set included all participants with measurable disease at Baseline who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Clinical Benefit Rate (CBR) | 16.7 percentage of participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Clinical Benefit Rate (CBR) | 16.7 percentage of participants |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Clinical Benefit Rate (CBR) | 11.8 percentage of participants |
| Phase 2, Dose Expansion, Melanoma: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Clinical Benefit Rate (CBR) | 13.8 percentage of participants |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Clinical Benefit Rate (CBR) | 16.1 percentage of participants |
Secondary
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.
Time frame: Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months
Population: Efficacy Analysis Set included all participants with measurable disease at Baseline who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Disease Control Rate (DCR) | 83.3 percentage of participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Disease Control Rate (DCR) | 33.3 percentage of participants |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Disease Control Rate (DCR) | 58.8 percentage of participants |
| Phase 2, Dose Expansion, Melanoma: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Disease Control Rate (DCR) | 48.3 percentage of participants |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Disease Control Rate (DCR) | 32.3 percentage of participants |
Secondary
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
Population: Efficacy Analysis Set included all participants with measurable disease at Baseline who received at least 1 dose of any study drug. Here, Overall Number of Participants Analyzed signifies participants who had CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Dose Expansion, Melanoma: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Duration of Response (DOR) | 14.1 months |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b and Phase 2 Parts: Duration of Response (DOR) | 7.5 months |
Secondary
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)
Population: Pharmacokinetic Analysis Set included all participants who had received at least 1 dose of study drug and had at least 1 evaluable plasma E7386 concentration. As planned, this PK parameter was assessed in Phase 1b Part only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | 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 | Cycle 1 Day 1 | 874 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 192 |
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | 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 | Cycle 1 Day 8 | 1830 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 180 |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | 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 | Cycle 1 Day 1 | 1400 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 52.5 |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | 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 | Cycle 1 Day 8 | 2540 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 81.3 |
Secondary
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)
Population: Pharmacokinetic Analysis Set included all participants who had received at least 1 dose of study drug and had at least 1 evaluable plasma E7386 concentration. As planned, this PK parameter was assessed in Phase 1b Part at Cycle 1 Day 8 only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part, CLss/F: Apparent Clearance From Plasma at Steady State for E7386 When Co-administered With Pembrolizumab | 54.0 liter per hour | Geometric Coefficient of Variation 181 |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part, CLss/F: Apparent Clearance From Plasma at Steady State for E7386 When Co-administered With Pembrolizumab | 46.9 liter per hour | Geometric Coefficient of Variation 80.7 |
Secondary
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)
Population: Pharmacokinetic Analysis Set included all participants who had received at least 1 dose of study drug and had at least 1 evaluable plasma E7386 concentration. As planned, this PK parameter was assessed in Phase 1b Part only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 1 | 401 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 232 |
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 8 | 386 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 240 |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 1 | 472 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 82.1 |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 8 | 706 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 86.4 |
Secondary
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
Population: Efficacy Analysis Set included all participants with measurable disease at Baseline who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | PR | 0 percentage of participants |
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | PD | 16.7 percentage of participants |
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | SD | 83.3 percentage of participants |
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | NA/NE | 0 percentage of participants |
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | CR | 0 percentage of participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | NA/NE | 16.7 percentage of participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | CR | 0 percentage of participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | PR | 0 percentage of participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | SD | 33.3 percentage of participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part: Percentage of Participants With Best Overall Response (BOR) | PD | 50.0 percentage of participants |
Secondary
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)
Population: Pharmacokinetic Analysis Set included all participants who had received at least 1 dose of study drug and had at least 1 evaluable plasma E7386 concentration. As planned, this PK parameter was assessed in Phase 1b Part only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 1 | 0.70 hour |
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 8 | 2.90 hour |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 1 | 2.00 hour |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab | Cycle 1 Day 8 | 1.38 hour |
Secondary
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)
Population: Safety Analysis Set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs | TEAEs | 17 Participants |
| Phase 1b, Dose Escalation: E7386 100 mg + Pembrolizumab 200 mg | Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs | Treatment Related TEAEs | 16 Participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs | TEAEs | 28 Participants |
| Phase 1b, Dose Escalation: E7386 120 mg + Pembrolizumab 200 mg | Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs | Treatment Related TEAEs | 26 Participants |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs | TEAEs | 30 Participants |
| Phase 2, Dose Expansion, CRC: E7386 120 mg + Pembrolizumab 200 mg | Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs | Treatment Related TEAEs | 28 Participants |