Advanced Solid Tumors
Conditions
Brief summary
This is a multicenter, open-label, Phase 1b/2 study which will be conducted in two parts: a Phase 1b part comprising a dose escalation and an expansion cohort; and a Phase 2 part which will comprise two cohorts. The purpose of the Phase 1b part is to identify the maximum tolerated dose (MTD) of E7050 and E7080 (lenvatinib) in combination in participants with unresectable advanced or metastatic solid tumors. In the subsequent Phase 1b expansion cohort and Phase 2 cohorts, additional participants with recurrent glioblastoma or unresectable Stage III or Stage IV melanoma and disease progression after prior systemic treatment will be enrolled to confirm the MTD (expansion cohort) and to further explore the clinical activity of E7050 and lenvatinib.
Interventions
DRUGGolvatinib
Participants will receive E7050 50 mg and/or 100 mg tablets. E7050 will be administered orally once daily, in 28-day cycles.
DRUGLenvatinib
Participants will receive lenvatinib 1 mg and/or 4 mg and/or 10 mg capsules. Lenvatinib will be administered orally once daily, in 28-day cycles.
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants must meet all of the following criteria to be included in this study: 1. Phase 1b: Unresectable advanced or metastatic solid tumors. 2. Phase 1b expansion cohort and Phase 2: Histological confirmed diagnosis of glioblastoma (expansion cohort and Cohort 1) or melanoma (expansion cohort and Cohort 2). Phase 1b expansion cohort glioblastoma participants, Phase 2 Cohort 1: 3. No evidence of active central nervous systems (CNS) hemorrhage on baseline scans other than in those participants with recurrent glioblastoma who are stable Grade 1. 4. Participants having first or second recurrence documented by magnetic resonance imaging (MRI), following primary management with surgical resection or biopsy, radiotherapy and up to two prior systemic treatments. 5. If participants is on corticosteroids, they must be on a stable dose for 1 week prior to first dose of study drug. 6. Measurable disease defined as bidimensionally contrast enhancing lesions with clearly defined margins by computerized tomography (CT) or MRI scan, with a minimal diameter of 1 cm, and visible on two axial slices which are preferably at most 5 millimeter (mm) apart with 0 mm skip. Phase 1b expansion cohort melanoma participants, Phase 2 Cohort 2: 7. Radiographic/ photographic evidence of disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Appendix 3) after no more than two prior systemic regimens for unresectable Stage III or Stage IV disease. 8. American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV melanoma. 9. Measurable disease meeting the following criteria: 1. At least one lesion of greater than or equal to 1.0 cm in the longest diameter for a non-lymph node or greater than or equal to 1.5 centimeter (cm) in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using CT/MRI or photography. If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of greater than or equal to 1.5 cm. 2. Lesions that have had external beam radiotherapy or loco-regional therapies such as radio frequency ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion. All participants: 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 11. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to 150/90 millimeter of mercury (mmHg) at screening and no change in antihypertensive medications within 1 week before the Screening Visit. 12. Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 milligrams per deciliter (mg/dL) or calculated creatinine clearance greater than or equal to 40 milliliters per minute (mL/min) per the Cockcroft and Gault formula (see Appendix 5). 13. Adequate bone marrow function: * Absolute neutrophil count greater than or equal to 1500/mm3 (greater than or equal to 1.5 x 10\^3/uL); * Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 x 10\^9/L); * Hemoglobin greater than or equal to 9.0 g/dL. 14.Adequate blood coagulation function, as evidenced by an International Normalized Ratio (INR) less than or equal to 1.5. 14. Adequate liver function: * Bilirubin less than or equal to 1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome; * ALP, ALT, and AST less than or equal to 3 x ULN (less than or equal to 5 x ULN if participant has liver metastases). 15. Males or females age greater than or equal to 18 years at the time of informed consent. 16. All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin \[B-hCG\] at the Screening and Baseline Visit (a separate Baseline assessment is not required if a negative Screening pregnancy test was obtained within 72 hours before the first dose of study drug). Females of child-bearing potential, if not practising total abstinence or having a vasectomized partner with confirmed azoospermia, must agree to use two highly effective methods of contraception: e.g., 1) an intrauterine device (IUD) or intrauterine system (IUS); 2) a barrier method such as a condom or occlusive cup (diaphragm or cervical/vault caps) + spermicide (foam, gel, cream, etc.); 3) oral, injected, or implanted hormonal contraceptives throughout the entire study period and for 30 days after study drug discontinuation. Use of a double-barrier method (i.e., use at the same time of a condom + occlusive cup \[diaphragm or cervical/vault caps\] + spermicide \[foam, gel, cream, etc.\]) is accepted as two highly effective methods of contraception. The only participants who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or participants who have been sterilized surgically or who are otherwise proven sterile (i.e., bilateral tubal ligation with surgery at least 1 month prior to dosing, total hysterectomy, or bilateral oophorectomy with surgery at least 1 month prior to dosing). All women who are of reproductive potential and who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. 17. Male participants who are partners of women of childbearing potential must use a condom + spermicide and their female partners, if of childbearing potential, must use a highly effective method of contraception (see methods described in Inclusion Criterion #18) beginning at least 1 menstrual cycle prior to starting study drug, throughout the entire study period, and for 30 days after the last dose of study drug, unless the male participants are totally abstinent sexually or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile (see Inclusion Criterion #16). 18. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
Exclusion criteria
Participants who meet any of the following criteria will be excluded from this study: 1. Phase 1b Dose Escalation: Participants who discontinued prior TK inhibitor (including VEGFR and c-Met receptor targeted therapy) due to toxicity will be ineligible. 2. Phase 1b Dose Escalation (3+3 portion) participants with primary CNS tumors 3. Phase 1b Dose Escalation participants, melanoma participants in expansion cohort and Phase 2 Cohort 2: Participants with untreated or unstable metastases to the central nervous system (CNS) are excluded. participants who have completed local therapy and have discontinued the use of steroids for this indication at least 4 weeks prior to commencing treatment and have remained asymptomatic for at least 4 weeks prior to commencing treatment are eligible. 4. Phase 2: Prior exposure to VEGF-targeted treatment or c-Met or hepatocyte growth factor (HGF) targeted treatment. 5. Phase 2: Active malignancy (except for glioblastoma (Cohort 1) or unresectable Stage III or Stage IV melanoma (Cohort 2); or melanoma in situ, basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix) within the past 24 months. Phase 1b expansion cohort glioblastoma participants and Phase 2 Cohort 1: 6. More than two recurrences of glioblastoma. 7. Prior bevacizumab treatment. 8. Surgical resection of brain tumor within 4 weeks, or prior stereotactic biopsy within 2 weeks of Screening visit. 9. Prior radiotherapy within 12 weeks unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field (beyond the high dose region or 80% isodose line), or there is biopsy-proven unequivocal viable tumor on histopathology sampling (e.g., solid tumor areas (i.e. greater than 70% tumor cell nuclei in areas), high or progressive increase in MIB-1 proliferation index compared to prior biopsy, or evidence for histological progression or increased anaplasia in the tumor). 10. Participants who have received enzyme-inducing anti epileptic agents within 14 days before the first dose of study drug (e.g., carbamazepine, phenytoin, phenobarbital, primidone, or oxcarbazepine). Phase 1b expansion cohort participants with melanoma and Phase 2 Cohort 2: 11. More than two prior systemic regimens for unresectable Stage III or Stage IV disease. All participants 12. Prior exposure to E7050 or lenvatinib. 13. Melanoma of intraocular origin. 14. participants who have received any anticancer treatment within 21 days (6 weeks for nitrosureas Cohort 1) or any investigational agent within 30 days prior to the first dose of study drug or who have not recovered from any acute toxicity related to previous anticancer treatment. 15. Major surgery within 3 weeks prior to the first dose of study drug. 16. Participants having greater than 1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein greater than or equal to 1 g/24-hour will be ineligible. 17. Inability to take oral medication, gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of E7050 or lenvatinib. 18. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment. 19. Prolongation of QTc interval to greater than 480 msec. 20. Bleeding disorder or thrombotic disorder requiring anticoagulant therapy, such as warfarin, or similar agents requiring therapeutic INR monitoring (treatment with low molecular weight heparin \[LMWH\] is allowed). 21. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug. 22. Active infection (any infection requiring antibiotics). 23. Known intolerance or known hypersensitivity to any of the study drugs (or any of the excipients). 24. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial. 25. Females who are pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)- Combination Treatment | Cycle 1 (Cycle length= 28 days) | DLT was defined as toxicity related to the combination therapy and was graded according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Hematological DLTs were Grade 4 neutropenia for greater than or equal to (\>=) 7 days or Grade 3 neutropenia with fever (greater than \[\>\] 38.5 degree Celsius (°C) in axilla), Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or lasting \>7 days and decrease of hemoglobin of Grade 4. Non-hematological DLTS were Grade 3 fatigue, or a 2 point decline in Eastern Cooperative Oncology Group (ECOG) performance status must persist for \>7days, Nausea, vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy, Grade 4 hypertension or Grade 3 hypertension not able to be controlled by medication and any Grade 3 or higher non-hematological laboratory abnormalities that require hospitalization. |
| Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Golvatinib in Combination With Lenvatinib | Cycle 1 (Cycle length= 28 days) | The MTD was defined as the highest dose level at which no more than 1/6 participants experienced a DLTs, with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. MTD was determined by summarizing the number and percentage of participants with DLTs for the first cycle, by study dosing schedule, initial dosing level and overall for the dose escalation part. The RP2D of golvatinib in Combination with lenvatinib was MTD determined by Dose Escalation Committee (DEC) based on safety, PK and clinical data. DLT was defined as toxicity related to the combination therapy and was graded according to CTCAE v4.0. |
| Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Golvatinib | Cycle 1 (Cycle length= 28 days) | The MTD was defined as the highest dose level at which no more than 1/6 participants experienced a DLTs, with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. MTD was determined by summarizing the number and percentage of participants with DLTs for the first cycle, by study dosing schedule, initial dosing level and overall for the dose escalation part. The RP2D of lenvatinib in Combination with golvatinib was MTD determined by DEC based on safety, PK and clinical data. DLT was defined as toxicity related to the combination therapy and was graded according to CTCAE v4.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | From baseline up to approximately up to 5 years 5 months | — |
| Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib When Administered as a Single Agent at Day -7 | Day -7: 0-24 hours post-dose | — |
| Phase 1b: Cmax; Maximum Observed Plasma Concentration for Lenvatinib When Administered as a Single Agent at Day -8 | Day -8: 0-24 hours post-dose | — |
| Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered as a Single Agent at Day -7 | Day -7: 0-24 hours post-dose | — |
| Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Lenvatinib When Administered as a Single Agent at Day -8 | Day -8: 0-24 hours post-dose | — |
| Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib When Administered as Single Agent at Day -7 | Day -7: 0-24 hours post-dose | — |
| Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Lenvatinib When Administered as Single Agent at Day -8 | Day -8: 0-24 hours post-dose | — |
| Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered as Single Agent at Day -7 | Day -7: 0-24 hours post-dose | — |
| Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Lenvatinib When Administered as Single Agent at Day -8 | Day -8: 0-24 hours post-dose | — |
| Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Golvatinib When Administered as Single Agent at Day -7 | Day -7: 0-24 hours post-dose | — |
| Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | Day -8: 0-24 hours post-dose | — |
| Phase 1b: t1/2; Terminal Elimination Half-life for Golvatinib When Administered as Single Agent at Day -7 | Day-7: 0-24 hours post-dose | — |
| Phase 1b: t1/2; Terminal Elimination Half-life for Lenvatinib When Administered as Single Agent at Day -8 | Day -8: 0-24 hours post-dose | — |
| Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib When Administered as Single Agent at Day -7 | Day -7: 0-24 hours post-dose | — |
| Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values- Combination Treatment | From baseline up to approximately 5 years 5 months | — |
| Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Golvatinib When Administered as Single Agent at Day -7 | Day -7: 0-24 hours post-dose | — |
| Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Lenvatinib When Administered as Single Agent at Day -8 | Day -8: 0-24 hours post dose | — |
| Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Cycle 1 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Cycle 1 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Cycle 1 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Cycle 1 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: CLss/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days) | — |
| Phase 1b: Objective Response Rate (ORR); Combination Treatment | 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 (approximately up to 5 years 5 months) | ORR was assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. ORR was defined as the percentage of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR). CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (\<)10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | Day -8: 0-24 hours post-dose | — |
| Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values- Combination Treatment | From baseline up to approximately 5 years 5 months | — |
| Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | From baseline up to approximately 5 years 5 months | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 2 investigative sites in the United States from 13 October 2011 to 01 March 2017.
Pre-assignment details
A total of 40 participants were screened, of which 10 were screen failures and 30 participants were enrolled in the study. This study was planned to be conducted in 2 parts: Phase 1b part and Phase 2 part. Study was terminated by the sponsor at the end of Phase 1b due to a change in corporate strategy, hence Phase 2 was not carried out. In this study, a single agent run-in period was conducted prior to the administration of combination treatment in treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg Participants received lenvatinib 12 mg capsules, orally, once on Day -8, followed by golvatinib 200 mg tablets, orally, once on Day -7 in single agent run in period. Eligible participants who completed run-in period were then entered in combination agent treatment period. In combination agent treatment period, participants received lenvatinib 12 mg capsules, orally, once daily in combination with golvatinib 200 mg tablets, orally, once daily in 28-days treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent (up to approximately 88 weeks). | 3 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg Participants received lenvatinib 20 mg capsules, orally, once on Day -8, followed by golvatinib 200 mg tablets, orally, once on Day -7 in single agent run in period. Eligible participants who completed run-in period were then entered in combination agent treatment period. In combination agent treatment period, participants received lenvatinib 20 mg capsules, orally, once daily in combination with golvatinib 200 mg tablets, orally, once daily in 28-days treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent (up to approximately 88 weeks). | 3 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg Participants received lenvatinib 20 mg capsules, orally, once on Day -8, followed by golvatinib 300 mg tablets, orally, once on Day -7 in single agent run in period. Eligible participants who completed run-in period were then entered in combination agent treatment period. In combination agent treatment period, participants received lenvatinib 20 mg capsules, orally, once daily in combination with golvatinib 300 mg tablets, orally, once daily in 28-days treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent (up to approximately 88 weeks). | 14 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg Participants received lenvatinib 20 mg capsules, orally, once on Day -8, followed by golvatinib 400 mg tablets, orally, once on Day -7 in single agent run in period. Eligible participants who completed run-in period were then entered in combination agent treatment period. In combination agent treatment period, participants received lenvatinib 20 mg capsules, orally, once daily in combination with golvatinib 400 mg tablets, orally, once daily in 28-days treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent (up to approximately 88 weeks). | 8 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Pretreatment Phase (Single Agent Run-in) | Did not enter into treatment phase | 2 | 0 | 0 | 0 |
| Treatment Phase (Combination Agent) | Adverse Event | 1 | 0 | 3 | 1 |
| Treatment Phase (Combination Agent) | Clinical progression | 0 | 1 | 2 | 3 |
| Treatment Phase (Combination Agent) | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Treatment Phase (Combination Agent) | Participant Choice | 0 | 0 | 0 | 1 |
| Treatment Phase (Combination Agent) | Progressive disease | 1 | 0 | 0 | 0 |
| Treatment Phase (Combination Agent) | Terminated by sponsor | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 58.0 years | 63.0 years | 64.5 years | 56.5 years | 62.0 years |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 3 Participants | 12 Participants | 8 Participants | 26 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 7 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 7 Participants | 4 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 3 | 0 / 14 | 3 / 8 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 13 / 14 | 8 / 8 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 8 / 14 | 3 / 8 |
Outcome results
Primary
Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Golvatinib in Combination With Lenvatinib
The MTD was defined as the highest dose level at which no more than 1/6 participants experienced a DLTs, with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. MTD was determined by summarizing the number and percentage of participants with DLTs for the first cycle, by study dosing schedule, initial dosing level and overall for the dose escalation part. The RP2D of golvatinib in Combination with lenvatinib was MTD determined by Dose Escalation Committee (DEC) based on safety, PK and clinical data. DLT was defined as toxicity related to the combination therapy and was graded according to CTCAE v4.0.
Time frame: Cycle 1 (Cycle length= 28 days)
Population: The safety analysis set (combination treatment) included all participants who received at least 1 dose of combination treatment and had at least 1 postbaseline safety evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Golvatinib in Combination With Lenvatinib | MTD | 300.0 milligram per day (mg/day) |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Golvatinib in Combination With Lenvatinib | RP2D | 300.0 milligram per day (mg/day) |
Primary
Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Golvatinib
The MTD was defined as the highest dose level at which no more than 1/6 participants experienced a DLTs, with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. MTD was determined by summarizing the number and percentage of participants with DLTs for the first cycle, by study dosing schedule, initial dosing level and overall for the dose escalation part. The RP2D of lenvatinib in Combination with golvatinib was MTD determined by DEC based on safety, PK and clinical data. DLT was defined as toxicity related to the combination therapy and was graded according to CTCAE v4.0.
Time frame: Cycle 1 (Cycle length= 28 days)
Population: The safety analysis set (combination treatment) included all participants who received at least 1 dose of combination treatment and had at least 1 postbaseline safety evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Golvatinib | MTD | 20.0 mg/day |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Golvatinib | RP2D | 20.0 mg/day |
Primary
Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)- Combination Treatment
DLT was defined as toxicity related to the combination therapy and was graded according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Hematological DLTs were Grade 4 neutropenia for greater than or equal to (\>=) 7 days or Grade 3 neutropenia with fever (greater than \[\>\] 38.5 degree Celsius (°C) in axilla), Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or lasting \>7 days and decrease of hemoglobin of Grade 4. Non-hematological DLTS were Grade 3 fatigue, or a 2 point decline in Eastern Cooperative Oncology Group (ECOG) performance status must persist for \>7days, Nausea, vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy, Grade 4 hypertension or Grade 3 hypertension not able to be controlled by medication and any Grade 3 or higher non-hematological laboratory abnormalities that require hospitalization.
Time frame: Cycle 1 (Cycle length= 28 days)
Population: The safety analysis set (combination treatment) included all participants who received at least 1 dose of combination treatment and had at least 1 postbaseline safety evaluation. Here, overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)- Combination Treatment | 0 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)- Combination Treatment | 0 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)- Combination Treatment | 4 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)- Combination Treatment | 2 Participants |
Secondary
Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2
Time frame: Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 68700 ng*h/mL | — |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1120 ng*h/mL | — |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 3060 ng*h/mL | Standard Deviation 247 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 45000 ng*h/mL | Standard Deviation 29700 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 57100 ng*h/mL | Standard Deviation 25300 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 2380 ng*h/mL | Standard Deviation 1430 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 138000 ng*h/mL | Standard Deviation 98900 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 4320 ng*h/mL | Standard Deviation 3860 |
Secondary
Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1
Time frame: Cycle 1 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure. Here number analyzed n are the participants who were evaluable for the outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 33800 ng*h/mL | Standard Deviation 4270 |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 1460 ng*h/mL | Standard Deviation 922 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 2370 ng*h/mL | Standard Deviation 35.4 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 22100 ng*h/mL | Standard Deviation 15900 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 38700 ng*h/mL | Standard Deviation 21700 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 2290 ng*h/mL | Standard Deviation 1250 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 60400 ng*h/mL | Standard Deviation 26200 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 2390 ng*h/mL | Standard Deviation 1710 |
Secondary
Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib When Administered as Single Agent at Day -7
Time frame: Day -7: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here, overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib When Administered as Single Agent at Day -7 | 25600 nanogram*hour per milliliter(ng*h/mL) | Standard Deviation 6720 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib When Administered as Single Agent at Day -7 | 19300 nanogram*hour per milliliter(ng*h/mL) | Standard Deviation 14000 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib When Administered as Single Agent at Day -7 | 34400 nanogram*hour per milliliter(ng*h/mL) | Standard Deviation 25600 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Golvatinib When Administered as Single Agent at Day -7 | 50000 nanogram*hour per milliliter(ng*h/mL) | Standard Deviation 27900 |
Secondary
Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Lenvatinib When Administered as Single Agent at Day -8
Time frame: Day -8: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Lenvatinib When Administered as Single Agent at Day -8 | 1540 ng*h/mL | Standard Deviation 581 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Lenvatinib When Administered as Single Agent at Day -8 | 2690 ng*h/mL | Standard Deviation 75.7 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Lenvatinib When Administered as Single Agent at Day -8 | 2620 ng*h/mL | Standard Deviation 1160 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUC24; Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Lenvatinib When Administered as Single Agent at Day -8 | 3200 ng*h/mL | Standard Deviation 2210 |
Secondary
Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Golvatinib When Administered as Single Agent at Day -7
Time frame: Day -7: 0-24 hours post-dose
Population: PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Golvatinib When Administered as Single Agent at Day -7 | 58300 ng*h/mL | Standard Deviation 23500 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Golvatinib When Administered as Single Agent at Day -7 | 51200 ng*h/mL | — |
Secondary
Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8
Time frame: Day -8: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here, overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | 1890 ng*h/mL | Standard Deviation 693 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | 3060 ng*h/mL | Standard Deviation 250 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | 2930 ng*h/mL | Standard Deviation 1360 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUC∞; Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | 3910 ng*h/mL | Standard Deviation 2680 |
Secondary
Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2
Time frame: Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 68700 ng*h/mL | — |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1120 ng*h/mL | — |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 3060 ng*h/mL | Standard Deviation 255 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 45200 ng*h/mL | Standard Deviation 29500 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 57100 ng*h/mL | Standard Deviation 25300 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 2380 ng*h/mL | Standard Deviation 1430 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 138000 ng*h/mL | Standard Deviation 98700 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 4330 ng*h/mL | Standard Deviation 3850 |
Secondary
Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1
Time frame: Cycle 1 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here number analyzed n are the participants who were evaluable for the outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 34000 ng*h/mL | Standard Deviation 4290 |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 1470 ng*h/mL | Standard Deviation 921 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 2370 ng*h/mL | Standard Deviation 42.4 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 22200 ng*h/mL | Standard Deviation 15900 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 39800 ng*h/mL | Standard Deviation 21800 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 2400 ng*h/mL | Standard Deviation 1270 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 60800 ng*h/mL | Standard Deviation 26700 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 2400 ng*h/mL | Standard Deviation 1730 |
Secondary
Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered as Single Agent at Day -7
Time frame: Day -7: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered as Single Agent at Day -7 | 26500 ng*h/mL | Standard Deviation 6380 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered as Single Agent at Day -7 | 34700 ng*h/mL | Standard Deviation 27900 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered as Single Agent at Day -7 | 38000 ng*h/mL | Standard Deviation 25400 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered as Single Agent at Day -7 | 64000 ng*h/mL | Standard Deviation 33000 |
Secondary
Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Lenvatinib When Administered as Single Agent at Day -8
Time frame: Day -8: 0-24 hours post-dose
Population: PK analysis set included participants who had at least 1 evaluable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Lenvatinib When Administered as Single Agent at Day -8 | 1800 ng*h/mL | Standard Deviation 697 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Lenvatinib When Administered as Single Agent at Day -8 | 3030 ng*h/mL | Standard Deviation 254 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Lenvatinib When Administered as Single Agent at Day -8 | 3030 ng*h/mL | Standard Deviation 1260 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: AUCt; Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Lenvatinib When Administered as Single Agent at Day -8 | 3780 ng*h/mL | Standard Deviation 2630 |
Secondary
Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib When Administered as Single Agent at Day -7
Time frame: Day -7: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib When Administered as Single Agent at Day -7 | 3.74 liter per hour (L/h) | Standard Deviation 1.51 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib When Administered as Single Agent at Day -7 | 5.87 liter per hour (L/h) | — |
Secondary
Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8
Time frame: Day -8: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | 7.01 liter per hour (L/h) | Standard Deviation 2.31 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | 6.57 liter per hour (L/h) | Standard Deviation 0.556 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | 8.63 liter per hour (L/h) | Standard Deviation 5.33 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: CL/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Lenvatinib When Administered as Single Agent at Day -8 | 7.23 liter per hour (L/h) | Standard Deviation 4.25 |
Secondary
Phase 1b: CLss/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2
Time frame: Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: CLss/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 5.69 liter per hour (L/h) | Standard Deviation 3.76 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: CLss/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 6.58 liter per hour (L/h) | Standard Deviation 0.54 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: CLss/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 3.49 liter per hour (L/h) | Standard Deviation 1.81 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: CLss/F; Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 7.96 liter per hour (L/h) | Standard Deviation 5.72 |
Secondary
Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2
Time frame: Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 3540 ng/mL | — |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 66.3 ng/mL | — |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 356 ng/mL | Standard Deviation 76.4 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 2750 ng/mL | Standard Deviation 870 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 3570 ng/mL | Standard Deviation 1350 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 245 ng/mL | Standard Deviation 110 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 6920 ng/mL | Standard Deviation 4130 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 408 ng/mL | Standard Deviation 250 |
Secondary
Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1
Time frame: Cycle 1 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure. Here number analyzed n are the participants who were evaluable for the outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 2890 ng/mL | Standard Deviation 1080 |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 182 ng/mL | Standard Deviation 137 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 315 ng/mL | Standard Deviation 35.4 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 1990 ng/mL | Standard Deviation 1470 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 3050 ng/mL | Standard Deviation 1030 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 258 ng/mL | Standard Deviation 148 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 4820 ng/mL | Standard Deviation 1510 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 251 ng/mL | Standard Deviation 144 |
Secondary
Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib When Administered as a Single Agent at Day -7
Time frame: Day -7: 0-24 hours post-dose
Population: The pharmacokinetic (PK) analysis set included participants who had at least 1 evaluable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib When Administered as a Single Agent at Day -7 | 2160 nanograms per milliliter (ng/mL) | Standard Deviation 848 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib When Administered as a Single Agent at Day -7 | 1710 nanograms per milliliter (ng/mL) | Standard Deviation 1410 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib When Administered as a Single Agent at Day -7 | 3020 nanograms per milliliter (ng/mL) | Standard Deviation 2130 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib When Administered as a Single Agent at Day -7 | 3930 nanograms per milliliter (ng/mL) | Standard Deviation 1800 |
Secondary
Phase 1b: Cmax; Maximum Observed Plasma Concentration for Lenvatinib When Administered as a Single Agent at Day -8
Time frame: Day -8: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Lenvatinib When Administered as a Single Agent at Day -8 | 174 ng/mL | Standard Deviation 88 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Lenvatinib When Administered as a Single Agent at Day -8 | 393 ng/mL | Standard Deviation 75 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Lenvatinib When Administered as a Single Agent at Day -8 | 297 ng/mL | Standard Deviation 159 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Cmax; Maximum Observed Plasma Concentration for Lenvatinib When Administered as a Single Agent at Day -8 | 388 ng/mL | Standard Deviation 250 |
Secondary
Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment
Time frame: From baseline up to approximately 5 years 5 months
Population: The safety analysis set (combination treatment) included all participants who received at least 1 dose of combination treatment and had at least 1 postbaseline safety evaluation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | Baseline and post-baseline data | 3 Participants |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline increase of greater than (>) 30 millisecond (msec) | 2 Participants |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline increase of > 60 msec | 1 Participants |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 450 msec | 2 Participants |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 480 msec | 1 Participants |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 500 msec | 1 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 500 msec | 0 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 450 msec | 2 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | Baseline and post-baseline data | 3 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline increase of > 60 msec | 0 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline increase of greater than (>) 30 millisecond (msec) | 0 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 480 msec | 0 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline increase of greater than (>) 30 millisecond (msec) | 1 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline increase of > 60 msec | 0 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 450 msec | 8 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 500 msec | 1 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 480 msec | 4 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | Baseline and post-baseline data | 13 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 480 msec | 1 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 500 msec | 0 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline increase of greater than (>) 30 millisecond (msec) | 4 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline value of > 450 msec | 4 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | Baseline and post-baseline data | 8 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment | At least 1 post-baseline increase of > 60 msec | 0 Participants |
Secondary
Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values- Combination Treatment
Time frame: From baseline up to approximately 5 years 5 months
Population: The safety analysis set (combination treatment) included all participants who received at least 1 dose of combination treatment and had at least 1 postbaseline safety evaluation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values- Combination Treatment | 0 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values- Combination Treatment | 0 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values- Combination Treatment | 0 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values- Combination Treatment | 0 Participants |
Secondary
Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values- Combination Treatment
Time frame: From baseline up to approximately 5 years 5 months
Population: The safety analysis set (combination treatment) included all participants who received at least 1 dose of combination treatment and had at least 1 postbaseline safety evaluation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values- Combination Treatment | 0 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values- Combination Treatment | 0 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values- Combination Treatment | 0 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values- Combination Treatment | 0 Participants |
Secondary
Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment
Time frame: From baseline up to approximately up to 5 years 5 months
Population: The safety analysis set (combination treatment) included all participants who received at least 1 dose of combination treatment and had at least 1 postbaseline safety evaluation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | TEAEs | 3 Participants |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | SAEs | 2 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | SAEs | 1 Participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | TEAEs | 3 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | TEAEs | 14 Participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | SAEs | 8 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | TEAEs | 8 Participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment | SAEs | 3 Participants |
Secondary
Phase 1b: Objective Response Rate (ORR); Combination Treatment
ORR was assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. ORR was defined as the percentage of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR). CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (\<)10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: 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 (approximately up to 5 years 5 months)
Population: Safety analysis set (combination treatment) included all participants who received at least 1 dose of combination treatment and had at least 1 postbaseline safety evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Objective Response Rate (ORR); Combination Treatment | 0 percentage of participants |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Objective Response Rate (ORR); Combination Treatment | 0 percentage of participants |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Objective Response Rate (ORR); Combination Treatment | 28.6 percentage of participants |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Objective Response Rate (ORR); Combination Treatment | 12.5 percentage of participants |
Secondary
Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2
Time frame: Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure. Here number analyzed n are the participants who were evaluable for the outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 2.35 ratio | — |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1.88 ratio | — |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1.29 ratio | Standard Deviation 0.127 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 3.96 ratio | Standard Deviation 2.14 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 1.90 ratio | Standard Deviation 0.905 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 0.928 ratio | Standard Deviation 0.295 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 2.10 ratio | Standard Deviation 0.254 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Rac(AUC); Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1.61 ratio | Standard Deviation 0.67 |
Secondary
Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2
Time frame: Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure. Here number analyzed n are the participants who were evaluable for the outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 2.11 ratio | — |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1.44 ratio | — |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1.13 ratio | Standard Deviation 0.12 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 3.16 ratio | Standard Deviation 2.24 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 1.30 ratio | Standard Deviation 0.481 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1.17 ratio | Standard Deviation 0.556 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 1.49 ratio | Standard Deviation 0.319 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Rac(Cmax); Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 1.63 ratio | Standard Deviation 1.27 |
Secondary
Phase 1b: t1/2; Terminal Elimination Half-life for Golvatinib When Administered as Single Agent at Day -7
Time frame: Day-7: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: t1/2; Terminal Elimination Half-life for Golvatinib When Administered as Single Agent at Day -7 | 34.6 hours | Standard Deviation 1.77 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: t1/2; Terminal Elimination Half-life for Golvatinib When Administered as Single Agent at Day -7 | 30.7 hours | — |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: t1/2; Terminal Elimination Half-life for Golvatinib When Administered as Single Agent at Day -7 | 57.0 hours | Standard Deviation 1.7 |
Secondary
Phase 1b: t1/2; Terminal Elimination Half-life for Lenvatinib When Administered as Single Agent at Day -8
Time frame: Day -8: 0-24 hours post-dose
Population: PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: t1/2; Terminal Elimination Half-life for Lenvatinib When Administered as Single Agent at Day -8 | 11.2 hours | Standard Deviation 3.27 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: t1/2; Terminal Elimination Half-life for Lenvatinib When Administered as Single Agent at Day -8 | 14.6 hours | Standard Deviation 6.69 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: t1/2; Terminal Elimination Half-life for Lenvatinib When Administered as Single Agent at Day -8 | 12.0 hours | Standard Deviation 5.49 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: t1/2; Terminal Elimination Half-life for Lenvatinib When Administered as Single Agent at Day -8 | 14.4 hours | Standard Deviation 6.86 |
Secondary
Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2
Time frame: Cycle 2 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 8.05 hours |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 10.55 hours |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 3.00 hours |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 2.00 hours |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 2.97 hours |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 3.90 hours |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Golvatinib: Cycle 2 Day 1 | 3.53 hours |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Multiple Dose on Day 1 Cycle 2 | Lenvatinib: Cycle 2 Day 1 | 3.53 hours |
Secondary
Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1
Time frame: Cycle 1 Day 1: 0-24 hours post-dose (cycle length is 28 days)
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure. Here number analyzed n are the participants who were evaluable for the outcome measure at given time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 3.02 hours |
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 3.02 hours |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 2.02 hours |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 4.00 hours |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 3.52 hours |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 3.95 hours |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Golvatinib: Cycle 1 Day 1 | 3.00 hours |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib and Lenvatinib When Administered in Combination Treatment as Single Dose on Day 1 Cycle 1 | Lenvatinib: Cycle 1 Day 1 | 3.98 hours |
Secondary
Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered as a Single Agent at Day -7
Time frame: Day -7: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered as a Single Agent at Day -7 | 2.00 hours |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered as a Single Agent at Day -7 | 4.00 hours |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered as a Single Agent at Day -7 | 2.54 hours |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered as a Single Agent at Day -7 | 2.54 hours |
Secondary
Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Lenvatinib When Administered as a Single Agent at Day -8
Time frame: Day -8: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Lenvatinib When Administered as a Single Agent at Day -8 | 3.00 hours |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Lenvatinib When Administered as a Single Agent at Day -8 | 2.00 hours |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Lenvatinib When Administered as a Single Agent at Day -8 | 3.01 hours |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Tmax; Time to Reach the Maximum Plasma Concentration (Cmax) for Lenvatinib When Administered as a Single Agent at Day -8 | 3.00 hours |
Secondary
Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Golvatinib When Administered as Single Agent at Day -7
Time frame: Day -7: 0-24 hours post-dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Golvatinib When Administered as Single Agent at Day -7 | 188 liter (L) | Standard Deviation 84.9 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Golvatinib When Administered as Single Agent at Day -7 | 260 liter (L) | — |
Secondary
Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Lenvatinib When Administered as Single Agent at Day -8
Time frame: Day -8: 0-24 hours post dose
Population: The PK analysis set included participants who had at least 1 evaluable plasma concentration. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Lenvatinib 12 mg + Golvatinib 200 mg | Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Lenvatinib When Administered as Single Agent at Day -8 | 112 liter (L) | Standard Deviation 53.4 |
| Cohort 2: Lenvatinib 20 mg + Golvatinib 200 mg | Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Lenvatinib When Administered as Single Agent at Day -8 | 135 liter (L) | Standard Deviation 55.1 |
| Cohort 3: Lenvatinib 20 mg + Golvatinib 300 mg | Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Lenvatinib When Administered as Single Agent at Day -8 | 182 liter (L) | Standard Deviation 209 |
| Cohort 4: Lenvatinib 20 mg + Golvatinib 400 mg | Phase 1b: Vz/F; Apparent Volume of Distribution at Terminal Phase for Lenvatinib When Administered as Single Agent at Day -8 | 137 liter (L) | Standard Deviation 87.5 |