Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck
Conditions
Keywords
Cancer, head and neck, squamous cell carcinoma of the head and neck, phase 1b, phase 2
Brief summary
The purpose of this study is to determine whether participants with platinum-resistant squamous cell carcinoma of the head and neck (SCCHN) who receive either E7050 administered with cetuximab or cetuximab alone experience greater benefit.
Detailed description
This open-label, multicenter, randomized study will consist of a Phase 1b: a safety run-in period with 3 ascending doses of E7050 in combination with cetuximab; and a Phase 2 portion: a randomized 2-arm period. Approximately 95 participants with platinum-resistant squamous cell carcinoma of the head and neck will be enrolled in the study (10-15 participants in the Phase 1b portion and 80 participants in the Phase 2 portion). Participants will only participate in either the Phase 1b or the Phase 2 portion of the study. In the Phase 2 portion, participants will receive study treatment (E7050 plus cetuximab or cetuximab alone) for approximately six 28-day cycles (24 weeks). Beyond 24 weeks, participants who are experiencing clinical benefit may continue E7050 plus cetuximab, cetuximab alone or E7050 alone (Arm 1), or may continue cetuximab alone (Arm 2), depending on the original randomization treatment arm, for as long as clinical benefit is sustained and the treatment is well tolerated.
Interventions
DRUGE7050
E7050 given orally at 200, 300, or 400 mg once daily.
DRUGCetuximab
Cetuximab is given at an initial dose of 400 mg/m2 given as a 2-hour intravenous (IV) infusion on Day 1 of Cycle 1, followed by a dose of 250 mg/m2 given as a 1-hour IV infusion on Day 8, Day 15, and Day 22 of Cycle 1, and Day 1, Day 8, Day 15, and Day 22 of each subsequent cycle.
Sponsors
PharmaBio Development Inc.
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
* Platinum-resistant (defined as failure to respond to treatment with a platinum agent or recurrence of disease after initial response to platinum within 12 months of completing therapy), locally advanced, recurrent and/or metastatic SCCHN, which is untreatable by surgical resection or radiation therapy * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2 * Blood pressure must be well-controlled. Participants must have no history of hypertensive crisis or hypertensive encephalopathy; Adequate end organ function
Exclusion criteria
* Nasopharyngeal tumors * Previously received E7050, anti-angiogenic therapy, or anti-epidermal growth factor receptor (EGFR) therapy (prior anti-angiogenic/EGFR therapy is permitted in Phase 1b only. Prior cetuximab is permitted if administered in combination with radiation * Presence of brain metastases, unless the participant has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization * Palliative radiotherapy is not permitted throughout the study period * Clinically significant hemoptysis * Serious non-healing wound, ulcer, or active bone fracture * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1, or anticipation of need for a major surgical procedure during the course of the study * Clinically significant gastrointestinal bleeding within 6 months prior to first dose.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Values | Up to 4 years 4 months | — |
| Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) | Cycle 1 (Cycle length is equal to [=] 28 days) | DLT:adverse events graded as NCI CTCAEv4.0 occurring less than or equal to(\<=)28 days after treatment.Events as: Non-hematological: 1)Grade greater than or equal to(\>=)3 peripheral neuropathy; 2)Grade 3 fatigue or 2 point decline in eastern cooperative oncology group performance status that persisted for greater than(\>)7 days; 3)Grade \>=3 nausea,vomiting despite optimal antiemetic treatment; 4)Any nonhematologic toxicity of Grade \>=3, with exceptions as alopecia,single laboratory values out of normal range,hypersensitivity reaction. Hematological 1)Grade 4 neutropenia lasting \>7 days; 2)Febrile neutropenia as fever \>=38.5 degree celsius with absolute neutrophil count less than(\<)1.0\*10\^9 per liter(/L); 3)Grade 3 thrombocytopenia with nontraumatic bleeding requiring platelet transfusion; 4)Grade 4 thrombocytopenia with/without nontraumatic bleeding. Other 1)Study drug related death; 2)Toxicity that dose escalation committee believed to be DLT that was not covered by above DLT criteria. |
| Phase 1b: Plasma Concentration of Golvatinib When Given in Combination With Cetuximab | Cycle 1: 0-48 hours post-dose (Each cycle=28 days) | — |
| Phase 2: Number of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) | Up to 5 years 11 months | TEAEs are defined as an adverse event that has an onset date, or a worsening in severity from baseline (pre-golvatinib), on or after the first dose of golvatinib. The severity was graded according to CTCAE v4.0. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event. |
| Phase 2: Number of Participants With Markedly Abnormal Vital Sign Values | Up to 4 years 4 months | — |
| Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Up to 4 years 4 months | Physical examination was performed and included evaluation of 1) General appearance, 2) Head; Eyes; Ears; Nose; Throat (HEENT), 3) Neck, 4) Heart, 5) Chest (Including Lungs), 6) Abdomen, 7) Extremities, 8) Skin, 9) Lymph Nodes, and 10) neurological status. Here, number of participants with markedly abnormal physical examinations were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Percentage of Participants With PFS at Week 12 | At Week 12 | PFS rate at week 12 is defined as the percentage of participants who were still alive without disease progression at 12 weeks from the date of randomization. PFS is defined as the time from the date of randomization until the earlier of the following two events: the date of PD or the date of death based on RECIST v1.1. PD is defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS rate was estimated and analyzed using Kaplan Meier method. |
| Phase 2: Time to Progression (TTP) | From the date of randomization until the date of PD (Up to approximately 4 years 4 months) | TTP is defined as the time from the date of randomization until the date of PD based on RECIST v1.1. PD is defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. TTP was estimated and analyzed using Kaplan Meier method. As planned, data for this endpoint was analyzed and collected till primary completion date. |
| Phase 2: Overall Survival (OS) | From the date of randomization until the date of death (Up to approximately 4 years 4 months) | OS is defined as the time from the date of randomization until the date of death. OS was analyzed using Kaplan Meier method. As planned, data for this endpoint was analyzed and collected till primary completion date. |
| Phase 2: Percentage of Participants With Overall Response | From the date of randomization until CR or PR (Up to approximately 4 years 4 months) | Overall response rate is defined as percentage of participants with complete response (CR) or partial response (PR) based on RECIST v1.1. CR is 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 \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As planned, data for this endpoint was analyzed and collected till primary completion date. |
| Phase 2: Progression-free Survival (PFS) | From the date of randomization until the earlier of the following two events: the date of PD or the date of death (Up to approximately 4 years 4 months) | PFS is defined as the time from the date of randomization until the earlier of the following two events: the date of PD or the date of death based on response evaluation criteria in solid tumor (RECIST) v1.1. PD is defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan Meier method. As planned, data for this endpoint was analyzed and collected till primary completion date. |
Countries
South Korea, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 28 investigative sites in the Republic of Korea, Ukraine, United Kingdom, and the United States from 19 September 2011 to 04 September 2017.
Pre-assignment details
This study consists of two phases Phase 1b and Phase 2. Phase 1b: 12 participants were enrolled and received the study treatment; Phase 2: 83 participants were enrolled and received the study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 Participants with platinum-resistant SCCHN received golvatinib 200 mg tablets, orally, once daily (run-in period) and cetuximab 400 mg/m\^2 intravenous infusion, once on Day 1 of Cycle 1, followed by cetuximab 250 mg/m\^2 intravenous infusion, once on Days 8, 15 and 22 of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles for determining MTD or RP2D, until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first. | 4 |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 Participants with platinum-resistant SCCHN received golvatinib 300 mg tablets, orally, once daily (run-in period) and cetuximab 400 mg/m\^2 intravenous infusion, once on Day 1 of Cycle 1, followed by cetuximab 250 mg/m\^2 intravenous infusion, once on Days 8, 15 and 22 of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles for determining MTD or RP2D, until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first. | 5 |
| Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2 Participants with platinum-resistant SCCHN received golvatinib 400 mg tablets, orally, once daily (run-in period) and cetuximab 400 mg/m\^2 intravenous infusion, once on Day 1 of Cycle 1, followed by cetuximab 250 mg/m\^2 intravenous infusion, once on Days 8, 15 and 22 of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles for determining MTD or RP2D, until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first. | 3 |
| Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2 Participants with platinum-resistant SCCHN received golvatinib 400 mg (RP2D) tablets, orally, once daily and cetuximab 400 mg/m\^2 intravenous infusion, once on Day 1 of Cycle 1, followed by cetuximab 250 mg/m\^2 intravenous infusion, once on Days 8, 15 and 22 of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles. After 6 cycles, at the discretion of the investigator, participants who experienced clinical benefit could continue for as long as clinical benefit was sustained and the treatment was well tolerated, until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first. | 42 |
| Phase 2: Arm 2: Cetuximab 400 mg/m^2 Participants with platinum-resistant SCCHN received cetuximab 400 mg/m\^2 intravenous infusion, once on Day 1 of Cycle 1, followed by 250 mg/m\^2 intravenous infusion, once on Days 8, 15 and 22 of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles. After 6 cycles, at the discretion of the Investigator, participants who experienced clinical benefit could continue for as long as clinical benefit was sustained and the treatment was well tolerated, until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first. | 41 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase 1b | Death | 3 | 3 | 2 | 0 | 0 |
| Phase 1b | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 |
| Phase 1b | Withdrawal by Subject | 1 | 1 | 1 | 0 | 0 |
| Phase 2 | Death | 0 | 0 | 0 | 33 | 36 |
| Phase 2 | Lost to Follow-up | 0 | 0 | 0 | 2 | 0 |
| Phase 2 | Physician Decision | 0 | 0 | 0 | 3 | 1 |
| Phase 2 | Progression Disease | 0 | 0 | 0 | 2 | 1 |
| Phase 2 | Symptomatic deterioration | 0 | 0 | 0 | 0 | 1 |
| Phase 2 | Withdrawal by Subject | 0 | 0 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Total | Phase 2: Arm 2: Cetuximab 400 mg/m^2 | Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2 | Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2 | Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 |
|---|---|---|---|---|---|---|
| Age, Continuous | 70.0 years STANDARD_DEVIATION 8.29 | 57.0 years STANDARD_DEVIATION 10.79 | 53.9 years STANDARD_DEVIATION 9.84 | 58.4 years STANDARD_DEVIATION 11.04 | 59.3 years STANDARD_DEVIATION 5.51 | 58.8 years STANDARD_DEVIATION 12.58 |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) ECOG: 0 (Fully Active) | 1 Participants | 21 Participants | 10 Participants | 10 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) ECOG: 1 (Restricted in Physical Activity; Ambulatory) | 3 Participants | 62 Participants | 24 Participants | 28 Participants | 3 Participants | 4 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) ECOG: 2 (Ambulatory and Capable of All Self-care) | 0 Participants | 5 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) ECOG: 3 (Capable of Only Limited Self-care) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) ECOG: 4 (Completely Disabled) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) ECOG: 5 (Dead) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) Not Specified | 0 Participants | 7 Participants | 4 Participants | 3 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 93 Participants | 41 Participants | 41 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 36 Participants | 12 Participants | 16 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 56 Participants | 29 Participants | 24 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 2 Participants | 13 Participants | 7 Participants | 4 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 82 Participants | 34 Participants | 38 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 3 / 5 | 2 / 3 | 33 / 42 | 36 / 41 |
| other Total, other adverse events | 4 / 4 | 5 / 5 | 3 / 3 | 42 / 42 | 38 / 41 |
| serious Total, serious adverse events | 1 / 4 | 4 / 5 | 2 / 3 | 15 / 42 | 15 / 41 |
Outcome results
Primary
Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)
DLT:adverse events graded as NCI CTCAEv4.0 occurring less than or equal to(\<=)28 days after treatment.Events as: Non-hematological: 1)Grade greater than or equal to(\>=)3 peripheral neuropathy; 2)Grade 3 fatigue or 2 point decline in eastern cooperative oncology group performance status that persisted for greater than(\>)7 days; 3)Grade \>=3 nausea,vomiting despite optimal antiemetic treatment; 4)Any nonhematologic toxicity of Grade \>=3, with exceptions as alopecia,single laboratory values out of normal range,hypersensitivity reaction. Hematological 1)Grade 4 neutropenia lasting \>7 days; 2)Febrile neutropenia as fever \>=38.5 degree celsius with absolute neutrophil count less than(\<)1.0\*10\^9 per liter(/L); 3)Grade 3 thrombocytopenia with nontraumatic bleeding requiring platelet transfusion; 4)Grade 4 thrombocytopenia with/without nontraumatic bleeding. Other 1)Study drug related death; 2)Toxicity that dose escalation committee believed to be DLT that was not covered by above DLT criteria.
Time frame: Cycle 1 (Cycle length is equal to [=] 28 days)
Population: Safety population was defined as all participants enrolled and randomized to treatment in study, except for those who drop out of the study prior to receiving any study treatment, or were without any safety assessments following the first dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) | 0 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) | 0 Participants |
| Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2 | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) | 0 Participants |
Primary
Phase 1b: Plasma Concentration of Golvatinib When Given in Combination With Cetuximab
Time frame: Cycle 1: 0-48 hours post-dose (Each cycle=28 days)
Population: Data was not collected and analyzed for this outcome measure because no pharmacokinetic analysis was conducted in this study due to incomplete pharmacokinetic sample bioanalysis due to unresolved queries leading to inadequate calculations and limited data interpretability.
Primary
Phase 2: Number of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs)
TEAEs are defined as an adverse event that has an onset date, or a worsening in severity from baseline (pre-golvatinib), on or after the first dose of golvatinib. The severity was graded according to CTCAE v4.0. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event.
Time frame: Up to 5 years 11 months
Population: Safety population was defined as all participants enrolled and randomized to treatment in study, except for those who drop out of the study prior to receiving any study treatment, or were without any safety assessments following the first dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) | 21 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) | 21 Participants |
Primary
Phase 2: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Values
Time frame: Up to 4 years 4 months
Population: Safety population was defined as all participants enrolled and randomized to treatment in study, except for those who drop out of the study prior to receiving any study treatment, or were without any safety assessments following the first dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Values | 0 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Values | 0 Participants |
Primary
Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings
Physical examination was performed and included evaluation of 1) General appearance, 2) Head; Eyes; Ears; Nose; Throat (HEENT), 3) Neck, 4) Heart, 5) Chest (Including Lungs), 6) Abdomen, 7) Extremities, 8) Skin, 9) Lymph Nodes, and 10) neurological status. Here, number of participants with markedly abnormal physical examinations were reported.
Time frame: Up to 4 years 4 months
Population: Safety population was defined as all participants enrolled and randomized to treatment in study, except for those who drop out of the study prior to receiving any study treatment, or were without any safety assessments following the first dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | General Appearance | 5 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | HEENT | 20 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Neck | 24 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Heart | 1 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Chest (Including Lungs) | 4 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Abdomen | 6 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Extremities | 2 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Skin | 4 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Lymph Nodes | 13 Participants |
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Neurologic | 3 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Skin | 5 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | General Appearance | 6 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Abdomen | 3 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | HEENT | 17 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Neurologic | 5 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Neck | 22 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Extremities | 0 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Heart | 0 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Lymph Nodes | 15 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Physical Examinations Findings | Chest (Including Lungs) | 5 Participants |
Primary
Phase 2: Number of Participants With Markedly Abnormal Vital Sign Values
Time frame: Up to 4 years 4 months
Population: Safety population was defined as all participants enrolled and randomized to treatment in study, except for those who drop out of the study prior to receiving any study treatment, or were without any safety assessments following the first dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Vital Sign Values | 0 Participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Number of Participants With Markedly Abnormal Vital Sign Values | 0 Participants |
Secondary
Phase 2: Overall Survival (OS)
OS is defined as the time from the date of randomization until the date of death. OS was analyzed using Kaplan Meier method. As planned, data for this endpoint was analyzed and collected till primary completion date.
Time frame: From the date of randomization until the date of death (Up to approximately 4 years 4 months)
Population: MITT analysis set included all participants randomized in the applicable study arm who received any comparator or study drug. Here Overall number of participants analyzed signifies participants with events (death).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Overall Survival (OS) | 39.71 weeks |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Overall Survival (OS) | 36.71 weeks |
95% CI: [0.53, 1.37]
Secondary
Phase 2: Percentage of Participants With Overall Response
Overall response rate is defined as percentage of participants with complete response (CR) or partial response (PR) based on RECIST v1.1. CR is 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 \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As planned, data for this endpoint was analyzed and collected till primary completion date.
Time frame: From the date of randomization until CR or PR (Up to approximately 4 years 4 months)
Population: MITT analysis set included all participants randomized in the applicable study arm who received any comparator or study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Percentage of Participants With Overall Response | 9.5 percentage of participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Percentage of Participants With Overall Response | 4.9 percentage of participants |
Secondary
Phase 2: Percentage of Participants With PFS at Week 12
PFS rate at week 12 is defined as the percentage of participants who were still alive without disease progression at 12 weeks from the date of randomization. PFS is defined as the time from the date of randomization until the earlier of the following two events: the date of PD or the date of death based on RECIST v1.1. PD is defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS rate was estimated and analyzed using Kaplan Meier method.
Time frame: At Week 12
Population: MITT analysis set included all participants randomized in the applicable study arm who received any comparator or study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Percentage of Participants With PFS at Week 12 | 68.9 percentage of participants |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Percentage of Participants With PFS at Week 12 | 59.4 percentage of participants |
Secondary
Phase 2: Progression-free Survival (PFS)
PFS is defined as the time from the date of randomization until the earlier of the following two events: the date of PD or the date of death based on response evaluation criteria in solid tumor (RECIST) v1.1. PD is defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan Meier method. As planned, data for this endpoint was analyzed and collected till primary completion date.
Time frame: From the date of randomization until the earlier of the following two events: the date of PD or the date of death (Up to approximately 4 years 4 months)
Population: Modified Intent-to-Treat (MITT) analysis set included all participants randomized in the applicable study arm who received any comparator or study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Progression-free Survival (PFS) | 15.71 weeks |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Progression-free Survival (PFS) | 15.71 weeks |
95% CI: [0.54, 1.46]
Secondary
Phase 2: Time to Progression (TTP)
TTP is defined as the time from the date of randomization until the date of PD based on RECIST v1.1. PD is defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. TTP was estimated and analyzed using Kaplan Meier method. As planned, data for this endpoint was analyzed and collected till primary completion date.
Time frame: From the date of randomization until the date of PD (Up to approximately 4 years 4 months)
Population: MITT analysis set included all participants randomized in the applicable study arm who received any comparator or study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2 | Phase 2: Time to Progression (TTP) | 15.43 weeks |
| Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2 | Phase 2: Time to Progression (TTP) | 16.00 weeks |
95% CI: [0.61, 1.73]