E7050 in Combination With Cetuximab Versus Cetuximab Alone in the Treatment of Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-Label, Multicenter, Randomized, Phase 1b/2 Study of E7050 in Combination With Cetuximab Versus Cetuximab Alone in the Treatment of Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck

Conditions
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Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: E7050
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Comparator; Phase 1b: Cohort 1,2,and 3<br>Phase 1b: Cohort 1; 200 mg E7050 + 250 mg/m2 cetuximab Cohort 2; 300 mg E7050 + 250 mg/m2 cetuximab Cohort 3; 400mg E7050 + 250mg/m2 cetuximab Phase 2: Arm 1; MTD E7050 + 250 mg cetuximab Arm 2; 250 mg cetuximab Interventions: Drug cetuximab | Drug: E7050<br>* E7050 given orally at 200, 300, or 400 mg once daily.<br>* Other names: Golvatinib;Drug: Cetuximab<br>* 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.<br>|
| Active Comparator: Phase 2<br>Phase 2: Arm 1; MTD E7050 + 250 mg/m2 cetuximab Arm 2; 250 mg/m2 cetuximab | Drug: E7050<br>* E7050 given orally at 200, 300, or 400 mg once daily.<br>* Other names: Golvatinib;Drug: Cetuximab<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 (Cycle length is equal to [=] 28 days) | 
| 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) | 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. | Up to 5 years 11 months | 
| 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 | 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. | Up to 4 years 4 months | 
| Phase 2: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Values |  | Up to 4 years 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | At Week 12 | 
| 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. | From the date of randomization until the date of PD (Up to approximately 4 years 4 months) | 
| 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. | From the date of randomization until the date of death (Up to approximately 4 years 4 months) | 
| 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. | From the date of randomization until CR or PR (Up to approximately 4 years 4 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, head and neck, squamous cell carcinoma of the head and neck, phase 1b, phase 2