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Clinical Trial Results:
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

Summary
EudraCT number	2011-000773-31
Trial protocol	GB
Global end of trial date	04 Sep 2017

Results information
Results version number	v2(current)
This version publication date	10 Mar 2022
First version publication date	30 Oct 2021
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

E7050-702

ISRCTN number

US NCT number

NCT01332266

WHO universal trial number (UTN)

Sponsor organisation name

Eisai Inc.

Sponsor organisation address

300 Tice Boulevard, Woodcliff Lake, New Jersey, United States, 07677

Public contact

Eisai Medical Information, Eisai Inc., +1 888-274-2378, esi_oncmedinfo@eisai.com

Scientific contact

Eisai Medical Information, Eisai Inc., +1 888-274-2378, esi_oncmedinfo@eisai.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Sep 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Sep 2017

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to determine whether subjects with platinum-resistant squamous cell carcinoma of the head and neck (SCCHN) who receive either Golvatinib (E7050) administered with Cetuximab or Cetuximab alone experience greater benefit.

Protection of trial subjects

This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008). - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312. - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Sep 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Korea, Republic of: 36

Country: Number of subjects enrolled

United Kingdom: 14

Country: Number of subjects enrolled

Ukraine: 36

Country: Number of subjects enrolled

United States: 9

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects 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.

Screening details

This study consists of two phases Phase 1b and Phase 2. Phase 1b: 12 subjects were enrolled and received the study treatment; Phase 2: 83 subjects were enrolled and received the study treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2

Arm description

Subjects with platinum-resistant SCCHN received golvatinib 200 milligram (mg) tablets, orally, once daily (run-in period) and cetuximab 400 milligram per square meter (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 progressive disease (PD), unacceptable toxicity, withdrawal of consent, withdrawal by the investigator, lost to follow-up, or death, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Cetuximab 400 mg/m^2

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received 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.

Investigational medicinal product name

Golvatinib 200 mg

Investigational medicinal product code

Other name

E7050

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received golvatinib 200 mg tablets, orally, once daily (run-in period) of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles.

Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Golvatinib 300 mg

Investigational medicinal product code

Other name

E7050

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received golvatinib 300 mg tablets, orally, once daily (run-in period) of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles.

Investigational medicinal product name

Cetuximab 400 mg/m^2

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Cetuximab 400 mg/m^2

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Golvatinib 400 mg

Investigational medicinal product code

Other name

E7050

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received golvatinib 400 mg tablets, orally, once daily (run-in period) of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles.

Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Arm description

Subjects 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, subjects 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.

Arm type

Experimental

Investigational medicinal product name

Golvatinib 400 mg

Investigational medicinal product code

Other name

E7050

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received golvatinib 400 mg (RP2D) tablets, orally, once daily (run-in period) of Cycle 1 in a 28-days treatment cycle for up to 6 subsequent cycles.

Investigational medicinal product name

Cetuximab 400 mg/m^2

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Phase 2: Arm 2: Cetuximab 400 mg/m^2

Arm description

Subjects 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, subjects 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.

Arm type

Experimental

Investigational medicinal product name

Cetuximab 400 mg/m^2

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects 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.

Number of subjects in period 1	Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Started	4	5	3	42	41
Completed	0	0	0	0	0
Not completed	4	5	3	42	41
Consent withdrawn by subject	1	1	1	2	2
Physician decision	-	-	-	3	1
Symptomatic deterioration	-	-	-	-	1
Death	3	3	2	33	36
Progression Disease	-	-	-	2	1
Lost to follow-up	-	1	-	2	-

Baseline characteristics

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Reporting group title

Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 2: Arm 2: Cetuximab 400 mg/m^2

Reporting group description

Reporting group values	Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2	Total
Number of subjects	4	5	3	42	41	95
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	70.0 ( 8.29 )	58.8 ( 12.58 )	59.3 ( 5.51 )	58.4 ( 11.04 )	53.9 ( 9.84 )	-
Gender categorical
Units: Subjects
Female	2	0	0	4	7	13
Male	2	5	3	38	34	82
Ethnicity
Units: Subjects
Hispanic or Latino	1	0	0	1	0	2
Not Hispanic or Latino	3	5	3	41	41	93
Unknown or Not Reported	0	0	0	0	0	0
Race
Units: Subjects
Asian	2	3	3	16	12	36
Black or African American	0	1	0	1	0	2
White	2	1	0	24	29	56
Unknown or Not Reported	0	0	0	1	0	1
Eastern Cooperative Oncology Group Performance Status (ECOG PS)
ECOG PS is used by doctors and researchers to assess how a subject’s disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. 0=Fully Active (Most Favorable Activity); 1=Restricted activity but ambulatory; 2=Ambulatory but unable to carry out work activities; 3=Limited Self-Care; 4=Completely Disabled, No self-care (Least Favorable Activity); 5=Dead.
Units: Subjects
ECOG: 0 (Fully Active)	1	0	0	10	10	21
ECOG:1(Restricted in Physical Activity;Ambulatory)	3	4	3	28	24	62
ECOG: 2 (Ambulatory and Capable of All Self-care)	0	1	0	1	3	5
ECOG: 3 (Capable of Only Limited Self-care)	0	0	0	0	0	0
ECOG: 4 (Completely Disabled)	0	0	0	0	0	0
ECOG: 5 (Dead)	0	0	0	0	0	0
Not Specified	0	0	0	3	4	7

End points

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Reporting group title

Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 2: Arm 2: Cetuximab 400 mg/m^2

Reporting group description

Primary: Phase 1b: Number of Subjects With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)

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End point title

Phase 1b: Number of Subjects With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) ^[1] ^[2]

End point description

DLT:adverse events graded as NCI CTCAEv4.0 occurring <=28 days after treatment.Events as:Non-hematological:1)Grade >=3 peripheral neuropathy;2)Grade 3 fatigue or 2 point decline in ECOG PS that persisted for >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 <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.Safety population:subjects 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.

End point type

Primary

End point timeframe

Cycle 1 (Cycle length is equal to [=] 28 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 1b are included in this endpoint.

End point values	Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2
Number of subjects analysed	4	5	3
Units: subjects	0	0	0

No statistical analyses for this end point

Primary: Phase 1b: Plasma Concentration of Golvatinib When Given in Combination With Cetuximab

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End point title

Phase 1b: Plasma Concentration of Golvatinib When Given in Combination With Cetuximab ^[3] ^[4]

End point description

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.

End point type

Primary

End point timeframe

Cycle 1: 0-48 hours post-dose (Each cycle=28 days)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 1b are included in this endpoint.

End point values	Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2
Number of subjects analysed	0 ^[5]	0 ^[6]	0 ^[7]
Units: Unitless

Notes
[5] - Data was not collected and analyzed because no pharmacokinetic analysis was done.
[6] - Data was not collected and analyzed because no pharmacokinetic analysis was done.
[7] - Data was not collected and analyzed because no pharmacokinetic analysis was done.

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs)

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End point title

Phase 2: Number of Subjects With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) ^[8] ^[9]

End point description

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. Safety population:all subjects 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.

End point type

Primary

End point timeframe

Up to 5 years 11 months

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint.
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	42	41
Units: subjects	21	21

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Markedly Abnormal Vital Sign Values

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End point title

Phase 2: Number of Subjects With Markedly Abnormal Vital Sign Values ^[10] ^[11]

End point description

Safety population was defined as all subjects 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.

End point type

Primary

End point timeframe

Up to 4 years 4 months

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint.
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	42	41
Units: subjects	0	0

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Markedly Abnormal Physical Examinations Findings

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End point title

Phase 2: Number of Subjects With Markedly Abnormal Physical Examinations Findings ^[12] ^[13]

End point description

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 subjects with markedly abnormal physical examinations were reported. Safety population was defined as all subjects 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.

End point type

Primary

End point timeframe

Up to 4 years 4 months

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint.
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	42	41
Units: subjects
General Appearance	5	6
HEENT	20	17
Neck	24	22
Heart	1	0
Chest (Including Lungs)	4	5
Abdomen	6	3
Extremities	2	0
Skin	4	5
Lymph Nodes	13	15
Neurologic	3	5

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Markedly Abnormal Electrocardiogram (ECG) Values

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End point title

Phase 2: Number of Subjects With Markedly Abnormal Electrocardiogram (ECG) Values ^[14] ^[15]

End point description

End point type

Primary

End point timeframe

Up to 4 years 4 months

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint.
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	42	41
Units: subjects	0	0

No statistical analyses for this end point

Secondary: Phase 2: Progression-free Survival (PFS)

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End point title

Phase 2: Progression-free Survival (PFS) ^[16]

End point description

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) version 1.1. 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. Modified Intent-to-Treat (MITT) analysis set included all subjects randomized in the applicable study arm who received any comparator or study drug. As planned, data for this endpoint was analyzed and collected till primary completion date.

End point type

Secondary

End point timeframe

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)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	42	41
Units: weeks
median (confidence interval 95%)	15.71 (12.14 to 23.86)	15.71 (9.29 to 18.71)

Phase 2: Arm 1; Arm 2

Comparison groups

Phase 2: Arm 2: Cetuximab 400 mg/m^2 v Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.46

Secondary: Phase 2: Percentage of Subjects With PFS at Week 12

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End point title

Phase 2: Percentage of Subjects With PFS at Week 12 ^[17]

End point description

PFS rate at week 12 was defined as the percentage of subjects 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. MITT analysis set included all subjects randomized in the applicable study arm who received any comparator or study drug.

End point type

Secondary

End point timeframe

At Week 12

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	42	41
Units: percentage of subjects
number (confidence interval 95%)	68.9 (50.79 to 81.44)	59.4 (41.90 to 73.23)

No statistical analyses for this end point

Secondary: Phase 2: Time to Progression (TTP)

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End point title

Phase 2: Time to Progression (TTP) ^[18]

End point description

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. MITT analysis set included all subjects randomized in the applicable study arm who received any comparator or study drug. As planned, data for this endpoint was analyzed and collected till primary completion date.

End point type

Secondary

End point timeframe

From the date of randomization until the date of PD (Up to approximately 4 years 4 months)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	42	41
Units: weeks
median (confidence interval 95%)	15.43 (12.14 to 23.14)	16.00 (9.29 to 19.14)

Phase 2: Arm 1; Arm 2

Comparison groups

Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2 v Phase 2: Arm 2: Cetuximab 400 mg/m^2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.73

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[19]

End point description

OS is defined as the time from the date of randomization until the date of death. OS was analyzed using Kaplan Meier method. MITT analysis set included all subjects randomized in the applicable study arm who received any comparator or study drug. Here "Overall number of subjects analyzed" signifies subjects with events (death). As planned, data for this endpoint was analyzed and collected till primary completion date.

End point type

Secondary

End point timeframe

From the date of randomization until the date of death (Up to approximately 4 years 4 months)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	33	36
Units: weeks
median (confidence interval 95%)	39.71 (28.43 to 49.71)	36.71 (28.00 to 44.43)

Phase 2: Arm 1; Arm 2

Comparison groups

Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2 v Phase 2: Arm 2: Cetuximab 400 mg/m^2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.37

Secondary: Phase 2: Percentage of Subjects With Overall Response

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End point title

Phase 2: Percentage of Subjects With Overall Response ^[20]

End point description

Overall response rate is defined as percentage of subjects 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. MITT analysis set included all subjects randomized in the applicable study arm who received any comparator or study drug. As planned, data for this endpoint was analyzed and collected till primary completion date.

End point type

Secondary

End point timeframe

From the date of randomization until CR or PR (Up to approximately 4 years 4 months)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only data from Phase 2 are included in this endpoint.

End point values	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Number of subjects analysed	42	41
Units: percentage of subjects
number (confidence interval 95%)	9.5 (0.7 to 18.4)	4.9 (0 to 11.5)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 5 years 11 months

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2

Reporting group description

Subjects 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.

Reporting group title

Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2

Reporting group description

Reporting group title

Phase 2: Arm 2: Cetuximab 400 mg/m^2

Reporting group description

Serious adverse events	Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 4 (25.00%)	4 / 5 (80.00%)	2 / 3 (66.67%)	15 / 42 (35.71%)	15 / 41 (36.59%)
number of deaths (all causes)	3	3	2	33	36
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour Haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	2 / 41 (4.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
Vascular disorders
Deep Vein Thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Hypotension
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Adverse Drug Reaction
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asphyxia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Aspiration
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Aspiration
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	2 / 42 (4.76%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Stridor
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper Airway Obstruction
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol Poisoning
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post Procedural Haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Pericardial Effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Sinus Tachycardia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Depressed Level Of Consciousness
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	3 / 41 (7.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 42 (4.76%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mechanical Ileus
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral Cavity Fistula
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Rectal Haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Haemorrhage Subcutaneous
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Neck Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain In Jaw
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Pyelonephritis Acute
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal Infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1b: Cohort 1: Golvatinib 200 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 2: Golvatinib 300 mg + Cetuximab 400 mg/m^2	Phase 1b: Cohort 3: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 1: Golvatinib 400 mg + Cetuximab 400 mg/m^2	Phase 2: Arm 2: Cetuximab 400 mg/m^2
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 4 (100.00%)	5 / 5 (100.00%)	3 / 3 (100.00%)	42 / 42 (100.00%)	38 / 41 (92.68%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR PAIN
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	2 / 41 (4.88%)
occurrences all number	0	0	0	4	2
Vascular disorders
Flushing
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
Hypertension
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	3	0	0	0	0
General disorders and administration site conditions
OEDEMA PERIPHERAL
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Pyrexia
subjects affected / exposed	1 / 4 (25.00%)	2 / 5 (40.00%)	1 / 3 (33.33%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	2	2	1	3	2
MUCOSAL INFLAMMATION
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	4 / 42 (9.52%)	1 / 41 (2.44%)
occurrences all number	0	0	0	6	1
CHEST PAIN
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	1	0	0	3	1
Asthenia
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	5 / 42 (11.90%)	1 / 41 (2.44%)
occurrences all number	1	1	1	5	1
FACE OEDEMA
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
Fatigue
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	5 / 42 (11.90%)	5 / 41 (12.20%)
occurrences all number	2	0	0	5	5
LOCALISED OEDEMA
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Pain
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	2 / 3 (66.67%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	3	0	0
PRODUCTIVE COUGH
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Epistaxis
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	0 / 41 (0.00%)
occurrences all number	1	0	0	3	0
Dyspnoea
subjects affected / exposed	3 / 4 (75.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	3 / 41 (7.32%)
occurrences all number	4	0	0	1	3
Cough
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	3 / 42 (7.14%)	2 / 41 (4.88%)
occurrences all number	0	1	1	3	2
HAEMOPTYSIS
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	2 / 42 (4.76%)	3 / 41 (7.32%)
occurrences all number	0	1	0	2	3
Nasal Ulcer
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Psychiatric disorders
DEPRESSION
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	0	0	0	3	1
INSOMNIA
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 42 (2.38%)	3 / 41 (7.32%)
occurrences all number	0	0	1	1	3
Substance-induced psychotic disorder
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Investigations
Neutrophil Count Decreased
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	3	0	0
PROTEIN TOTAL DECREASED
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
WEIGHT DECREASED
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	6 / 42 (14.29%)	3 / 41 (7.32%)
occurrences all number	0	0	0	6	3
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS Worsened
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	3 / 41 (7.32%)
occurrences all number	0	0	0	1	3
Alanine Aminotransferase Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 3 (66.67%)	10 / 42 (23.81%)	3 / 41 (7.32%)
occurrences all number	0	0	9	12	3
Blood Alkaline Phosphatase Increased
subjects affected / exposed	0 / 4 (0.00%)	3 / 5 (60.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	0 / 41 (0.00%)
occurrences all number	0	4	0	4	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	0 / 41 (0.00%)
occurrences all number	0	0	0	3	0
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 3 (66.67%)	10 / 42 (23.81%)	2 / 41 (4.88%)
occurrences all number	0	3	2	10	3
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
Nervous system disorders
LETHARGY
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	0	0	0	4	2
Dizziness
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	2	0	0	0
Dysgeusia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	3 / 42 (7.14%)	0 / 41 (0.00%)
occurrences all number	0	0	1	3	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 4 (50.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	4 / 42 (9.52%)	5 / 41 (12.20%)
occurrences all number	4	1	0	5	6
Ear and labyrinth disorders
Otorrhoea
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Eye disorders
Blepharitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Eyelid oedema
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
Pinguecula
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Gastrointestinal disorders
ORAL PAIN
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	0 / 41 (0.00%)
occurrences all number	0	0	0	4	0
STOMATITIS
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	2 / 41 (4.88%)
occurrences all number	0	0	0	3	3
Abdominal Pain Upper
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	0	0	1	3	1
Abdominal Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	4 / 42 (9.52%)	1 / 41 (2.44%)
occurrences all number	0	0	1	8	1
Nausea
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	19 / 42 (45.24%)	3 / 41 (7.32%)
occurrences all number	0	1	2	35	3
Constipation
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	2 / 3 (66.67%)	10 / 42 (23.81%)	3 / 41 (7.32%)
occurrences all number	2	1	2	13	3
Diarrhoea
subjects affected / exposed	2 / 4 (50.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	10 / 42 (23.81%)	4 / 41 (9.76%)
occurrences all number	2	1	1	22	4
Dyspepsia
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	1	0	0
Dysphagia
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	5 / 42 (11.90%)	2 / 41 (4.88%)
occurrences all number	1	0	1	6	2
HAEMORRHOIDS
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	14 / 42 (33.33%)	2 / 41 (4.88%)
occurrences all number	0	1	1	19	2
Anal pruritus
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Oesophageal ulcer
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0
Skin and subcutaneous tissue disorders
PRURITUS
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0
Rash
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 3 (66.67%)	19 / 42 (45.24%)	8 / 41 (19.51%)
occurrences all number	0	1	3	22	9
Skin Fissures
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	4 / 42 (9.52%)	0 / 41 (0.00%)
occurrences all number	1	0	0	5	0
Skin Ulcer
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	1	0	0
DRY SKIN
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	5 / 42 (11.90%)	1 / 41 (2.44%)
occurrences all number	0	0	0	7	1
RASH MACULO-PAPULAR
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	4 / 42 (9.52%)	5 / 41 (12.20%)
occurrences all number	0	0	0	5	12
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	2 / 41 (4.88%)
occurrences all number	0	0	0	4	2
ONYCHOMADESIS
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	3 / 41 (7.32%)
occurrences all number	0	0	0	1	3
Dermatitis Acneiform
subjects affected / exposed	3 / 4 (75.00%)	0 / 5 (0.00%)	2 / 3 (66.67%)	10 / 42 (23.81%)	7 / 41 (17.07%)
occurrences all number	6	0	3	17	9
Erythema
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Renal and urinary disorders
POLLAKIURIA
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
PROTEINURIA
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	6 / 42 (14.29%)	2 / 41 (4.88%)
occurrences all number	0	0	0	7	2
DYSURIA
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
Haematuria
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	1	0	1	4	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
BACK PAIN
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Muscle Spasms
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
MUSCULAR WEAKNESS
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
NECK PAIN
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	3 / 42 (7.14%)	2 / 41 (4.88%)
occurrences all number	0	0	1	3	2
PAIN IN EXTREMITY
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	0	0	0	4	1
Periarthritis
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0
Infections and infestations
Paronychia
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	4 / 42 (9.52%)	0 / 41 (0.00%)
occurrences all number	1	0	0	10	0
Upper Respiratory Tract Infection
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	1	0	0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	0	0	0	3	1
Candida infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	2 / 4 (50.00%)	2 / 5 (40.00%)	1 / 3 (33.33%)	10 / 42 (23.81%)	3 / 41 (7.32%)
occurrences all number	2	2	1	12	3
HYPERCALCAEMIA
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0
Hyperglycaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0
HYPOALBUMINAEMIA
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	1	0	0
Hypocalcaemia
subjects affected / exposed	2 / 4 (50.00%)	2 / 5 (40.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	2	2	0	0
Hypokalaemia
subjects affected / exposed	1 / 4 (25.00%)	2 / 5 (40.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	2 / 41 (4.88%)
occurrences all number	1	2	0	4	2
Hypomagnesaemia
subjects affected / exposed	2 / 4 (50.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	2 / 42 (4.76%)	3 / 41 (7.32%)
occurrences all number	3	1	1	3	5
HYPONATRAEMIA
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 42 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0
Hypophosphataemia
subjects affected / exposed	2 / 4 (50.00%)	0 / 5 (0.00%)	2 / 3 (66.67%)	3 / 42 (7.14%)	1 / 41 (2.44%)
occurrences all number	2	0	6	3	1

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Were there any global substantial amendments to the protocol? Yes

09 Mar 2011

Amendment 01: The maximum dose to be tested was changed from 360 mg to 400 mg (with additional information in the Introduction to justify the change). Additional PK sampling times were added. For subjects experiencing clinical benefit after six cycles, continuing treatment was changed from cetuximab with or without golvatinib to golvatinib with or without cetuximab or cetuximab alone, depending on original treatment arm. Revised procedure for crushing tablets. Changed time for radiological scans from every two cycles to every eight weeks for the first six cycles and then at least every 12 weeks thereafter. Added efficacy endpoints to be used for evaluation of the secondary objective. Added postdose PK samples for Day 8 and 15 of Cycle 1 and Day 1 of all subsequent cycles in Phase 1b. Added nonoptional predose PK trough samples to Day 1, Day 15, and Day 22 of Cycle 1 and Day 1 of all subsequent cycles of Phase 2. Added nonoptional predose blood sample to Day 1 of all cycles for cetuximab immunogenicity determination. Specified that subjects should arrive at clinic in a fasted state on days that PK samples were to be drawn. Added visit schedule modification for subjects continuing beyond Cycle 6. Added 4-week washout period from any previous anticancer therapy (Exclusion Criterion 4). Added active hemoptysis as an exclusion criterion. Allowed for intrasubject dose escalation of golvatinib in Phase 1b in consultation with the Medical Monitor and provided the next highest dose had been deemed tolerable. Changed frequency of pregnancy test in female subjects of childbearing potential. Clarified that if one agent was held for toxicity, the other agent may have been continued as long as toxicity for the second agent was not suspected. The role of the DSMC was clarified.

14 Oct 2011

Amendment 02: The Introduction was updated with new PK data. Changed the golvatinib sampling period from Day -7 through Day -4 of Cycle 1 in Phase 1b to Day -2 and -1 of Cycle 1. Removed serial PK sampling on Days 1 and 2 of Cycle 1 for both Phase 1b and the optional Phase 2 sampling. A “Rationale for the Current Study” subsection was added to the Introduction. Clarified that after discontinuation of study treatment, follow-up would be until death. Clarified treatment options for subjects continuing past Cycle 6. Clarified prior cetuximab treatment allowed in Phase 1b, only allowed in Phase 2 if administered in combination with radiotherapy. Changed to allow prior antiangiogenic therapy in Phase 1b. Clarified that subjects could take golvatinib with or without food and clarified for subjects on golvatinib who experienced nausea to take golvatinib with food and antiemetic therapy per local guidelines and Investigator practice. Updated the definition of SAEs to conform with new FDA guidelines.

17 Sep 2012

Amendment 03: Added disease progression to Section 4.4.3 “Patient Withdrawal”. Clarified that for subjects participating in the optional PK sampling, the predose samples on Days 15 and 22 of Cycle 1 would serve as the nonoptional predose trough samples. Provided language clarifying the use of anti-emetics medication to Section 5.1.4 “Precautions”. Provided guidance for treatment of subjects with elevated alkaline phosphatase to Section 5.1.4 “Precautions”. Modified the cetuximab supply information. Moved the caution for subjects who were taking drugs that were strong or moderate inhibitors and/or inducers of cytochrome P450 3A4 from excluded medications to allowed medications. Clarified that progression of disease would not be considered an AE or SAE. Clarified that if iodinated CT contrast was contraindicated, CT of the chest may have been performed without IV contrast.

05 Nov 2014

Amendment 04: Removed the long-term overall survival follow-up. Revised language requiring central reading of radiological scans. Revised language regarding scans after the first 6 treatment cycles. After the first 6 treatment cycles, radiological scans will be in accordance with local institutional guidelines.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

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.

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Clinical trials

Clinical Trial Results:
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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Number of Subjects With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)

Primary: Phase 1b: Number of Subjects With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)

Primary: Phase 1b: Plasma Concentration of Golvatinib When Given in Combination With Cetuximab

Primary: Phase 1b: Plasma Concentration of Golvatinib When Given in Combination With Cetuximab

Primary: Phase 2: Number of Subjects With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs)

Primary: Phase 2: Number of Subjects With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs)

Primary: Phase 2: Number of Subjects With Markedly Abnormal Vital Sign Values

Primary: Phase 2: Number of Subjects With Markedly Abnormal Vital Sign Values

Primary: Phase 2: Number of Subjects With Markedly Abnormal Physical Examinations Findings

Primary: Phase 2: Number of Subjects With Markedly Abnormal Physical Examinations Findings

Primary: Phase 2: Number of Subjects With Markedly Abnormal Electrocardiogram (ECG) Values

Primary: Phase 2: Number of Subjects With Markedly Abnormal Electrocardiogram (ECG) Values

Secondary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 2: Percentage of Subjects With PFS at Week 12

Secondary: Phase 2: Percentage of Subjects With PFS at Week 12

Secondary: Phase 2: Time to Progression (TTP)

Secondary: Phase 2: Time to Progression (TTP)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Percentage of Subjects With Overall Response

Secondary: Phase 2: Percentage of Subjects With Overall Response

Adverse events

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Number of Subjects With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)

Primary: Phase 1b: Number of Subjects With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)

Primary: Phase 1b: Plasma Concentration of Golvatinib When Given in Combination With Cetuximab

Primary: Phase 1b: Plasma Concentration of Golvatinib When Given in Combination With Cetuximab

Primary: Phase 2: Number of Subjects With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs)

Primary: Phase 2: Number of Subjects With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs)

Primary: Phase 2: Number of Subjects With Markedly Abnormal Vital Sign Values

Primary: Phase 2: Number of Subjects With Markedly Abnormal Vital Sign Values

Primary: Phase 2: Number of Subjects With Markedly Abnormal Physical Examinations Findings

Primary: Phase 2: Number of Subjects With Markedly Abnormal Physical Examinations Findings

Primary: Phase 2: Number of Subjects With Markedly Abnormal Electrocardiogram (ECG) Values

Primary: Phase 2: Number of Subjects With Markedly Abnormal Electrocardiogram (ECG) Values

Secondary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 2: Percentage of Subjects With PFS at Week 12

Secondary: Phase 2: Percentage of Subjects With PFS at Week 12

Secondary: Phase 2: Time to Progression (TTP)

Secondary: Phase 2: Time to Progression (TTP)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Percentage of Subjects With Overall Response

Secondary: Phase 2: Percentage of Subjects With Overall Response

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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