Trial Outcomes & Findings for Safety and Efficacy of Tipifarnib in Head and Neck Cancer With HRAS Mutations and Impact of HRAS on Response to Therapy (NCT NCT03719690)

NCT ID: NCT03719690

Last Updated: 2024-06-21

Results Overview

ORR was defined as the percentage of participants who experienced a best overall response (BOR) of complete response (CR; disappearance of all target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by IRF. 95% confidence interval (CI) was calculated by the exact binomial (Clopper-Pearson) method.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

296 participants

Primary outcome timeframe

Up to approximately 28 months

Results posted on

2024-06-21

Participant Flow

A total of 296 participants were enrolled (59 participants in AIM-HN and 237 participants in SEQ-HN) in 14 countries between March 2019 and May 2023.

This study consisted of 2 non-comparative sub-studies: (1) an interventional open-label, single-arm, pivotal study evaluating the efficacy of tipifarnib in mHRAS HNSCC (AIM-HN) and (2) an observational study to evaluate the impact of HRAS mutations on response to first line systemic therapies for HNSCC (SEQ-HN).

Participant milestones

Participant milestones
Measure	Tipifarnib Treatment Cohort: AIM-HN Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, twice a day (bid) on Days 1-7 and 15-21 of 28-day cycles.	Observational Cohort: SEQ-HN Participants with HNSCC in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consented to provide first line outcome data and additional follow-up.
Overall Study STARTED	59	237
Overall Study Safety Analysis Set (SAS)	59	0
Overall Study Modified Intent-to-Treat Analysis Set (mITT)	59	0
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	59	237

Reasons for withdrawal

Reasons for withdrawal
Measure	Tipifarnib Treatment Cohort: AIM-HN Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, twice a day (bid) on Days 1-7 and 15-21 of 28-day cycles.	Observational Cohort: SEQ-HN Participants with HNSCC in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consented to provide first line outcome data and additional follow-up.
Overall Study Withdrawal by Subject	5	10
Overall Study Death	40	149
Overall Study Miscellaneous	12	56
Overall Study Lost to Follow-up	2	18
Overall Study Unwilling or unable to comply with study requirements	0	4

Baseline Characteristics

Data collection and analysis of VAF status for participants in the Observational SEQ-HN Cohort was not pre-specified.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tipifarnib Treatment Cohort: AIM-HN n=59 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.	Observational Cohort: SEQ-HN n=237 Participants Participants with HNSCC in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consented to provide first line outcome data and additional follow-up.	Total n=296 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=59 Participants	0 Participants n=237 Participants	0 Participants n=296 Participants
Age, Categorical Between 18 and 65 years	31 Participants n=59 Participants	144 Participants n=237 Participants	175 Participants n=296 Participants
Age, Categorical >=65 years	28 Participants n=59 Participants	93 Participants n=237 Participants	121 Participants n=296 Participants
Sex: Female, Male Female	15 Participants n=59 Participants	59 Participants n=237 Participants	74 Participants n=296 Participants
Sex: Female, Male Male	44 Participants n=59 Participants	178 Participants n=237 Participants	222 Participants n=296 Participants
Race/Ethnicity, Customized White	33 Participants n=59 Participants	180 Participants n=237 Participants	213 Participants n=296 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=59 Participants	10 Participants n=237 Participants	11 Participants n=296 Participants
Race/Ethnicity, Customized Asian	23 Participants n=59 Participants	37 Participants n=237 Participants	60 Participants n=296 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=59 Participants	2 Participants n=237 Participants	2 Participants n=296 Participants
Race/Ethnicity, Customized Other	2 Participants n=59 Participants	7 Participants n=237 Participants	9 Participants n=296 Participants
Race/Ethnicity, Customized Missing	0 Participants n=59 Participants	1 Participants n=237 Participants	1 Participants n=296 Participants
Race/Ethnicity, Customized Hispanic or Latino	0 Participants n=59 Participants	8 Participants n=237 Participants	8 Participants n=296 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	55 Participants n=59 Participants	217 Participants n=237 Participants	272 Participants n=296 Participants
Race/Ethnicity, Customized Not Reported	3 Participants n=59 Participants	9 Participants n=237 Participants	12 Participants n=296 Participants
Race/Ethnicity, Customized Unknown	1 Participants n=59 Participants	3 Participants n=237 Participants	4 Participants n=296 Participants
Variant Allele Frequency (VAF) Status Participants with low VAF (< 20%)	9 Participants n=59 Participants • Data collection and analysis of VAF status for participants in the Observational SEQ-HN Cohort was not pre-specified.	—	9 Participants n=59 Participants • Data collection and analysis of VAF status for participants in the Observational SEQ-HN Cohort was not pre-specified.
Variant Allele Frequency (VAF) Status Participants with high VAF (>=20%)	50 Participants n=59 Participants • Data collection and analysis of VAF status for participants in the Observational SEQ-HN Cohort was not pre-specified.	—	50 Participants n=59 Participants • Data collection and analysis of VAF status for participants in the Observational SEQ-HN Cohort was not pre-specified.

PRIMARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF only. Data collection and analysis of ORR for participants in the Observational SEQ-HN Cohort was not pre-specified.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=50 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
Objective Response Rate (ORR) in High Variable Allele Frequency (VAF) Population, as Assessed by Independent Review Facility (IRF)	20.0 percentage of participants Interval 10.03 to 33.72

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants. Data collection and analysis of ORR for participants in the Observational SEQ-HN Cohort was not pre-specified.

ORR was defined as the percentage of participants who experienced a BOR of CR or PR and was assessed using RECIST v1.1 by IRF. 95% CI was calculated by the exact binomial (Clopper-Pearson) method.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=59 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
ORR in All VAF Population, as Assessed by IRF	18.6 percentage of participants Interval 9.69 to 30.91

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF and available data only. Data collection and analysis of DoR for participants in the Observational SEQ-HN Cohort was not pre-specified.

DoR was defined as the time from the date of first response (CR or PR \[whichever occurred first\]) to the date of progression of disease or death of any cause, whichever occurred first, in participants with a confirmed CR or PR and was assessed using RECIST v1.1 by IRF. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=10 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
Duration of Response (DoR) in High VAF Population, as Assessed by IRF	6.51 months Interval 3.877 to Upper CI was not reached due to lack of events.

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants with available data. Data collection and analysis of DoR for participants in the Observational SEQ-HN Cohort was not pre-specified.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=11 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
DoR in All VAF Population, as Assessed by IRF	6.51 months Interval 3.877 to Upper CI was not reached due to lack of events.

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF and available data only. Data collection and analysis of PFS for participants in the Observational SEQ-HN Cohort was not pre-specified.

PFS was defined as months from the first dose of the study drug to the first documented progressive disease (PD, appearance of one or more new lesions or at least a 20% increase in the sum of the diameters of target lesions) or death, whichever came first and was assessed using RECIST v1.1 by IRF. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=50 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
Progression Free Survival (PFS) in High VAF Population, as Assessed by IRF	2.60 months Interval 1.873 to 4.402

SECONDARY outcome

Timeframe: Up to 28 approximately months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants with available data. Data collection and analysis of PFS for participants in the Observational SEQ-HN Cohort was not pre-specified.

PFS was defined as months from the first dose of the study drug to the first documented PD or death, whichever came first and was assessed using RECIST v1.1 by IRF. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=59 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
PFS in All VAF Population, as Assessed by IRF	2.23 months Interval 1.873 to 3.548

SECONDARY outcome

Timeframe: 6 months and 9 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF and available data only. Data collection and analysis of PFS for participants in the Observational SEQ-HN Cohort was not pre-specified.

PFS rate was defined as the percentage of participants who had not experienced documented PD or death, whichever came first and was assessed using RECIST v1.1 by IRF at 6 and 9 month timepoints. Percentage of participants was calculated using the Kaplan-Meier method. 95% CI was calculated using normal approximation to the log transformed cumulative hazard rate

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=50 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
PFS Rate in High VAF Population, as Assessed by IRF 6 months	29 percentage of participants Interval 16.2 to 42.9
PFS Rate in High VAF Population, as Assessed by IRF 9 months	20 percentage of participants Interval 8.9 to 33.6

SECONDARY outcome

Timeframe: 6 months and 9 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants and available data. Data collection and analysis of PFS for participants in the Observational SEQ-HN Cohort was not pre-specified.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=59 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
PFS Rate in All VAF Population, as Assessed by IRF 6 months	26 percentage of participants Interval 14.9 to 38.4
PFS Rate in All VAF Population, as Assessed by IRF 9 months	18 percentage of participants Interval 8.9 to 30.8

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF only. Data collection and analysis of OS for participants in the Observational SEQ-HN Cohort was not pre-specified.

OS was defined as months from first dose date until death from any cause. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=50 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
Overall Survival (OS) in High VAF Population	6.97 months Interval 4.895 to 11.466

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants. Data collection and analysis of OS for participants in the Observational SEQ-HN Cohort was not pre-specified.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=59 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
OS in All VAF Population	6.21 months Interval 4.37 to 9.035

SECONDARY outcome

Timeframe: 12 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF only. Data collection and analysis of OS for participants in the Observational SEQ-HN Cohort was not pre-specified.

OS rate was defined as the percentage of participants who had not experienced or death and was assessed at 12 months. Percentage of participants was calculated using the Kaplan-Meier method. 95% CI was calculated using normal approximation to the log transformed cumulative hazard rate.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=50 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
OS Rate at 12 Months in High VAF Population	31 percentage of participants Interval 17.2 to 46.6

SECONDARY outcome

Timeframe: 12 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants. Data collection and analysis of OS for participants in the Observational SEQ-HN Cohort was not pre-specified.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=59 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
OS Rate at 12 Months in All VAF Population	30 percentage of participants Interval 17.2 to 43.7

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF and available data only. Data collection and analysis of TTR for participants in the Observational SEQ-HN Cohort was not pre-specified.

TTR was defined as months from treatment start to first CR or PR (whichever was first recorded) in participants with confirmed CR or PR and was assessed using RECIST v1.1 by IRF. TTR was summarized descriptively by summary statistics.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=10 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
Time to Response (TTR) in High VAF Population, as Assessed by IRF	1.9 months Interval 1.7 to 3.8

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants with available data. Data collection and analysis of TTR for participants in the Observational SEQ-HN Cohort was not pre-specified.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=11 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
TTR in All VAF Population, as Assessed by IRF	1.9 months Interval 1.7 to 18.4

SECONDARY outcome

Timeframe: Up to approximately 28 months

Population: SAS: consisted of all participants in the AIM-HN who received at least one dose of tipifarnib. Analysis was pre-specified for participants in the AIM-HN Cohort only. Data collection and analysis of safety for participants in the Observational SEQ-HN Cohort was not pre-specified.

TEAEs were defined as adverse events (AEs) that started on or after the first dose of the study drug and within 30 days of the last administration of the study drug. Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was used for toxicity grading (Grade 3: severe or disabling; Grade 4: life-threatening; Grade 5: death related to AE). Clinically significant changes in laboratory tests, vital signs, and electrocardiogram results were reported as AEs.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=59 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) Any TEAEs	58 Participants
Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) Any Grade 3 or Higher TEAEs	43 Participants

SECONDARY outcome

Timeframe: Baseline and End of Treatment Visit (up to approximately 28 months)

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants in the AIM-HN Cohort with available data. Data collection and analysis of EORTC QLQ-H\&N35 for participants in the Observational SEQ-HN Cohort was not pre-specified.

Change from Baseline score in pain, swallowing, speech problems, and senses problems subscales of EORTC QLQ-H\&N35 are summarized individually. Raw scores for each subscale were linear transformations and standardized to range (0 - 100), with higher scores representing worse levels of symptoms. Change from Baseline was calculated as End of Treatment Observed - Baseline with a negative change representing a reduction in symptoms.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=27 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module 35 (EORTC QLQ-H&N35) Subscales Pain	0.0 score on a scale Interval -41.7 to 58.3
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module 35 (EORTC QLQ-H&N35) Subscales Swallowing	8.3 score on a scale Interval -58.3 to 75.0
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module 35 (EORTC QLQ-H&N35) Subscales Senses problems	0.0 score on a scale Interval -50.0 to 66.7
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module 35 (EORTC QLQ-H&N35) Subscales Speech problems	0.0 score on a scale Interval -44.4 to 66.7

SECONDARY outcome

Timeframe: Baseline and End of Treatment Visit (up to approximately 28 months)

Population: mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants in the AIM-HN Cohort with available data. Data collection and analysis of EQ-VAS for participants in the Observational SEQ-HN Cohort was not pre-specified.

The EQ-VAS forms part of the EQ-5D-5L and collects the self-rating health status from 0 (the worst imaginable health) to 100 (the best imaginable health). Change from Baseline was calculated as End of Treatment Observed - Baseline with a negative change representing an increase in symptoms.

Outcome measures

Outcome measures
Measure	Tipifarnib Treatment Cohort: AIM-HN n=26 Participants Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.
Change From Baseline in the EuroQol-Visual Analog Scale (EQ-VAS) Score	3.5 score on a scale Interval -30.0 to 60.0

Adverse Events

Tipifarnib Treatment Cohort: AIM-HN

Serious events: 28 serious events

Other events: 56 other events

Deaths: 41 deaths

Observational Cohort: SEQ-HN

Serious events: 0 serious events

Other events: 0 other events

Deaths: 149 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Operations

Kura Oncology, Inc.

Phone: 617-588-3755

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee There are agreements in place between clinical trial sites and the Sponsor (or its agents) that govern discussion or publication of trial results by the sites or their employees after the trial is completed.
Publication restrictions are in place

Restriction type: OTHER