Safety and Efficacy of Tipifarnib in Head and Neck Cancer With HRAS Mutations and Impact of HRAS on Response to Therapy

HNSCC Clinical Trial

— AIM-HN/SEQ-HN  

Official title:

A 2 Cohort, Non-comparative, Pivotal Study Evaluating the Efficacy of Tipifarnib in Patients With Head and Neck Squamous Cell Carcinoma (HNSCC) With HRAS Mutations (AIM-HN) and the Impact of HRAS Mutations on Response to First Line Systemic Therapies for HNSCC (SEQ-HN)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03719690
• Other study ID #: KO-TIP-007
• Status: Completed
• Phase: Phase 2
• Start date: March 15, 2019
• Est. completion date: May 2, 2023

Study information

• Verified date: May 2024
• Source: Kura Oncology, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

An international, multicenter, open-label, 2 cohort, non-comparative, pivotal study evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN). The first cohort will assess the objective response rate (ORR) of tipifarnib in subjects with HNSCC with HRAS mutations. The second study cohort, SEQ-HN, is an observational sub-study including HNSCC patients in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consent to provide first line outcome data and additional follow up.

Description:

KO-TIP-007 is an international, multicenter, open-label, 2 cohort, non-comparative, pivotal study evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) and the impact of HRAS mutations on response to first line systemic therapies for HNSCC (SEQ-HN). KO-TIP-007 has 2 study cohorts. The first study cohort, named AIM-HN, includes HNSCC subjects with HRAS mutations. AIM-HN subjects will receive treatment with tipifarnib and the outcome of this cohort will be evaluated for ORR by an independent review facility.

The second study cohort, SEQ-HN, is an observational sub-study including HNSCC patients in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consent to provide first line outcome data and additional follow up.

HNSCC patients in whom HRAS mutations are identified and who meet eligibility criteria will be offered participation in AIM-HN. HNSCC patients in whom HRAS mutations are not identified may participate in SEQ-HN only. These patients will be followed and the comparison of outcomes of HRAS mutant and HRAS wild type HNSCC will address the exploratory objective to determine the effect of HRAS mutation on the ORR of first line systemic therapy in patients with recurrent/metastatic HNSCC. Outcome data from subsequent lines of therapy will be collected.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 296
• Est. completion date: May 2, 2023
• Est. primary completion date: May 2, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

AIM-HN

1. At least 18 years of age.

2. Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).

3. Documented treatment failure from most recent prior therapy (e.g. tumor progression, clinical deterioration, or recurrence), and from at least one prior platinum-containing regimen, in any treatment setting.

4. Known tumor missense HRAS mutation.

5. Measurable disease by RECIST v1.1.

6. ECOG performance status of 0-1.

7. Acceptable liver, renal and hematological function

8. Other protocol defined inclusion criteria may apply.

Exclusion Criteria:

1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g. mucosal melanoma).

2. Received treatment for unstable angina within prior year, myocardial infarction within the prior year, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.

3. Non-tolerable Grade 2 or = Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1.

4. Active, uncontrolled bacterial, viral or fungal infections requiring systemic therapy. Known history of infection with human immunodeficiency virus or an active infection with hepatitis B or hepatitis C.

5. Received treatment for non-cancer related liver disease within prior year.

6. Other protocol defined exclusion criteria may apply

Inclusion Criteria: SEQ-HN

1. At least 18 years of age.

2. Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology.

3. Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC.

4. HRAS wildtype (i.e., have no identified tumor missense HRAS mutation).

5. Other protocol defined inclusion criteria may apply

Exclusion Criteria: SEQ-HN

1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g. mucosal melanoma).

5. Other protocol defined exclusion criteria may apply

Related Conditions & MeSH terms

• HNSCC
• HRAS Gene Mutation
• Squamous Cell Carcinoma of Head and Neck

Intervention

Drug:
• Tipifarnib
Tablet for oral administration

Device:
• HRAS Detection Assay
In Vitro Assay to detect HRAS mutations

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne
Australia	Royal North Shore Hospital	Saint Leonards
Austria	Allgemeines Krankenhaus der Stadt Wien	Wien
Austria	Hanusch Krankenhaus Wiener Gebietskrankenkasse	Wien
Belgium	Ziekenhuis Netwerk Antwerpen Middelheim	Antwerpen
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	Universitair Ziekenhuis Leuven	Leuven
Belgium	Centre Hospitalier Universitaire Universite Catholique de Louvain Site Godinne	Yvoir	Namur
Denmark	Rigshospitalet	Copenhagen
Denmark	Herlev Hospital	Herlev
Germany	Charité Universitätsmedizin Berlin	Berlin
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Universitätsmedizin Mannheim	Mannheim
Germany	Universitätsklinikum Würzburg	Würzburg
Greece	University General Hospital of Athens Attikon	Chaidari
Greece	University General Hospital of Larissa	Larissa
Greece	Bioclinic - Thessaloniki	Thessaloniki
Italy	Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi	Bologna
Italy	Azienda Ospedaliera S. Croce e Carle Cuneo	Cuneo
Italy	Ospedale Mater Salutis di Legnago	Legnago
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	Fondazione IRCCS - Istituto Nazionale dei Tumori - Milano	Milano
Italy	Istituto Nazionale Tumori IRCCS Fondazione Pascale	Napoli
Italy	Azienda Ospedaliera Universitaria Senese-L'ospedale Santa Maria alle Scotte	Siena
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Chonbuk National University Hospital	Jeonju
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	The Catholic University of Korea - Seoul St. Mary's Hospital	Seoul
Korea, Republic of	Yonsei University Health System Severance Hospital	Seoul
Korea, Republic of	The Catholic University of Korea St. Vincent's Hospital	Suwon
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Malaysia	Institut Kanser Negara	Putrajaya
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Maastricht University Medical Centre	Maastricht
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Norway	Haukeland Universitetssjukehus	Bergen
Norway	Radiumhospitalet	Oslo
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i de Sant Pau	Barcelona
Spain	Hospital del Mar - Parc de Salut Mar	Barcelona
Spain	Hospital Duran i Reynals	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona
Spain	HM Centro Integral Oncológico Clara Campal	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Spain	Hospital Costa Del Sol	Marbella
Spain	Complejo Hospitalario de Navarra	Pamplona
Spain	Hospital Clínico Universitario de Santiago de Compostela	Santiago De Compostela
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	Chang Gung Medical Foundation Keelung Chang Gung Memorial Hospital	Keelung
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Mackay Memorial Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital	Taoyuan
Thailand	King Chulalongkorn Memorial Hospital	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai
Thailand	Songklanagarind Hospital	Hat Yai
United Kingdom	NHS Greater Glasgow and Clyde	Glasgow
United Kingdom	Guy's and Saint Thomas' NHS Foundation Trust	London	England
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton
United States	Winship Cancer Institute	Atlanta	Georgia
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Marlene and Stewart Greenebaum Cancer Center	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Chicago	Chicago	Illinois
United States	The Ohio State University	Columbus	Ohio
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	San Antonio Military Medical Center	Fort Sam Houston	Texas
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	University of Kentucky Markey Cancer Center	Lexington	Kentucky
United States	UCLA - Jonsson Comprehensive Cancer Center	Los Angeles	California
United States	University of Southern California Norris Comprehensive Cancer Center	Los Angeles	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	University of Wisconsin	Madison	Wisconsin
United States	Miami Cancer Institute	Miami	Florida
United States	Vanderbilt University Medical Center-Vanderbilt Ingram Cancer Center	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Siteman Cancer Center - Washington University Medical Campus	Saint Louis	Missouri
United States	University of Texas Health San Antonio - Mays Cancer Center	San Antonio	Texas
United States	UCSF - Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	University of South Florida H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	University Of Kansas Medical Center	Westwood	Kansas
United States	The Oncology Institute of Hope and Innovation - Anaheim	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
Kura Oncology, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Denmark,  Germany,  Greece,  Italy,  Korea, Republic of,  Malaysia,  Netherlands,  Norway,  Spain,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) in High Variable Allele Frequency (VAF) Population, as Assessed by Independent Review Facility (IRF)	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.	Up to approximately 28 months
Secondary	ORR in All VAF Population, as Assessed by IRF	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.	Up to approximately 28 months
Secondary	Duration of Response (DoR) in High VAF Population, as Assessed by IRF	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.	Up to approximately 28 months
Secondary	DoR in All VAF Population, as Assessed by IRF	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.	Up to approximately 28 months
Secondary	Progression Free Survival (PFS) in High VAF Population, as Assessed by IRF	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.	Up to approximately 28 months
Secondary	PFS in All VAF Population, as Assessed by IRF	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.	Up to 28 approximately months
Secondary	PFS Rate in High VAF Population, as Assessed by IRF	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	6 months and 9 months
Secondary	PFS Rate in All VAF Population, as Assessed by IRF	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.	6 months and 9 months
Secondary	Overall Survival (OS) in High VAF Population	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.	Up to approximately 28 months
Secondary	OS in All VAF Population	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.	Up to approximately 28 months
Secondary	OS Rate at 12 Months in High VAF Population	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.	12 months
Secondary	OS Rate at 12 Months in All VAF Population	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.	12 months
Secondary	Time to Response (TTR) in High VAF Population, as Assessed by IRF	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.	Up to approximately 28 months
Secondary	TTR in All VAF Population, as Assessed by IRF	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.	Up to approximately 28 months
Secondary	Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)	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.	Up to approximately 28 months
Secondary	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	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.	Baseline and End of Treatment Visit (up to approximately 28 months)
Secondary	Change From Baseline in the EuroQol-Visual Analog Scale (EQ-VAS) Score	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.	Baseline and End of Treatment Visit (up to approximately 28 months)