Safety and Efficacy of Tipifarnib in Head and Neck Cancer With HRAS Mutations and Impact of HRAS on Response to Therapy (AIM-HN/SEQ-HN)

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)

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.

Study Overview

• Status: Completed
• Conditions: HNSCC; HRAS Gene Mutation
• Intervention / Treatment: Drug: Tipifarnib; Device: HRAS Detection Assay

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 296
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3000
    • Peter MacCallum Cancer Centre
  • Saint Leonards, Australia, 2065
    • Royal North Shore Hospital
• Austria
  • Wien, Austria, 1090
    • Allgemeines Krankenhaus der Stadt Wien
  • Wien, Austria, 1140
    • Hanusch Krankenhaus Wiener Gebietskrankenkasse
• Belgium
  • Antwerpen, Belgium, 2020
    • Ziekenhuis Netwerk Antwerpen Middelheim
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Edegem, Belgium, 2650
    • Universitair Ziekenhuis Antwerpen
  • Leuven, Belgium, 3000
    • Universitair Ziekenhuis Leuven
  • Namur
    • Yvoir, Namur, Belgium, 5530
      • Centre Hospitalier Universitaire Universite Catholique de Louvain Site Godinne
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
  • Herlev, Denmark, 2730
    • Herlev Hospital
• Germany
  • Berlin, Germany, 12203
    • Charité Universitätsmedizin Berlin
  • Leipzig, Germany, 04103
    • Universitätsklinikum Leipzig
  • Mannheim, Germany, 68167
    • Universitätsmedizin Mannheim
  • Würzburg, Germany, 97080
    • Universitatsklinikum Wurzburg
• Greece
  • Chaidari, Greece, 12462
    • University General Hospital of Athens Attikon
  • Larissa, Greece, 41110
    • University General Hospital of Larissa
  • Thessaloniki, Greece, 54622
    • Bioclinic - Thessaloniki
• Italy
  • Bologna, Italy, 40138
    • Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi
  • Cuneo, Italy, 12100
    • Azienda Ospedaliera S. Croce e Carle Cuneo
  • Legnago, Italy, 37045
    • Ospedale Mater Salutis di Legnago
  • Meldola, Italy, 47014
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
  • Milano, Italy, 20133
    • Fondazione IRCCS - Istituto Nazionale dei Tumori - Milano
  • Napoli, Italy, 80131
    • Istituto Nazionale Tumori IRCCS Fondazione Pascale
  • Siena, Italy, 53100
    • Azienda Ospedaliera Universitaria Senese-L'ospedale Santa Maria alle Scotte
• Korea, Republic of
  • Goyang-si, Korea, Republic of, 10408
    • National Cancer Center
  • Jeonju, Korea, Republic of, 54907
    • Chonbuk National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Yonsei University Health System Severance Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 02841
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea - Seoul St. Mary's Hospital
  • Suwon, Korea, Republic of, 16247
    • The Catholic University Of Korea St. Vincent's Hospital
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Putrajaya, Malaysia, 62250
    • Institut Kanser Negara
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen
  • Maastricht, Netherlands, 6229 HX
    • Maastricht University Medical Centre
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
• Norway
  • Bergen, Norway, 1521
    • Haukeland Universitetssjukehus
  • Oslo, Norway, 0379
    • Radiumhospitalet
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona
  • Barcelona, Spain, 08003
    • Hospital del Mar - Parc de Salut Mar
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i de Sant Pau
  • Barcelona, Spain, 08908
    • Hospital Duran i Reynals
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28050
    • HM Centro Integral Oncológico Clara Campal
  • Marbella, Spain, 29603
    • Hospital Costa Del Sol
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Pamplona, Spain, 31008
    • Complejo Hospitalario de Navarra
  • Santiago De Compostela, Spain, 15707
    • Hospital Clinico Universitario de Santiago de Compostela
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe de Valencia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital
  • Kaohsiung, Taiwan, 83301
    • Kaohsiung Chang Gung Memorial Hospital
  • Keelung, Taiwan, 20442
    • Chang Gung Medical Foundation Keelung Chang Gung Memorial Hospital
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital
  • Tainan, Taiwan, 70403
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Taipei, Taiwan, 10099
    • Mackay Memorial Hospital
  • Taoyuan, Taiwan, 33305
    • Chang Gung Memorial Hospital
• Thailand
  • Bangkok, Thailand, 10330
    • King Chulalongkorn Memorial Hospital
  • Chiang Mai, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Hospital
  • Hat Yai, Thailand, 90110
    • Songklanagarind Hospital
• United Kingdom
  • Glasgow, United Kingdom, G12 0XH
    • NHS Greater Glasgow and Clyde
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust
  • London, United Kingdom, NW1 2BU
    • University College London Hospitals NHS Foundation Trust
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden NHS Foundation Trust
  • England
    • London, England, United Kingdom, SE1 9Rt
      • Guy's and Saint Thomas' NHS Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA - Jonsson Comprehensive Cancer Center
    • San Francisco, California, United States, 94158
      • UCSF - Helen Diller Family Comprehensive Cancer Center
    • Whittier, California, United States, 90603
      • The Oncology Institute of Hope and Innovation - Anaheim
  • Florida
    • Miami, Florida, United States, 33176
      • Miami Cancer Institute
    • Tampa, Florida, United States, 33612
      • University of South Florida H. Lee Moffitt Cancer Center and Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University Of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Markey Cancer Center
    • Louisville, Kentucky, United States, 40202
      • Norton Cancer Institute
  • Maryland
    • Baltimore, Maryland, United States, 21204
      • Greater Baltimore Medical Center
    • Baltimore, Maryland, United States, 21287
      • Marlene and Stewart Greenebaum Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63129
      • Siteman Cancer Center - Washington University Medical Campus
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center-Vanderbilt Ingram Cancer Center
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • San Antonio Military Medical Center
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • University of Texas Health San Antonio - Mays Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AIM-HN; Tipifarnib, Oral Tablet. Dose Level 1 orally, bid on days 1-7 and 15-21 of 28-day treatment cycles	Drug: Tipifarnib; Tablet for oral administration; Device: HRAS Detection Assay; In Vitro Assay to detect HRAS mutations
No Intervention: SEQ-HN; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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)

Collaborators and Investigators

• Sponsor: Kura Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2019
• Primary Completion (Actual): May 2, 2023
• Study Completion (Actual): May 2, 2023

Study Registration Dates

• First Submitted: October 16, 2018
• First Submitted That Met QC Criteria: October 23, 2018
• First Posted (Actual): October 25, 2018

Study Record Updates

• Last Update Posted (Actual): June 21, 2024
• Last Update Submitted That Met QC Criteria: May 28, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: TIPIFARNIB; HEAD AND NECK CANCER
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Antineoplastic Agents; Tipifarnib
• Other Study ID Numbers: KO-TIP-007

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No