Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations

Phase 2

Completed

Conditions: Squamous Cell Carcinoma Head and Neck Cancer (HNSCC)
HRAS Mutant Tumor
Thyroid Cancer
Other Squamous Cell Carcinoma (SCC) With HRAS Mutant Tumor

Interventions: Drug: Tipifarnib

Registration Number: NCT02383927

Lead Sponsor: Kura Oncology, Inc.

Brief Summary: Phase II study to investigate the antitumor activity in terms of objective response rate (ORR) of tipifarnib in subjects with advanced tumors that carry HRAS mutations and for whom there is no standard curative therapy available.

Detailed Description: This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with locally advanced, unresectable or metastatic, relapsed and/or refractory tumors that carry HRAS mutations and for whom there is no curative therapy available. Subjects with information available on tumor HRAS status previously generated are eligible. All subjects must consent to provide at least 10 tumor slides from a prior diagnostic biopsy for a retrospective testing of HRAS gene status at a central facility.

Subjects will be enrolled into three nonrandomized cohorts:

* Cohort 1: Malignant thyroid tumors with HRAS mutations.

* Cohort 2: Squamous Cell Carcinoma Head and Neck Cancer with HRAS mutations.

* Cohort 3: Squamous Cell Carcinoma (SCC) with HRAS mutations other than HNSCC.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 63

Inclusion Criteria

histologically or cytologically confirmed diagnosis of thyroid cancer (cohort 1) or Squamous Cell Carcinoma head and neck cancer (cohort 2) or Squamous Cell Carcinoma other than HNSCC (cohort 3) for which there is no curative therapy available.
tumor that carries a missense HRAS mutation ith a variant allele frequency (VAF) > 20%.
Subject consents to provide at least 10 unstained tumor slides for retrospective testing of HRAS gene tumor status
Subject has measurable disease according to RECIST v1.1 and has relapsed or is refractory to prior therapy.
At least 2 weeks since the last systemic therapy or radiotherapy regimen prior to enrolment
ECOG PS 0 or 1
Acceptable liver function
Acceptable renal function
Acceptable hematologic status • Serum albumin ≥ 3.5 g/dL. Subjects with tumors potentially highly sensitive to tipifarnib (HRAS mutant VAF ≥ 35%) may be enrolled despite a serum albumin < 3.5 g/dL.

Exclusion Criteria

Prior treatment with an FTase inhibitor
History of relevant coronary heart disease or myocardial infarction within last 3 years, NYHA Grade III or greater congestive heart failure, cerebro-vascular attack within the prior year, or serious cardiac arrhythmia requiring medication except atrial fibrillation.
Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 4 weeks prior to Cycle 1 Day 1). Controlled brain metastases that require continuous high dose corticosteroid use within 4 weeks of Day 1.
Non-tolerable > Grade 2 neuropathy or evidence of unstable neurological symptoms within 4 weeks first dose
Major surgery, other than diagnostic surgery, within 4 weeks prior to first dose, without complete recovery.
Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Known infection with HIV, or an active infection with hepatitis B or hepatitis C

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 2	Tipifarnib	Squamous Head and Neck Cancer
Cohort 1	Tipifarnib	Thyroid Cancer

Primary Outcome Measures

Name	Time	Method
Antitumor Activity by Objective Response Rate (ORR)	Up to approximately 3 years	The ORR of tipifarnib was response assessments according to RECIST 1.1. The estimate of the ORR was calculated based on the maximum likelihood estimator (i.e., crude percentage of subjects whose best overall response was complete response \[CR\] or partial response \[PR\]). The estimate of the ORR was accompanied by 2-sided 95% confidence interval (CI). The 95% CI was estimated using the Wilson score test-based method. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.

Secondary Outcome Measures

Name	Time	Method
Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs)	Up to approximately 3 years	An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. TEAEs were defined as AEs that started on or after the first dose of study drug and within 30 days of the last administration of study drug or immediately before the initiation of any other anticancer therapy. The Investigator was required to grade the severity/ intensity of each AE according to NCI-CTCAE version 4.03. If a severity/intensity of Grade 4 (life-threatening) or 5 (death) was applied to an AE, then the Investigator also reported the event as a serious AE.

Trial Locations

Locations (35): Wihship Cancer Institute of Emory University
🇺🇸
Atlanta, Georgia, United States
Oklahoma University Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
The University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Royal Marsden
🇬🇧
London, England, United Kingdom
Instituto Nazionale Tumori
🇮🇹
Milan, Italy
Insitut Bergonie
🇫🇷
Bordeaux, France
Attikon University Hospital
🇬🇷
Attikí, Greece
Institute Gustave Roussy (IGR)
🇫🇷
Paris, France
Centre Antoine Lacassagne
🇫🇷
Nice, France
Centre Léon Bérard
🇫🇷
Lyon, France
Hospital del Mar
🇪🇸
Barcelona, Spain
Asan Medical Center
🇰🇷
Seoul, Korea, Republic of
University Medical Center
🇳🇱
Groningen, Netherlands
Hospital Universitario Virgen de la Rocio
🇪🇸
Sevilla, Spain
Hospital Vall d' Hebron
🇪🇸
Barcelona, Spain
Hospital Universitario y Politécnico La Fe
🇪🇸
Valencia, Spain
University Hospital Wuerazburg
🇩🇪
Würzburg, Germany
Hospital Clinic de Barcelona
🇪🇸
Barcelona, Spain
Hospital Universitario La Paz
🇪🇸
Madrid, Spain
MD Anderson Cancer Center Madrid
🇪🇸
Madrid, Spain
START, Centro Integral Oncologico Clara Campal
🇪🇸
Madrid, Spain
Complejo Hospitalario de Navarro
🇪🇸
Navarro, Spain
University of Michigan Comprehensive Cancer Center
🇺🇸
Ann Arbor, Michigan, United States
University of California, Los Angeles
🇺🇸
Los Angeles, California, United States
Samsung Medical Center
🇰🇷
Seoul, Korea, Republic of
Hospital Universitario Virgen de la Victoria
🇪🇸
Málaga, Spain
Hospital Universitario Doce de Octubre
🇪🇸
Madrid, Spain
Cliniques universitaires Saint-Luc
🇧🇪
Brussels, Belgium
CHU
🇧🇪
Yvoir, Belgium
University College Hospital
🇬🇧
London, England, United Kingdom
University Hospital Antwerp
🇧🇪
Antwerp, Belgium
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Fox Chase Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States