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Clinical Trial 19855

Cancer Type: Head & Neck
Study Type: Treatment
NCT#: NCT03719690

Phase: Phase III
Principal Investigator: Chung, Christine

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Overview

Study Title

The AIM-HN and SEQ-HN Study: 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)

Summary

This is 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 and includes 2 types of patients: (1) the historical record of first line therapy in subjects with HRAS mutant HNSCC participating in Cohort 1 in whom first line outcome data are available and (2) matched control 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.

Objective

Primary Objective: To determine the ORR of tipifarnib in subjects with HNSCC with HRAS mutations as assessed by IRF. Secondary Objectives: To determine the anti-tumor activity of tipifarnib in terms of: time to response, DOR, TTP, PFS, one year progression free rate, one year survival and OS. To investigate the safety and tolerability of tipifarnib according to the NCI CTCAE v5.0. To assess population PK of tipifarnib in subjects with HNSCC with HRAS mutations. Exploratory Objectives: To identify HRAS mutations and assess their effect on the ORR of first line systemic therapy in patients with recurrent/metastatic HNSCC. To assess the treatment outcome to first line systemic therapy in terms of PFS, DOR, and OS in patients with recurrent/metastatic HNSCC with HRAS mutations. To describe demographic characteristics prevalent in patients with HNSCC with HRAS mutations. To explore the frequency and treatment outcome interaction of other HNSCC genetic alterations. To identify trends in the data that may suggest relationships between covariates of interest and treatment outcome in patients with HNSCC with HRAS mutations.

Treatments

Therapies

Medications

Zarnestra (tipifarnib); tipifarnib ()

Inclusion Criteria

  • Histologically confirmed head and neck cancer of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
  • 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.
  • Known tumor missense HRAS mutation detected by Next Generation Sequencing (NGS) or any other methodology approved by the Sponsor.
  • Measurable disease by RECIST v1.1
  • At least 2 weeks or 5 half-lives, whichever is longer, since the last systemic therapy regimen prior to Cycle 1 Day 1. Last dose of any prior checkpoint inhibitor therapy must have been administered at least 2 weeks prior to C1D1.
  • At least 2 weeks since last radiotherapy. Participants must have recovered from all acute toxicities from radiotherapy.
  • ECOG performance status of 0-1
  • Acceptable liver function per protocol. Patient must meet/continue to meet these criteria at the time of first dosing as confirmed by analysis within 72 hours of C1D1.
  • Acceptable renal function. Patient must meet/continue to meet these criteria at the time of first dosing as confirmed by analysis within 72 hours of C1D1.
  • Acceptable hematologic status per protocol. Patient must meet/continue to meet these criteria at the time of first dosing as confirmed by analysis within 72 hours of C1D1.
  • Female subjects must be: Of non-child-bearing potential (surgically sterilized or at least 2 years post-menopausal); or If of child-bearing potential, subject must use a highly effective method of contraception, such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence. Both females and male subjects with female partners of child-bearing potential must agree to use a highly effective method of contraception from the first dose of tipifarnib, during tipifarnib treatment, and at least 28 days after last dose of tipifarnib for females and 90 days for males. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication.
  • Not breast feeding at any time during the study.
  • Inclusion Criteria: SEQ-HN
  • Histologically confirmed head and neck cancer of squamous histology.
  • HRAS wildtype (i.e. have no identified tumor missense HRAS mutation) determined by a test preferred by the investigator and approved by the Sponsor or through central HRAS testing.
  • Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC for which there is available outcome information in terms of ORR, or can be determined based on the subject’s records. Subjects who have not yet received or completed at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC must consent to the collection of treatment outcome information and additional follow up contact in order to participate in the SEQ-HN portion of the study.

    • Exclusion Criteria

  • If a participant initially meets any exclusion criteria, the subject may be re-screened at a later time.
  • Has disease that is suitable for local therapy administered with curative intent.
  • Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g. mucosal melanoma).
  • Known additional malignancy that is progressing or requires active treatment (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
  • Ongoing treatment with an anticancer agent not contemplated in this protocol (excluding adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
  • Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor (FTI).
  • Any use of investigational therapy within 2 weeks of Cycle 1 Day 1 (C1D1) or 5 half-lives (whichever is longer). Last dose of any prior checkpoint inhibitor therapy must have been administered at least 2 weeks prior to C1D1.
  • 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.
  • Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable Grade 2 toxicities are defined as those with moderate symptoms that the subject is not able to endure for the conduct of instrumental activities of daily life or that persists ≥ 7 days.
  • Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery.
  • Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy, including known history of infection with human immunodeficiency virus or an active infection with hepatitis B or hepatitis C.
  • Participants who have exhibited allergic reactions to tipifarnib or structural compounds similar to tipifarnib or to its excipients. This includes hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class. Subjects with hypersensitivity to these agents will be excluded from enrollment.
  • Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4, Table 11) or UDP-glucuronosyltransferase (UGT).
  • Concomitant disease or condition that could interfere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.
  • Female subjects who are pregnant or lactating.
  • Unwillingness or inability to comply with the study protocol for any reason.
  • Exclusion Criteria: SEQ-HN
  • A participant may not be enrolled in the noninterventional portion of the study (SEQ-HN), if any of the following exclusion criteria apply:
  • Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g. mucosal melanoma).
  • Concomitant disease or condition that could interfere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.
  • The subject has legal incapacity or limited legal capacity.

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