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Completed

NCT Number: NCT04997902

Combination Trial of Tipifarnib and Alpelisib in Adult Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)

This phase 1/2 combination trial of tipifarnib, a farnesyltransferase inhibitor, and alpelisib, a PI3K inhibitor in participants with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) whose tumors overexpress the HRAS protein and/or are PIK3CA-mutated and/or PIK3CA-amplified.

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Key information

Conditions

HNSCC Carcinoma Carcinoma, Squamous Cell Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Disease Attributes Genetic Diseases, Inborn Head and Neck Neoplasms Hereditary Sensory and Autonomic Neuropathies Heredodegenerative Disorders, Nervous System Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Nervous System Diseases Nervous System Malformations Neurodegenerative Diseases Neuromuscular Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Peripheral Nervous System Diseases Polyneuropathies Recurrence Squamous Cell Carcinoma of Head and Neck

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

City of Hope Comprehensive Cancer Center, Duarte, California, United States

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • At least 18 years of age.
  • 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 at least 1 prior systemic therapy in the R/M setting, unless determined not appropriate.
  • Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
  • Has a tumor that is dependent upon HRAS and/or PIK3CA.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  • Acceptable liver, renal, endocrine, and hematologic function.
  • Must be able to swallow alpelisib whole tablet or oral suspension containing crushed tablets. Feeding tube may not be used for alpelisib administration.
  • Other protocol defined inclusion criteria may apply.

Exclusion criteria

  • Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (eg, mucosal melanoma).
  • Ongoing treatment with certain anticancer agents.
  • Prior treatment (at least 1 full treatment cycle) with an FTI or PI3K, mTOR, or AKT inhibitor.
  • Received treatment for unstable angina, myocardial infarction, and/or cerebro-vascular attack within the prior 6 months.
  • Non-tolerable Grade 2, or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1.
  • 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.
  • Participant with an established diagnosis of diabetes mellitus Type 1 or not controlled Type 2.
  • Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs based on Investigator discretion.
  • Participant has currently documented pneumonitis/interstitial lung disease.
  • Participant has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
  • Other protocol defined exclusion criteria may apply.

Treatment and study plan

tipifarnib

Drug

Oral administration

Alpelisib

Drug

Oral administration

Other names: BYL719

Primary outcomes

  1. Dose-limiting toxicity (DLT)

    Time frame: First 28 days (1 cycle) of combination therapy

    Rate of DLTs evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. A Treatment-Emergent Adverse Event (TEAE) is an AE occurring on or after Cycle 1 Day 1 and within 30 days of the last dose of tipifarnib or alpelisib, whichever is later. Patients with multiple events are counted only once at the highest CTCAE grade.

  2. Descriptive statistics of Adverse Events (AEs)

    Time frame: From Cycle 1 Day 1 until 30 days after last trial intervention dose or 30 days after trial completion, whichever comes first, assessed up to 2 years

    Descriptive statistics of Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs; AE severity will be assessed per the NCI CTCAE v 5.0. AEs are coded using the MedDRA dictionary version 28.0. A TEAE is an AE occurring on or after Cycle 1 Day 1 and within 30 days of the last dose of tipifarnib or alpelisib, whichever is later. At each level of summation (system organ class, preferred term), a patient reporting more than one adverse event is counted only once.

Secondary outcomes

  1. Objective Response Rate (ORR)

    Time frame: From Cycle 1 Day 1 until first documentation of disease progression, the start of new anti-cancer therapy, or death, whichever occurs first, assessed up to 2 years

    Defined as the proportion of participants with best overall response as a confirmed complete response (CR) or confirmed partial response (PR) by RECIST v1.1. Clopper-Pearson 95% confidence intervals are calculated based on binomial distribution.

  2. Median duration of response

    Time frame: From first documentation of response to first documentation of disease progression, the start of new anti-cancer therapy, or death, whichever occurs first, assessed up to 2 years

    Defined for participants with confirmed objective response as the time from the first documentation of response to the first documentation of disease progression by RECIST v1.1 or to death due to any cause before new anti-cancer treatment, whichever occurs first. Median is calculated using Kaplan-Meier method. Confidence interval for median is calculated using the Brookmeyer-Crowley method. Minimum and maximum are actual values rather than estimates.

  3. Disease control rate (DCR)

    Time frame: From Cycle 1 Day 1 until first documentation of disease progression, the start of new anti-cancer therapy, or death, whichever occurs first, assessed up to 2 years

    Disease control rate (CR + PR + SD)

  4. Median duration of Disease Control

    Time frame: From first documentation of response until first documentation of disease progression, the start of new anti-cancer therapy, or death, whichever occurs first, assessed up to 2 years

    Defined for participants with confirmed objective response as the time in months from the first documentation of response to the first documentation of disease progression by RECIST v1.1 or to death due to any cause before new anti-cancer treatment, whichever occurs first, in patients with confirmed CR/PR

  5. Rate of Stable Disease

    Time frame: From Cycle 1 Day 1 until first documentation of disease progression, the start of new anti-cancer therapy, or death, whichever occurs first, assessed up to 2 years

  6. Median duration of Stable Disease (SD)

    Time frame: From first documentation of response until first documentation of disease progression, the start of new anti-cancer therapy, or death, whichever occurs first, assessed up to 2 years

    Defined as durable SD (>= 12 weeks) by RECIST v1.1

  7. Cmax of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Maximum observed concentration following single dose and multiple dose administration

  8. Tmax of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Time to reach maximum observed concentration following single dose and multiple dose administration

  9. AUC(0-last) of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Area under the concentration-time curve from time zero to time of last quantifiable concentration following single dose and multiple dose administration

  10. AUC(tau) of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Area under the concentration-time curve during a dosage interval following single dose and multiple dose administration

  11. AUC(0-infinity) of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Area under the concentration-time curve from time zero to infinity following single dose administration

  12. CL/F of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Apparent total clearance of the drug following single dose and multiple dose administration

  13. Vd/F of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Apparent volume of distribution following single dose and multiple dose administration

  14. Half-life of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Time required for the amount of drug in the body to decrease by half following single dose and multiple dose administration

  15. Accumulation ratio of tipifarnib and alpelisib when administered in combination

    Time frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days.

    Defined as the ratio of drug exposure at steady state to exposure following a single dose. For tipifarnib, the accumulation ratio was calculated as the ratio of area under the plasma concentration-time curve over the dosing interval (AUCτ) on Cycle 2 Day 1 (C2D1) to AUC from time zero to 12 hours (AUC₀-12) on Cycle 1 Day 1 (C1D1). For alpelisib, the accumulation ratio was calculated as the ratio of AUCτ on C2D1 to AUC from time zero to 24 hours (AUC₀-24) on C1D1.

  16. Progression-free survival (PFS)

    Time frame: From Cycle 1 Day 1 until first documentation of disease progression, the start of new anti-cancer therapy, or death, whichever occurs first, assessed up to 3 years

    Defined as the time in months from C1D1 to the first documentation of disease progression or death due to any cause before new anti-cancer treatment. Median is calculated using Kaplan-Meier method. Confidence interval for median is calculated using the Brookmeyer-Crowley method. Minimum and maximum are actual values rather than estimates.

  17. Proportion of participants with PFS at 6 months

    Time frame: From Cycle 1 Day 1 until first documentation of disease progression, the start of new anti-cancer therapy, or death, whichever occurs first, assessed up to 6 months

    Proportion of participants alive and without disease progression at 6 months and before new anti-cancer treatment. Survival probability and confidence interval are calculated based on Kaplan-Meier product-limit method and Greenwood's formula.

  18. Overall Survival (OS)

    Time frame: From Cycle 1 Day 1 until 3 years of treatment or death from any cause, whichever comes first

    OS is the time in months from C1D1 to the date of death due to any cause. For patients with no events, OS will be censored at the last known to be alive date. Median is calculated using Kaplan-Meier method. Confidence interval for median is calculated using the Brookmeyer-Crowley method. Minimum and maximum are actual values rather than estimates.

  19. Proportion of patients with OS at 12 months

    Time frame: From Cycle 1 Day 1 until 12 months of treatment or death from any cause, whichever comes first

    Proportion of participants alive at 12 months. For patients with no events, OS will be censored at the last known to be alive date. Survival probability and confidence interval are calculated based on Kaplan-Meier product-limit method and Greenwood's formula.

Sponsors and collaborators

Lead sponsor

Kura Oncology, Inc.

Industry

Registry information

Official study title

A Phase 1/2 Open-label, Biomarker-defined Cohort Trial to Evaluate the Safety, Determine the Recommended Combination Dosing, and Assess Early Antitumor Activity of Tipifarnib and Alpelisib for the Treatment of Adult Participants Who Have HRAS-overexpressing and/or PIK3CA-mutated and/or - Amplified Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Important dates

Study start
2021
Primary completion
2025
Study completion
2025
First posted
Aug 10, 2021
Registry last updated
Jun 5, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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