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

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

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.

Study Overview

• Status: Completed
• Conditions: HNSCC
• Intervention / Treatment: Drug: Tipifarnib; Drug: Alpelisib

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
  • Florida
    • Orlando, Florida, United States, 32827
      • Lake Nona DDU (Florida Cancer Specialists)
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine (Marlene and Stewart Greenebaum Comprehensive Cancer Center)
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University School of Medicine (Sidney Kimmel Comprehensive Cancer Center)
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute (Head and Neck Cancer Treatment Center)
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University, School of Medicine
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center (Harold C. Simmons Comprehensive Cancer Center)
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. At least 18 years of age.
2. 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).
3. Documented treatment failure from at least 1 prior systemic therapy in the R/M setting, unless determined not appropriate.
4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
5. Has a tumor that is dependent upon HRAS and/or PIK3CA.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7. Acceptable liver, renal, endocrine, and hematologic function.
8. Must be able to swallow alpelisib whole tablet or oral suspension containing crushed tablets. Feeding tube may not be used for alpelisib administration.
9. Other protocol defined inclusion criteria may apply.

Exclusion Criteria:

1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (eg, mucosal melanoma).
2. Ongoing treatment with certain anticancer agents.
3. Prior treatment (at least 1 full treatment cycle) with an FTI or PI3K, mTOR, or AKT inhibitor.
4. Received treatment for unstable angina, myocardial infarction, and/or cerebro-vascular attack within the prior 6 months.
5. Non-tolerable Grade 2, or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1.
6. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery.
7. Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
8. Participant with an established diagnosis of diabetes mellitus Type 1 or not controlled Type 2.
9. Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs based on Investigator discretion.
10. Participant has currently documented pneumonitis/interstitial lung disease.
11. 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).
12. Other protocol defined exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PIK3CA-dependent (Cohort 1); Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications	Drug: Tipifarnib; Oral administration; Drug: Alpelisib; Oral administration; Other Names: BYL719
Experimental: HRAS-dependent (Cohort 2); Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression	Drug: Tipifarnib; Oral administration; Drug: Alpelisib; Oral administration; Other Names: BYL719

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity (DLT)	Rate of DLTs per dose level	First 28 days (1 cycle) of combination therapy
Descriptive statistics of Adverse Events (AEs)	Descriptive statistics of Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs; AE severity will be assessed per the NCI CTCAE v 5.0	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of tipifarnib and alpelisib when administered in combination	Peak drug concentration for single dose and multiple dose	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.
Tmax of tipifarnib and alpelisib when administered in combination	Time to reach peak concentration following drug administration for single dose and multiple dose	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.
AUC(0-last) of tipifarnib and alpelisib when administered in combination	Area under the concentration-time curve from time zero to time of last measurable concentration for single dose and multiple dose	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.
AUC(tau) of tipifarnib and alpelisib when administered in combination	Area under the concentration-time curve during a dosage interval for single dose and multiple dose	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.
AUC(0-infinity) of tipifarnib and alpelisib when administered in combination	Area under the concentration-time curve from time zero to infinity for single dose	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.
CL/F of tipifarnib and alpelisib when administered in combination	Apparent total clearance of the drug after administration for single dose and multiple dose	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.
Vd/F of tipifarnib and alpelisib when administered in combination	Apparent volume of distribution after administration for single dose and multiple dose	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.
Half-life of tipifarnib and alpelisib when administered in combination	Time required for the amount of drug in the body to decrease by half for single dose and multiple dose	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.
Accumulation ratio of tipifarnib and alpelisib when administered in combination	Ratio of accumulation of a drug after multiple doses compared to a single dose	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.
Objective Response Rate (ORR)	Overall confirmed response rate (Complete Response or Partial Response)	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
Median duration of response	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	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
Disease control rate (DCR)	Disease control rate (CR + PR + SD)	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
Median duration of Disease Control	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	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
Rate of Stable Disease		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
Median duration of Stable Disease (SD)	Defined as durable SD (>= 12 weeks) by RECIST v1.1	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
Progression-free survival (PFS)	Median PFS	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
Proportion of participants with PFS at 6 months	Proportion of participants alive and without progression at 6 months	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
Overall Survival (OS)	Median OS; for patients with no events, OS will be censored at the last known to be alive date	From Cycle 1 Day 1 until 3 years of treatment or death from any cause, whichever comes first
Proportion of patients with OS at 12 months	For patients with no events, OS will be censored at the last known to be alive date	From Cycle 1 Day 1 until 12 months of treatment or death from any cause, whichever comes first

Collaborators and Investigators

• Sponsor: Kura Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2021
• Primary Completion (Actual): July 30, 2025
• Study Completion (Actual): July 30, 2025

Study Registration Dates

• First Submitted: July 27, 2021
• First Submitted That Met QC Criteria: August 5, 2021
• First Posted (Actual): August 10, 2021

Study Record Updates

• Last Update Posted (Estimated): December 23, 2025
• Last Update Submitted That Met QC Criteria: December 19, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Head and Neck Cancer; PIK3CA; PI3K; SCCHN; HRAS; Tipifarnib; Alpelisib; R/M HNSCC (Recurrent/metastatic Head and Neck Squamous Cell Carcinoma)
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Neuromuscular Diseases; Disease Attributes; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neoplasms by Histologic Type; Neurodegenerative Diseases; Neoplasms, Glandular and Epithelial; Carcinoma; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Carcinoma, Squamous Cell; Polyneuropathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Squamous Cell Carcinoma of Head and Neck; Recurrence; Head and Neck Neoplasms; Hereditary Sensory and Autonomic Neuropathies; Antineoplastic Agents; Alpelisib; tipifarnib
• Other Study ID Numbers: KO-TIP-013

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No