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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HNSCC

Intervention / Treatment
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* Drug: Tipifarnib
* Drug: Alpelisib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the recommended dose and regimen and evaluate the safety and tolerability of the combination of tipifarnib and alpelisib | Rate of DLT per dose level and Descriptive statistics of adverse events per the NCI CTCAE v 5.0 | DLTs will be evaluated during the first 28 days (1 cycle) of combination therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the Objective Response Rate (ORR) | Overall confirmed response rate (CR + PR) and Median duration of response | Up to approximately 3 years | 
| Disease control rate (DCR) | Disease control rate (CR + PR + SD), Median duration of disease control, Rate of SD, Median duration of SD | Up to approximately 3 years | 
| 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. | 
| Antitumor activity in terms of PFS and rate of PFS at 6 months | Median PFS and Proportion of participants alive and without progression at 6 months | Up to approximately 3 years | 
| Overall Survival (OS) and rate of OS at 12 months | Median OS and Proportion of participants alive at 12 months | Up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Head and Neck Cancer, SCCHN, HRAS, PIK3CA, PI3K, Tipifarnib, Alpelisib, R/M HNSCC (Recurrent/metastatic Head and Neck Squamous Cell Carcinoma)