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 (The Kurrent Trial)

Description
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.

Objective
Primary Objective: To determine the recommended dose and regimen, and evaluate the safety and tolerability of the combination of tipifarnib and alpelisib

Secondary Objectives:
1) To determine the ORR
2) To determine the disease control rate
3) Pharmacokinetics of tipifarnib and alpelisib when administered in combination
4) To determine the antitumor activity in terms of PFS and rate of PFS at 6 months
5) To estimate the OS and rate of OS at 12 months

Exploratory Objectives:
1) Evaluate biomarkers related to HNSCC biology and their potential correlation to efficacy and resistance to study medications.
2) Evaluate the antitumor activity in patients with different levels of HRAS expression

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 Name: 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 Name: BYL719

Key Eligibility 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.

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.

Applicable Disease Sites
Head and Neck

Participating Institutions
UW Health University Hospital