Clinical trial NCT04997902: Combination Trial of Tipifarnib and Alpelisib in Adult Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)
Official 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: HNSCC
Keywords: HRAS
PIK3CA
PI3K
Tipifarnib
Alpelisib
R/M HNSCC (Recurrent/metastatic Head and Neck Squamous Cell Carcinoma)
Head and Neck Cancer
SCCHN
Lead sponsor: Kura Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2021-08-10
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: To determine the recommended dose and regimen and evaluate the safety and tolerability of the combination of tipifarnib and alpelisib
timeFrame: DLTs will be evaluated during the first 28 days (1 cycle) of combination therapy
Secondary outcomes:
measure: Determine the Objective Response Rate (ORR)
timeFrame: Up to approximately 3 years
measure: Disease control rate (DCR)
timeFrame: Up to approximately 3 years
measure: Cmax of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: Tmax of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: AUC(0-last) of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: AUC(tau) of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: AUC(0-infinity) of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: CL/F of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: Vd/F of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: Half-life of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: Accumulation ratio of tipifarnib and alpelisib when administered in combination
timeFrame: 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.
measure: Antitumor activity in terms of PFS and rate of PFS at 6 months
timeFrame: Up to approximately 3 years
measure: Overall Survival (OS) and rate of OS at 12 months
timeFrame: Up to approximately 3 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Orlando
country: United States
facility: Lake Nona DDU (Florida Cancer Specialists)
state: Florida
city: Baltimore
country: United States
facility: University of Maryland School of Medicine (Marlene and Stewart Greenebaum Comprehensive Cancer Center)
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine (Sidney Kimmel Comprehensive Cancer Center)
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute (Head and Neck Cancer Treatment Center)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University, School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center (Harold C. Simmons Comprehensive Cancer Center)
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center
state: Wisconsin
Study officials:
References: