Combination Trial of Tipifarnib and Alpelisib in Adult Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)
- Registration Number
- NCT04997902
- Lead Sponsor
- Kura Oncology, Inc.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 40
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description PIK3CA-dependent (Cohort 1) Alpelisib Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications HRAS-dependent (Cohort 2) Alpelisib Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression PIK3CA-dependent (Cohort 1) Tipifarnib Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications HRAS-dependent (Cohort 2) Tipifarnib Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression
- Primary Outcome Measures
Name Time Method To determine the recommended dose and regimen and evaluate the safety and tolerability of the combination of tipifarnib and alpelisib DLTs will be evaluated during the first 28 days (1 cycle) of combination therapy Rate of DLT per dose level and Descriptive statistics of adverse events per the NCI CTCAE v 5.0
- Secondary Outcome Measures
Name Time Method Disease control rate (DCR) Up to approximately 3 years Disease control rate (CR + PR + SD), Median duration of disease control, Rate of SD, Median duration of SD
Tmax of tipifarnib and alpelisib when administered in combination 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 peak concentration following drug administration for single dose and multiple dose
AUC(0-infinity) of tipifarnib and alpelisib when administered in combination 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 for single dose
Cmax of tipifarnib and alpelisib when administered in combination 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. Peak drug concentration for single dose and multiple dose
AUC(tau) of tipifarnib and alpelisib when administered in combination 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 for single dose and multiple dose
Half-life of tipifarnib and alpelisib when administered in combination 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 for single dose and multiple dose
Determine the Objective Response Rate (ORR) Up to approximately 3 years Overall confirmed response rate (CR + PR) and Median duration of response
AUC(0-last) of tipifarnib and alpelisib when administered in combination 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 measurable concentration for single dose and multiple dose
Accumulation ratio of tipifarnib and alpelisib when administered in combination 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. Ratio of accumulation of a drug after multiple doses compared to a single dose
Vd/F of tipifarnib and alpelisib when administered in combination 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 after administration for single dose and multiple dose
Antitumor activity in terms of PFS and rate of PFS at 6 months Up to approximately 3 years Median PFS and Proportion of participants alive and without progression at 6 months
CL/F of tipifarnib and alpelisib when administered in combination 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 after administration for single dose and multiple dose
Overall Survival (OS) and rate of OS at 12 months Up to approximately 3 years Median OS and Proportion of participants alive at 12 months
Trial Locations
- Locations (11)
Lake Nona DDU (Florida Cancer Specialists)
🇺🇸Orlando, Florida, United States
University of Maryland School of Medicine (Marlene and Stewart Greenebaum Comprehensive Cancer Center)
🇺🇸Baltimore, Maryland, United States
Johns Hopkins University School of Medicine (Sidney Kimmel Comprehensive Cancer Center)
🇺🇸Baltimore, Maryland, United States
Dana-Farber Cancer Institute (Head and Neck Cancer Treatment Center)
🇺🇸Boston, Massachusetts, United States
Washington University, School of Medicine
🇺🇸Saint Louis, Missouri, United States
UT Southwestern Medical Center (Harold C. Simmons Comprehensive Cancer Center)
🇺🇸Dallas, Texas, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
UPMC Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
University of Wisconsin Carbone Cancer Center
🇺🇸Madison, Wisconsin, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States