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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PIK3CA-dependent (Cohort 1) | Experimental | Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications |
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| HRAS-dependent (Cohort 2) | Experimental | Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tipifarnib | Drug | Oral administration |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dose-limiting toxicity (DLT) | Rate of DLTs evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. A Treatment-Emergent Adverse Event (TEAE) is an AE occurring on or after Cycle 1 Day 1 and within 30 days of the last dose of tipifarnib or alpelisib, whichever is later. Patients with multiple events are counted only once at the highest CTCAE grade. | 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. AEs are coded using the MedDRA dictionary version 28.0. A TEAE is an AE occurring on or after Cycle 1 Day 1 and within 30 days of the last dose of tipifarnib or alpelisib, whichever is later. At each level of summation (system organ class, preferred term), a patient reporting more than one adverse event is counted only once. | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Objective Response Rate (ORR) | Defined as the proportion of participants with best overall response as a confirmed complete response (CR) or confirmed partial response (PR) by RECIST v1.1. Clopper-Pearson 95% confidence intervals are calculated based on binomial distribution. | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| City of Hope Comprehensive Cancer Center | Duarte | California | 91010 | United States | ||
| Lake Nona DDU (Florida Cancer Specialists) |
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| Alpelisib | Drug | Oral administration |
|
|
| 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. Median is calculated using Kaplan-Meier method. Confidence interval for median is calculated using the Brookmeyer-Crowley method. Minimum and maximum are actual values rather than estimates. | 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 |
| Cmax of tipifarnib and alpelisib when administered in combination | Maximum observed concentration following single dose and multiple dose administration | 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 maximum observed concentration following single dose and multiple dose administration | 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 quantifiable concentration following single dose and multiple dose administration | 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 following single dose and multiple dose administration | 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 following single dose administration | 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 following single dose and multiple dose administration | 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 following single dose and multiple dose administration | 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 following single dose and multiple dose administration | 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 | Defined as the ratio of drug exposure at steady state to exposure following a single dose. For tipifarnib, the accumulation ratio was calculated as the ratio of area under the plasma concentration-time curve over the dosing interval (AUCτ) on Cycle 2 Day 1 (C2D1) to AUC from time zero to 12 hours (AUC₀-12) on Cycle 1 Day 1 (C1D1). For alpelisib, the accumulation ratio was calculated as the ratio of AUCτ on C2D1 to AUC from time zero to 24 hours (AUC₀-24) on C1D1. | 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. |
| Progression-free survival (PFS) | Defined as the time in months from C1D1 to the first documentation of disease progression or death due to any cause before new anti-cancer treatment. Median is calculated using Kaplan-Meier method. Confidence interval for median is calculated using the Brookmeyer-Crowley method. Minimum and maximum are actual values rather than estimates. | 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 disease progression at 6 months and before new anti-cancer treatment. Survival probability and confidence interval are calculated based on Kaplan-Meier product-limit method and Greenwood's formula. | 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) | OS is the time in months from C1D1 to the date of death due to any cause. For patients with no events, OS will be censored at the last known to be alive date. Median is calculated using Kaplan-Meier method. Confidence interval for median is calculated using the Brookmeyer-Crowley method. Minimum and maximum are actual values rather than estimates. | 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 | Proportion of participants alive at 12 months. For patients with no events, OS will be censored at the last known to be alive date. Survival probability and confidence interval are calculated based on Kaplan-Meier product-limit method and Greenwood's formula. | From Cycle 1 Day 1 until 12 months of treatment or death from any cause, whichever comes first |
| Orlando |
| Florida |
| 32827 |
| United States |
| University of Maryland School of Medicine (Marlene and Stewart Greenebaum Comprehensive Cancer Center) | Baltimore | Maryland | 21201 | United States |
| Johns Hopkins University School of Medicine (Sidney Kimmel Comprehensive Cancer Center) | Baltimore | Maryland | 21231 | United States |
| Dana-Farber Cancer Institute (Head and Neck Cancer Treatment Center) | Boston | Massachusetts | 02215 | United States |
| Washington University, School of Medicine | St Louis | Missouri | 63110 | United States |
| Memorial Sloan Kettering Cancer Center | New York | New York | 10065 | United States |
| UPMC Hillman Cancer Center | Pittsburgh | Pennsylvania | 15232 | United States |
| UT Southwestern Medical Center (Harold C. Simmons Comprehensive Cancer Center) | Dallas | Texas | 75390 | United States |
| University of Texas MD Anderson Cancer Center | Houston | Texas | 77030 | United States |
| University of Wisconsin Carbone Cancer Center | Madison | Wisconsin | 53792 | United States |
| ID | Term |
|---|---|
| D000077195 | Squamous Cell Carcinoma of Head and Neck |
| D009477 | Hereditary Sensory and Autonomic Neuropathies |
| D012008 | Recurrence |
| D006258 | Head and Neck Neoplasms |
| ID | Term |
|---|---|
| D002294 | Carcinoma, Squamous Cell |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D009371 | Neoplasms by Site |
| D009421 | Nervous System Malformations |
| D009422 | Nervous System Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D011115 | Polyneuropathies |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C402769 | tipifarnib |
| C585539 | Alpelisib |
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