HNSCC
Conditions
Keywords
HRAS, PIK3CA, PI3K, Tipifarnib, Alpelisib, R/M HNSCC (Recurrent/metastatic Head and Neck Squamous Cell Carcinoma), Head and Neck Cancer, SCCHN
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.
Interventions
DRUGTipifarnib
Oral administration
DRUGAlpelisib
Oral administration
Sponsors
Kura Oncology, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting toxicity (DLT) | First 28 days (1 cycle) of combination therapy | 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. |
| Descriptive statistics of Adverse Events (AEs) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 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 | 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. |
| Median duration of response | 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 | 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. |
| Disease control rate (DCR) | 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 | Disease control rate (CR + PR + SD) |
| Median duration of Disease Control | 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 | 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 |
| 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) | 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 | Defined as durable SD (\>= 12 weeks) by RECIST v1.1 |
| 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. | Maximum observed concentration following single dose and multiple dose administration |
| 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 maximum observed concentration following single dose and multiple dose administration |
| 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 quantifiable concentration following single dose and multiple dose administration |
| 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 following single dose and multiple dose administration |
| 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 following single dose administration |
| 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 following single dose and multiple dose administration |
| 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 following single dose and multiple dose administration |
| 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 following single dose and multiple dose administration |
| 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. | 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. |
| Progression-free survival (PFS) | 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 | 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. |
| Proportion of participants with PFS at 6 months | 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 | 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. |
| Overall Survival (OS) | From Cycle 1 Day 1 until 3 years of treatment or death from any cause, whichever comes first | 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. |
| Proportion of patients with OS at 12 months | From Cycle 1 Day 1 until 12 months of treatment or death from any cause, whichever comes first | 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. |
Countries
United States
Outcome results
None listed