NCT04997902已完成1 期
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
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 45
- 试验地点
- 22
- 主要终点
- Dose-limiting toxicity (DLT)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Has a tumor that is dependent upon HRAS and/or PIK3CA.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •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.
排除标准
- •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
- •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
- •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.
研究组 & 干预措施
HRAS-dependent (Cohort 2)
Experimental
Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression
干预措施: Tipifarnib (Drug)
PIK3CA-dependent (Cohort 1)
Experimental
Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications
干预措施: Alpelisib (Drug)
HRAS-dependent (Cohort 2)
Experimental
Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression
干预措施: Alpelisib (Drug)
PIK3CA-dependent (Cohort 1)
Experimental
Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications
干预措施: Tipifarnib (Drug)
结局指标
主要结局
Dose-limiting toxicity (DLT)
时间窗: 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)
时间窗: 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.
次要结局
- 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)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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)
- Overall Survival (OS)(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(From Cycle 1 Day 1 until 12 months of treatment or death from any cause, whichever comes first)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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.)
- 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.)
- 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.)
研究者
研究点 (22)
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