Tipifarnib and Osimertinib in EGFR-mutated Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a Phase 1a/b, multicenter, open-label, dose escalation (1a) and dose expansion (1b) study. The purpose of this study is to measure safety, tolerability, and preliminary efficacy with the combination of tipifarnib with osimertinib in patients with advanced/metastatic EGFR-mutated non-small cell lung cancer.

Official Title
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Phase 1 Study of Tipifarnib and Osimertinib in EGFR-mutated Non-Small Cell Lung Cancer

Conditions
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NSCLC

Intervention / Treatment
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* Drug: Tipifarnib
* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at the time of signing informed consent. Histologically or cytologically confirmed stage IIIB (locally-advanced) or IV (metastatic) adenocarcinoma of the lung. The tumor harbors an Ex19del or Ex21-L858R substitution (based on tumor tissue or plasma [ctDNA] assessment). Treatment-naïve for locally advanced/metastatic EGFR-mutated NSCLC and osimertinib treatment-naïve for NSCLC. ECOG performance score of 0 or 1 with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks. Measurable disease by RECIST v1.1 that meets the criteria for selection as a target lesion according to RECIST v1.1. Adequate organ function, as evidenced by the laboratory results. Other protocol-defined inclusion criteria may apply. Exclusion Criteria: Treatment with any of the following: Major surgery Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug Medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4 or uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT), or inhibitors of breast cancer resistance protein (BCRP). Investigational therapy within 2 weeks of Cycle 1 Day 1 Concurrent and/or other active malignancy that has required systemic treatment within 2 years of first dose of study drug (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal treatment for castration-sensitive prostate cancer) Spinal cord compression or symptomatic and unstable brain metastases requiring steroids over the last 4 weeks prior. Evidence of severe or uncontrolled systemic diseases. Refractory nausea and vomiting, chronic gastrointestinal (GI) diseases, inability to swallow the formulated product, or previous significant bowel resection. Clinically significant cardiovascular symptoms or disease. Received treatment for unstable angina within prior year, myocardial infarction within the prior 6 months, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring medication except atrial fibrillation. Past medical history of Interstitial Lung Disease (ILD), drug induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. Other protocol-defined exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escalation Cohort<br>Adult participants with EGFR-mutated Non-Small Cell Lung Cancer | Drug: Tipifarnib<br>* Oral administration<br>Drug: Osimertinib<br>* Oral administration<br>|
| Experimental: Expansion Cohort<br>Adult participants with EGFR-mutated Non-Small Cell Lung Cancer | Drug: Tipifarnib<br>* Oral administration<br>Drug: Osimertinib<br>* Oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Dose Escalation determine a safe and tolerable Phase 2 dose of tipifarnib when used in combination with osimertinib | Occurrence of DLTs during first treatment cycle | At the end of Cycle 1 (each cycle is 28 days) | 
| For Dose Escalation characterize the safety of the combination DLTs will be listed for patients who complete the evaluation period for DLT | Descriptive statistics of adverse events per NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) | DLTs will be evaluated at the end of cycle 1 (28 days), but also through study completion, an average of 1.5 years | 
| For Dose Expansion characterize the safety profile of tipifarnib in combination with osimertinib as per NCI CTCAE v5.0 using descriptive statistics of adverse events | Descriptive statistics of adverse events per the NCI CTCAE v5.0 | Through study completion, an average of 2 years | 
| For Dose Expansion characterize the safety profile of tipifarnib in combination with osimertinib as per NCI CTCAE v5.0 using the percentage of patients who discontinue the combination for related adverse events | Percentage of patients who discontinue the combination for tipifarnib and/or osimertinib related adverse events prior to completing 6 cycles of treatment | First 6 cycles of treatment (28 day treatment cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of tipifarnib in combination with osimertinib | Objective Response Rate (ORR), measures evaluated according to RECIST v.1.1 assessed by investigator | Assessed every 8 weeks for the first year and every 12 weeks thereafter up to end of study at approximately 2 years | 
| To evaluate the efficacy of tipifarnib in combination with osimertinib | Duration of Response (DOR) assessed from (CR) or (PR) until (PD), initiation of new anticancer treatment or study withdrawal | Assessed every 8 weeks for the first year and every 12 weeks thereafter up to end of study at approximately 2 years | 
| To evaluate the efficacy of tipifarnib in combination with osimertinib | Progression-free survival (PFS) measures evaluated according to RECIST v.1.1 assessed by investigator | Assessed every 8 weeks for the first year and every 12 weeks thereafter up to end of study at approximately 2 years | 
| To study pharmacokinetics (PK) of tipifarnib and osimertinib in combination | Area under the concentration-time curve (AUC) from time 0 to time of last concentration measured and from time 0 extrapolated to infinity | Cycles 1-6 (28 day treatment cycle) | 
| To study pharmacokinetics (PK) of tipifarnib and osimertinib in combination | Maximum plasma concentration | Cycles 1-6 (28 day treatment cycle) | 
| To study pharmacokinetics (PK) of tipifarnib and osimertinib in combination | Time to maximum observed concentration | Cycles 1-6 (28 day treatment cycle) | 
| To study pharmacokinetics (PK) of tipifarnib and osimertinib in combination | Terminal elimination rate constant | Cycles 1-6 (28 day treatment cycle) | 
| To study pharmacokinetics (PK) of tipifarnib and osimertinib in combination | Terminal half-life | Cycles 1-6 (28 day treatment cycle) | 
| To study pharmacokinetics (PK) of tipifarnib and osimertinib in combination | Apparent clearance and apparent volume of distribution | Cycles 1-6 (28 day treatment cycle) | 
| To evaluate circulating tumor DNA (ctDNA) as an indicator or response in both ctDNA positive and negative patients by changes in genetic alterations | Determine prevalence of tumor-derived genetic alterations of ctDNA collected at baseline, on-treatment and at disease progression | Monthly for duration of trial participation (an average of 2 years) | 
| To evaluate circulating tumor DNA (ctDNA) clearance rates for patients positive at baseline | Clearance rates for patients who are ctDNA positive at baseline | Monthly for duration of trial participation (an average of 2 years) | 
| To evaluate circulating tumor DNA (ctDNA) time to detection changes associated with disease progression | Time to detection of ctDNA changes associated with disease progression | Monthly for duration of trial participation (an average of 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR, Tipifarnib, Osimertinib, NSCLC locally advanced, NSCLC metastatic