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

Sponsor

Kura Oncology, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05693090

Collaborator

(none)

Enrollment

Locations

Arms

53.8

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
NSCLC	Drug: Tipifarnib Drug: Osimertinib	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Jul 27, 2027

Anticipated Study Completion Date :

Jul 27, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Escalation Cohort Adult participants with EGFR-mutated Non-Small Cell Lung Cancer	Drug: Tipifarnib Oral administration Drug: Osimertinib Oral administration
Experimental: Expansion Cohort Adult participants with EGFR-mutated Non-Small Cell Lung Cancer	Drug: Tipifarnib Oral administration Drug: Osimertinib Oral administration

Arm

Intervention/Treatment

Experimental: Escalation Cohort

Adult participants with EGFR-mutated Non-Small Cell Lung Cancer

Drug: Tipifarnib

Oral administration

Drug: Osimertinib

Oral administration

Experimental: Expansion Cohort

Adult participants with EGFR-mutated Non-Small Cell Lung Cancer

Drug: Tipifarnib

Oral administration

Drug: Osimertinib

Oral administration

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.