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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: NSCLC
• Intervention / Treatment: Drug: Tipifarnib; Drug: Osimertinib

• Study Type: Interventional
• Phase: Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Clinical Operations; Phone Number: 781-346-9925; Email: KO-TIP-015@kuraoncology.com

Study Locations

• United States
  • California
    • Santa Rosa, California, United States, 95403
      • Providence Medical Group
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • The Valley Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Major surgery
  2. 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
  3. 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).
  4. Investigational therapy within 2 weeks of Cycle 1 Day 1
  5. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Kura Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2023
• Primary Completion (Anticipated): July 27, 2027
• Study Completion (Anticipated): July 27, 2027

Study Registration Dates

• First Submitted: December 12, 2022
• First Submitted That Met QC Criteria: January 11, 2023
• First Posted (Actual): January 20, 2023

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: March 2, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: EGFR; Osimertinib; Tipifarnib; NSCLC locally advanced; NSCLC metastatic
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Osimertinib; Tipifarnib
• Other Study ID Numbers: KO-TIP-015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No