Study to Evaluate Safety, Pharmacokinetics, and Efficacy of Rociletinib (CO-1686) in Previously Treated Mutant Epidermal Growth Factor Receptor (EGFR) in Non-Small Cell Lung Cancer (NSCLC) Patients
- Conditions
- Locally Advanced or Metastatic Non Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT01526928
- Lead Sponsor
- Clovis Oncology, Inc.
- Brief Summary
Rociletinib is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation.
- Detailed Description
Lung cancer remains the most common cancer worldwide with non-small cell lung cancer accounting for 85% of cases. Cytotoxic chemotherapy has been the mainstay of patients with NSCLC; however, survival rates remain low and toxicity is significant. Molecularly targeted therapies have proven to be superior to chemotherapy for NSCLC patients whose tumors have mutations in EGFR. Recent studies have established tyrosine kinase inhibitors (TKIs) as the gold standard for treating EGFR-mutation-positive NCSLC. However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. There are currently no approved therapies for patients who progress on TKIs. Rociletinib may provide an effective therapy for a patient population with few alternative treatment options. Nonclinical data demonstrate that rociletinib inhibits T790M. It is anticipated that rociletinib may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to first generation TKIs.
This is a two-part, open-label study of oral rociletinib administered daily in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as erlotinib, gefitinib or afatinib.
This study will include 2 parts:
Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22
Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have:
Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 612
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Rociletinib <900 mg BID FB formulation Rociletinib Rociletinib free base (FB) dose \<900 mg twice a day (BID) Rociletinib 500 mg BID HBr formulation Rociletinib Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID) Rociletinib 900 mg BID FB formulation Rociletinib Rociletinib free base (FB) dose 900 mg twice a day (BID) Rociletinib 625 mg BID HBr formulation Rociletinib Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID) Rociletinib 750 mg BID HBr formulation Rociletinib Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID) Rociletinib 1000 mg BID HBr formulation Rociletinib Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID)
- Primary Outcome Measures
Name Time Method Dose Limiting Toxicity (DLT) Incidence Cycle 1 Day 1 to Cycle 1 Day 21 The number of Phase 1 patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.
Percentage of T790M Positive Patients With Confirmed Response Per Investigator Cycle 1 Day 1 to End of Treatment, up to approximately 42 months Percentage of patients with a T790M mutation (determined by central lab) with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.
Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment Cycle 1 Day 1 to End of Treatment, up to approximately 36 months Duration of Response in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.
- Secondary Outcome Measures
Name Time Method QTcF Values Post Baseline by Daily Dose Screening to End of Treatment, up to approximately 42 months Frequency of QT interval prolongation by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.
Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) Cycle 1 Day 1 to End of Treatment, up to approximately 42 months Progression-free survival was calculated as the number of days from the date of the first dose of study drug to the date of disease progression or death due to any cause + 1. Patients without a documented event of disease progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments have been performed. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
PK Profile of Rociletinib - Cmax Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days Cmax = maximum concentration following administration of rociletinib
PK Profile of Rociletinib - Tmax Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days Tmax = time to maximum concentration following administration of rociletinib
PK Profile of Rociletinib - AUC 0-24 Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days AUC 0-24 = area under the curve from 0 to 24 hours
Food Effect on PK of Rociletinib - T 1/2 Day -7 prior to Cycle 1 Day 1, or approximately 7 days T 1/2 = elimination half-life following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
PK Profile of Rociletinib - T 1/2 Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days T 1/2 = elimination half-life following administration of rociletinib
Overall Survival (OS) Determined by Investigator Assessment Cycle 1 Day 1 to date of death, assessed up to 42 months Overall survival was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive.
Food Effect on PK of Rociletinib - AUC 0-24 Day -7 prior to Cycle 1 Day 1, or approximately 7 days AUC 0-24 = area under the curve from 0 to 24 hours. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
Food Effect on PK of Rociletinib - Cmax Day -7 prior to Cycle 1 Day 1, or approximately 7 days Cmax = maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
Food Effect on PK of Rociletinib - Tmax Day -7 prior to Cycle 1 Day 1, or approximately 7 days Tmax = time to maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
Food Effect on PK of Rociletinib - C24 Day -7 prior to Cycle 1 Day 1, or approximately 7 days C24 = rociletinib plasma concentration at 24 hours post the morning dose. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR Cycle 1 Day 1 to End of Treatment / End of Follow-up Objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) per RECIST Version 1.1 as determined by independent radiology review (IRR)
QTcF Value Change From Baseline Screening to End of Treatment, up to approximately 42 months QTcF value change from baseline by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.
Trial Locations
- Locations (49)
University of California, Irvine
🇺🇸Orange, California, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
UCLA Health System
🇺🇸Santa Monica, California, United States
East Valley Hematology and Oncology Medical Group, Inc.
🇺🇸Whittier, California, United States
Regional Cancer Center
🇺🇸New Brunswick, New Jersey, United States
Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
Regional Cancer Care Associates
🇺🇸Morristown, New Jersey, United States
University of Chicago Medical Center, The Duchossois Center for Advanced Medicine
🇺🇸Chicago, Illinois, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Peter MacCallum Cancer Centre
🇦🇺East Melbourne, Australia
Centre Antoine Lacassagne
🇫🇷Nice Cedex 2, Provence Alpes COTE D'azur, France
Centre Léon Bérard
🇫🇷Lyon Cedex 04, Rhone-alpes, France
Centre Hospitalier Universitaire de Grenoble
🇫🇷Grenoble Cedex 9, Rhone-alpes, France
Centre Hospitalier Régional Universitaire de Lille
🇫🇷Lille, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Med University Gdansk
🇵🇱Gdansk, Poland
Centre Hospitalier Intercommunal Créteil
🇫🇷Creteil cedex, France
Chris O'Brien Lifehouse
🇦🇺Camperdown, New South Wales, Australia
Stanford Cancer Institute
🇺🇸Stanford, California, United States
The Oncology Institute of Hope and Innovations
🇺🇸Whittier, California, United States
Ohio State University, Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
University Cancer & Blood Center
🇺🇸Athens, Georgia, United States
Monter Cancer Center
🇺🇸Lake Success, New York, United States
Tulsa Cancer Institute
🇺🇸Tulsa, Oklahoma, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
Compassionate Care Research Group, Inc.
🇺🇸Fountain Valley, California, United States
Samuel Oschin Cancer Center
🇺🇸Los Angeles, California, United States
University of Southern California, Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Mass General Hospital
🇺🇸Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Perelman Center for Advanced Medicine
🇺🇸Philadelphia, Pennsylvania, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
University of Pittsburgh Cancer Institute (UPMC), Div. of Medical Oncology
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Virginia Cancer Specialists, PC
🇺🇸Fairfax, Virginia, United States
Centre François Baclesse
🇫🇷Caen Cedex 05, France
University of California Davis Medical Center
🇺🇸Sacramento, California, United States
University of Colorado Anschutz Medical Campus
🇺🇸Aurora, Colorado, United States
Sylvester Comprehensive Cancer Center/UMHC
🇺🇸Miami, Florida, United States
Florida Hospital Cancer Institute
🇺🇸Orlando, Florida, United States
Providence CancerCenter Oncology and Hematology Care Clinic-Eastside Portland
🇺🇸Portland, Oregon, United States
Saint Joseph Mercy Hospital
🇺🇸Ann Arbor, Michigan, United States
Karmanos Cancer Care Institute
🇺🇸Detroit, Michigan, United States
University of Cincinnati Medical Center
🇺🇸Cincinnati, Ohio, United States
Vanderbilt University
🇺🇸Nashville, Tennessee, United States
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
Swedish Cancer Institute
🇺🇸Seattle, Washington, United States
University of Washington
🇺🇸Seattle, Washington, United States