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

Study Overview
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Brief Summary
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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
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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

Official Title
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A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Locally Advanced or Metastatic Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Rociletinib
* Drug: Rociletinib
* Drug: Rociletinib
* Drug: Rociletinib
* Drug: Rociletinib
* Drug: Rociletinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - All patients must meet the following inclusion criteria: Metastatic or unresectable locally advanced NSCLC Evidence of a tumor with one or more EGFR mutations excluding exon 20 insertion Biopsy of either primary or metastatic tumor tissue within 60 days of dosing Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Minimum age of 18 years Adequate hematological and biological function Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study-specific evaluation Phase 2 Cohorts must also meet the following inclusion criteria: Disease progression confirmed by radiologic assessment while on treatment with EGFR- TKI Or Disease progression confirmed by radiologic assessment while on treatment with the first single agent EGFR TKI and Documented evidence of T790M mutation in EGFR following disease progression on the first single agent EGFR TKI. Measureable disease according to RECIST Version 1.1 Exclusion Criteria - Any of the following criteria will exclude patients from study participation: Documented evidence of an Exon 20 insertion activating mutation in the EGFR gene Active second malignancy Known pre-existing interstitial lung disease Patients with Leptomeningeal carcinomatosis are excluded. Other CNS metastases are only permitted if treated, asymptomatic and stable (not requiring steroids for at least 4 weeks prior to start of study treatment). Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib Prior treatment with rociletinib or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR Certain cardiac abnormalities or history Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib Females who are pregnant or breastfeeding Refusal to use adequate contraception for fertile patients (females and males) for 12 weeks after the last dose of rociletinib Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study Any other reason the investigator considers the patient should not participate in the study

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: Rociletinib <900 mg BID FB formulation<br>Rociletinib free base (FB) dose <900 mg twice a day (BID) | Drug: Rociletinib<br>* Phase 1: Rociletinib <900 mg BID FB will be administered in escalating dosages in a period of 21-day cycles<br>* Other names: CO-1686;|
| Experimental: Rociletinib 900 mg BID FB formulation<br>Rociletinib free base (FB) dose 900 mg twice a day (BID) | Drug: Rociletinib<br>* Phase 1: Rociletinib 900 mg BID FB will be administered in escalating dosages in a period of 21-day cycles<br>* Other names: CO-1686;|
| Experimental: Rociletinib 500 mg BID HBr formulation<br>Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID) | Drug: Rociletinib<br>* Phase 1: Rociletinib 500 mg BID HBr will be administered in escalating dosages in a period of 21-day cycles Phase 2: Rociletinib 500 mg BID HBr will be administered daily<br>* Other names: CO-1686;|
| Experimental: Rociletinib 625 mg BID HBr formulation<br>Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID) | Drug: Rociletinib<br>* Phase 1: Rociletinib 625 mg BID HBr will be administered in escalating dosages in a period of 21-day cycles Phase 2: Rociletinib 625 mg BID HBr will be administered daily<br>* Other names: CO-1686;|
| Experimental: Rociletinib 750 mg BID HBr formulation<br>Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID) | Drug: Rociletinib<br>* Phase 1: Rociletinib 750 mg BID HBr will be administered in escalating dosages in a period of 21-day cycles Phase 2: Rociletinib 750 mg BID HBr will be administered daily<br>* Other names: CO-1686;|
| Experimental: Rociletinib 1000 mg BID HBr formulation<br>Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID) | Drug: Rociletinib<br>* Phase 1: Rociletinib 1000 mg BID HBr will be administered in escalating dosages in a period of 21-day cycles Phase 2: Rociletinib 1000 mg BID HBr will be administered daily<br>* Other names: CO-1686;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of T790M Positive Patients With Confirmed Response Per Investigator | 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. | Cycle 1 Day 1 to End of Treatment, up to approximately 42 months | 
| Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment | 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. | Cycle 1 Day 1 to End of Treatment, up to approximately 36 months | 
| Dose Limiting Toxicity (DLT) Incidence | The number of Phase 1 patients who experienced dose limiting toxicities after one cycle (21 days) of study drug. | Cycle 1 Day 1 to Cycle 1 Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QTcF Values Post Baseline by Daily Dose | 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. | Screening to End of Treatment, up to approximately 42 months | 
| QTcF Value Change From Baseline | 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. | Screening to End of Treatment, up to approximately 42 months | 
| Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR | 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) | Cycle 1 Day 1 to End of Treatment / End of Follow-up | 
| Overall Survival (OS) Determined by Investigator Assessment | 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. | Cycle 1 Day 1 to date of death, assessed up to 42 months | 
| Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) | 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. | Cycle 1 Day 1 to End of Treatment, up to approximately 42 months | 
| PK Profile of Rociletinib - Cmax | Cmax = maximum concentration following administration of rociletinib | Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days | 
| PK Profile of Rociletinib - Tmax | Tmax = time to maximum concentration following administration of rociletinib | Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days | 
| PK Profile of Rociletinib - AUC 0-24 | AUC 0-24 = area under the curve from 0 to 24 hours | Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days | 
| PK Profile of Rociletinib - T 1/2 | T 1/2 = elimination half-life following administration of rociletinib | Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days | 
| Food Effect on PK of Rociletinib - Cmax | 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. | Day -7 prior to Cycle 1 Day 1, or approximately 7 days | 
| Food Effect on PK of Rociletinib - Tmax | 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. | Day -7 prior to Cycle 1 Day 1, or approximately 7 days | 
| Food Effect on PK of Rociletinib - AUC 0-24 | 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. | Day -7 prior to Cycle 1 Day 1, or approximately 7 days | 
| Food Effect on PK of Rociletinib - C24 | 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. | Day -7 prior to Cycle 1 Day 1, or approximately 7 days | 
| Food Effect on PK of Rociletinib - T 1/2 | 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. | Day -7 prior to Cycle 1 Day 1, or approximately 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unresectable, recurrent, cancer, metastatic, locally advanced, lung, non-small cell lung cancer, NSCLC, epidermal growth factor receptor, EGFR, T790M, CO-1686, EGFR-directed therapy, irreversible EGFR inhibitor, TIGER, Rociletinib