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Rociletinib free base (FB) dose \<900 mg twice a day (BID)

Rociletinib free base (FB) dose 900 mg twice a day (BID)

Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID)

Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID)

Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID)

Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID)

Phase 1: Rociletinib \<900 mg BID FB will be administered in escalating dosages in a period of 21-day cycles

Rociletinib

Phase 1: Rociletinib 900 mg BID FB will be administered in escalating dosages in a period of 21-day cycles

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

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

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

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

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.

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

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

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)

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 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.

The number of Phase 1 patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.

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.

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.

Cmax = maximum concentration following administration of rociletinib

Tmax = time to maximum concentration following administration of rociletinib

AUC 0-24 = area under the curve from 0 to 24 hours

T 1/2 = elimination half-life following administration of rociletinib

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.

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.

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.

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.

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.

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.

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.

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)

Clovis Oncology, Inc.

If a subject experiences the same preferred term (system organ class) multiple times, then the subject will be counted only once for that preferred term (system organ class).

Rociletinib free base (FB) dose \<900 mg twice a day (BID).

Rociletinib <900 mg BID FB Capsules

Rociletinib free base (FB) dose 900 mg twice a day (BID).

Rociletinib 900 mg BID FB Capsules

Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID).

Rociletinib 500 mg BID HBr Tablets

Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID).

Rociletinib 625 mg BID HBr Tablets

Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID).

Rociletinib 750 mg BID HBr Tablets

Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).

Rociletinib 1000 mg BID HBr Tablets

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

White

Black or African American

Asian

Other

Race/Ethnicity, Customized

Data not available for one participant in the 500 mg BID Hbr treatment group.

Time Since Diagnosis of NSCLC (months)

T790M Status ( Determined by Central Lab)

History of CNS Metastases

Number of Previous Therapies

Number of Previous TKI Therapies

Medical Information Department

Intent-to-treat: All randomized patients who are confirmed by central lab to be T790M positive

Percentage of T790M Positive Patients With Confirmed Response Per Investigator

The DOR was measured only in T790M positive patients with a Complete Response (CR) or Partial Response (PR). There were no responders in the Rociletinib \<900 mg BID treatment group so DOR is not applicable and thus not reported.

Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment

Since an MTD was never reached for any of the rociletinib FB or HBr formulations/doses, a 750 mg BID HBr starting dose was selected based on early efficacy data from Phase 1, and enrollment into Phase 2 was initiated at this dosage. As the Phase 1 efficacy data matured, the recommended dose was adjusted to 625 mg BID based on antitumor activity and safety evaluations.

The dose limiting toxicity (DLT) evaluable population includes all patients who have completed Cycle 1, and who were enrolled while the dose escalation (Phase 1) part of the study was ongoing.

Dose Limiting Toxicity (DLT) Incidence

The overall number of patients analyzed contains centrally determined T790M positive patients only. There are 2 less patients in the \<900 mg BID FB group, and 1 less patient in each of the 500, 625 and 750 mg BID dose groups because they were not followed for OS.

Overall Survival (OS) Determined by Investigator Assessment

The overall number of patients analyzed contains centrally determined T790M positive patients only. There are 2 less patients in the \<900 mg BID FB group, and 1 less patient in each of the 500 and 625 mg BID dose groups because they were not followed for PFS.

Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)

Day 1 Cmax

Day 15 Cmax

Rociletinib free base (FB) dose 150 mg once a day (QD).

Rociletinib 150 mg QD FB Capsules

Rociletinib free base (FB) dose 200 mg once a day (QD).

Rociletinib 200 mg QD FB Capsules

Rociletinib free base (FB) dose 300 mg once a day (QD).

Rociletinib 300 mg QD FB Capsules

Rociletinib free base (FB) dose 450 mg once a day (QD).

Rociletinib 450 mg QD FB Capsules

Rociletinib free base (FB) dose 600 mg once a day (QD).

Rociletinib 600 mg QD FB Capsules

Rociletinib free base (FB) dose 900 mg once a day (QD).

Rociletinib 900 mg QD FB Capsules

Rociletinib free base (FB) dose 100 mg twice a day (BID).

Rociletinib 100 mg BID FB Capsules

Rociletinib free base (FB) dose 300 mg twice a day (BID).

Rociletinib 300 mg BID FB Capsules

Rociletinib free base (FB) dose 600 mg twice a day (BID).

Rociletinib 600 mg BID FB Capsules

Rociletinib free base (FB) dose 400 mg three times a day (TID).

Rociletinib 400 mg TID FB Capsules

PK parameters were assessed in a subset of patients treated with rociletinib. For some parameters, the number analyzed at Day 1 and Day 15 differs from the overall number analyzed based on the number of evaluable samples collected at each time point.

PK Profile of Rociletinib - Cmax

Day 1 Tmax

Day 15 Tmax

PK Profile of Rociletinib - Tmax

Day 1 AUC 0-24

Day 15 AUC 0-24

PK parameters were assessed in a subset of patients treated with rociletinib. For some parameters, the number analyzed at Day 1 and Day 15 differs from the overall number analyzed based on the number of evaluable samples collected at each time point. AUC was not calculated for patients in the 400 mg TID treatment group.

PK Profile of Rociletinib - AUC 0-24

Day 1 T 1/2

Day 15 T 1/2

PK parameters were assessed in a subset of patients treated with rociletinib. For some parameters, the number analyzed at Day 1 and Day 15 differs from the overall number analyzed based on the number of evaluable samples collected at each time point. Elimination half-life was not calculated for patients in the 400 mg TID treatment group.

PK Profile of Rociletinib - T 1/2

Rociletinib 150 mg FB single dose given while fasting

Cmax Fasting

Rociletinib 150 mg FB single dose given with a high-fat breakfast

Cmax Fed

A subset of 3 patients treated with rociletinib 150 mg FB capsules

Food Effect on PK of Rociletinib - Cmax

Tmax Fasting

Tmax Fed

Food Effect on PK of Rociletinib - Tmax

AUC 0-24 Fasting

AUC 0-24 Fed

A subset of 3 patients treated with rociletinib 150 mg FB capsules. AUC could not be determined for 1 patient in the Fed arm.

Food Effect on PK of Rociletinib - AUC 0-24

C24 Fasting

C24 Fed

Food Effect on PK of Rociletinib - C24

T 1/2 Fasting

T 1/2 Fed

A subset of 3 patients treated with rociletinib 150 mg FB capsules. Data did not allow the calculation of half-life with high fat mean in 2 patients.

Food Effect on PK of Rociletinib - T 1/2

QTcF Values Post Baseline by Daily Dose

QTcF Value Change From Baseline

Tumor scans were collected for independent evaluation, however ORR, DOR and PFS analyses were not performed by the central reader since the sponsor deemed not necessary following early study termination. Therefore, all IRR outcome measures were not collected and can not be reported.

Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR

Rociletinib free base (FB) dose \<900 mg twice a day (BID). FB doses tested ranged from 150 mg once a day (QD) up to 900 mg twice a day (BID). This arm also includes a 400 mg three times a day (TID) dose. Rociletinib FB capsules were administered in Phase 1 only (until November 2013) and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day treatment cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved.

Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib FB capsules were administered in Phase 1 only (until November 2013) and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day treatment cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved.

Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) tablets were administered in Phase 1 (starting in August 2013) and in all Phase 2 cohorts and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved.

Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) tablets were administered in Phase 1 (starting in August 2013) and in all Phase 2 cohorts and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved.

Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) tablets were administered in Phase 1 (starting in August 2013) and in all Phase 2 cohorts and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved.

Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID). Rociletinib hydrobromide (HBr) tablets were administered in Phase 1 (starting in August 2013) and in all Phase 2 cohorts and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved.

Spots Global Cancer Trial Database for locally advanced or metastatic non small cell lung cancer