CO-1686-008

Clovis Oncology UK Ltd

Granta Centre, Granta Park, Great Abington, Cambridge, United Kingdom, CB21 6GP

Dr Lindsey Rolfe, Clovis Oncology UK Ltd, +44 12233645500, lrolfe@clovisoncology.com

Dr Lindsey Rolfe, Clovis Oncology UK Ltd, +44 12233645500, lrolfe@clovisoncology.com

No

No

No

Final

27 Aug 2018

Yes

03 Jul 2018

Yes

27 Aug 2018

Yes

Phase 1: To evaluate the toxicity profile of escalating doses of CO-1686 and to determine the MTD and RP2D To characterize the PK profile of CO-1686 Phase 2: To evaluate tumor response (ORR + duration of response) to CO-1686 in patients with T790M

Safety measures in Phase 1 included monitoring for dose limiting toxicities (DLTs), as specified in the protocol, that occurred during Cycle 1 in patients enrolled into a DLT-evaluable cohort and were assessed by the investigator as probably, possibly or definitively related to rociletinib, as well as monitoring for adverse events (AEs). Safety measures in Phase 2 included monitoring of AEs, clinical laboratory evaluations, physical examination, vital signs and body weight, 12-lead ECGs, ECOG performance status, and concomitant medications and procedures. Patients were monitored for AEs from the time the first dose of rociletinib was administered through 28 days after the last dose (End of Treatment Visit), including study procedure-related AEs that occurred after signing of the informed consent and before administration of rociletinib. Any ongoing serious AEs were followed until resolution or stabilization. Quality of Life assessments were performed at baseline, every 2 cycles through Cycle 6, and then every 3 cycles thereafter.

27 Mar 2012

No

No

Poland: 5

France: 61

Australia: 28

United States: 518

612

66

0

0

0

0

0

0

327

272

13

Overall Trial (overall period)

Non-randomised - controlled

Yes

Rociletinib free base (FB) capsules

Capsule

Oral use

Rociletinib free base (FB) capsule 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 free base (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) capsules

Capsule

Oral use

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) tablets

Tablet

Oral use

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 as 125 mg (round) or 250 mg (oval) yellow tablets. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after ameal. 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) tablets

Tablet

Oral use

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 as 125 mg (round) or 250 mg (oval) yellow tablets. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after ameal. 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) tablets

Tablet

Oral use

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 as 125 mg (round) or 250 mg (oval) yellow tablets. 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) tablets

Tablet

Oral use

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 as 125 mg (round) or 250 mg (oval) yellow tablets. 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 <900 mg BID FB Capsules

Rociletinib 900 mg BID FB Capsules

Rociletinib 500 mg BID HBr Tablets

Rociletinib 625 mg BID HBr Tablets

Rociletinib 750 mg BID HBr Tablets

Rociletinib 1000 mg BID HBr Tablets

Rociletinib <900 mg BID FB Capsules

Rociletinib 900 mg BID FB Capsules

Rociletinib 500 mg BID HBr Tablets

Rociletinib 625 mg BID HBr Tablets

Rociletinib 750 mg BID HBr Tablets

Rociletinib 1000 mg BID HBr Tablets

Rociletinib 150 mg QD FB Capsules

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

Rociletinib 200 mg QD FB Capsules

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

Rociletinib 300 mg QD FB Capsules

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

Rociletinib 450 mg QD FB Capsules

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

Rociletinib 600 mg QD FB Capsules

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

Rociletinib 900 mg QD FB Capsules

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

Rociletinib 100 mg BID FB Capsules

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

Rociletinib 300 mg BID FB Capsules

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

Rociletinib 600 mg BID FB Capsules

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

Rociletinib 400 mg TID FB Capsules

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

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

Primary

Cycle 1 Day 1 to End of Treatment, up to approximately 42 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. Analysis Population Description: 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.

Primary

Cycle 1 Day 1 to End of Treatment, up to approximately 36 months

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

Primary

Cycle 1 Day 1 to Cycle 1 Day 21

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. Analysis Population Description - Safety population by daily dose.

Secondary

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. Analysis Population Description - Safety population by daily dose.

Secondary

Screening to End of Treatment, up to approximately 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. Please note: The upper CI limit for the 900 mg BID, 500 mg BID, and 1000 mg BID treatment groups was NA and was replaced with the maximum. Those numbers are 35, 43, and 19 months, respectively.

Secondary

Cycle 1 Day 1 to date of death, assessed up to 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.

Secondary

Cycle 1 Day 1 to End of Treatment, up to approximately 42 months

Cmax = maximum concentration following administration of rociletinib. Analysis Population Description: 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.

Secondary

Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Tmax = time to maximum concentration following administration of rociletinib. Analysis Population Description: 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.

Secondary

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. Analysis Population Description: 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.

Secondary

Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

T 1/2 = elimination half-life following administration of rociletinib. Analysis Population Description: 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.

Secondary

Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 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.

Secondary

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.

Secondary

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.

Secondary

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.

Secondary

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. Please note: Since N=1, the standard deviation for the T 1/2 Fed category can not be calculated. Thus "999" is entered as a placeholder.

Secondary

Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Adverse events were reported from the date of first dose of study drug and within 28 days after last dose of study drug, or approximately 9 months.

In addition, study procedure-related AEs that occur after signing of the informed consent form and before first dose of study drug were expected to be reported. Any Serious Adverse Events or Adverse Events of Special Interest were followed until resolution or stabilization, or until patient is lost to follow-up.

18.0

Rociletinib <900 mg BID FB Capsules

Rociletinib 900 mg BID FB Capsules

Rociletinib 500 mg BID HBr Tablets

Rociletinib 625 mg BID HBr Tablets

Rociletinib 750 mg BID HBr Tablets

Rociletinib 1000 mg BID HBr Tablets