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

• ClinicalTrials.gov Identifier: NCT01526928
• Recruitment Status: Terminated
• First Posted: February 6, 2012
• Results First Posted: January 6, 2020
• Last Update Posted: August 4, 2020
• Sponsor: Clovis Oncology, Inc.
• Information provided by (Responsible Party): Clovis Oncology, Inc.

Tracking Information

• First Submitted Date: January 31, 2012
• First Posted Date: February 6, 2012
• Results First Submitted Date: June 11, 2019
• Results First Posted Date: January 6, 2020
• Last Update Posted Date: August 4, 2020
• Actual Study Start Date: March 27, 2012
• Actual Primary Completion Date: July 3, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 17, 2019)

• Percentage of T790M Positive Patients With Confirmed Response Per Investigator [ Time Frame: 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 [ Time Frame: 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.
• Dose Limiting Toxicity (DLT) Incidence [ Time Frame: 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.

Original Primary Outcome Measures (submitted: February 2, 2012)

• Incidence of Grade 3 or 4 AEs and clinical lab abnormalities defined as DLTs (Part 1) [ Time Frame: Cycle 1 (Days 1-21) ]
• PK Profile (Part 1) [ Time Frame: Cycle 1 (Days 1, 2, 15 and 16) ]
  AUC - area under curve from time zero to time t or infinity; Cmax - max concentration; T max - time to max concentration; T 1/2 - elimination half-life; Kel - elimination rate constant; Vss/F volume of distribution at steady state after nonintravenous administration; Cl/F - total plasma clearance
• ORR and duration of response per RECIST version 1.1 (Part 2) [ Time Frame: Screening; End of Cycles 2,4,6 (between Days 14-21); Every 3 cycles after Cycle 6 (between Days 14-21); and End of study (patient discontinuation) ]

Current Secondary Outcome Measures (submitted: December 17, 2019)

• Overall Survival (OS) Determined by Investigator Assessment [ Time Frame: 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.
• Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
• PK Profile of Rociletinib - T 1/2 [ Time Frame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days ]
  T 1/2 = elimination half-life following administration of rociletinib
• Food Effect on PK of Rociletinib - Cmax [ Time Frame: 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 [ Time Frame: 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 - AUC 0-24 [ Time Frame: 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 - C24 [ Time Frame: 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.
• Food Effect on PK of Rociletinib - T 1/2 [ Time Frame: 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.
• QTcF Values Post Baseline by Daily Dose [ Time Frame: 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.
• QTcF Value Change From Baseline [ Time Frame: 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.
• Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR [ Time Frame: 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)

Original Secondary Outcome Measures (submitted: February 2, 2012)

• PK Profile (fasted and fed) (Part 1) [ Time Frame: Cycle 1 (Day -7 and Day 1) ]
  AUC and Cmax
• Change from baseline in QT/QTc interval (ECG) (Part 1) [ Time Frame: Screening, Cycle 1 (Days 1 and 15), and End of study (patient discontinuation) ]
• Metabolic profile in the Day 15 plasma samples (Part 1) [ Time Frame: Cycle 1 (Day 15) ]
• ORR and duration of response per RECIST version 1.1 (Part 1) [ Time Frame: Screening; End of Cycles 2,4,6 (between Days 14-21); Every 3 cycles after Cycle 6 (between Days 14-21); and End of study (patient discontinuation) ]
• Incidence of AEs, clinical laboratory abnormalities, and ECG abnormalities (Part 2) [ Time Frame: Screening, C1+ (Days 1 and 15), End of Study (patient discontinuation) ]
• PFS per Recist version 1.1 (Part 2) [ Time Frame: Screening; End of Cycles 2,4,6 (between Days 14-21); Every 3 cycles after Cycle 6 (between Days 14-21); and End of study (patient discontinuation) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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)
• 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

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Locally Advanced or Metastatic Non Small Cell Lung Cancer

Intervention

• Drug: Rociletinib
  Phase 1: Rociletinib <900 mg BID FB will be administered in escalating dosages in a period of 21-day cycles
  Other Name: CO-1686
• Drug: Rociletinib
  Phase 1: Rociletinib 900 mg BID FB will be administered in escalating dosages in a period of 21-day cycles
  Other Name: CO-1686
• Drug: Rociletinib

  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

  Other Name: CO-1686
• Drug: Rociletinib

  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

  Other Name: CO-1686
• Drug: Rociletinib

  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

  Other Name: CO-1686
• Drug: Rociletinib

  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

  Other Name: CO-1686

Study Arms

• Experimental: Rociletinib <900 mg BID FB formulation
  Rociletinib free base (FB) dose <900 mg twice a day (BID)
  Intervention: Drug: Rociletinib
• Experimental: Rociletinib 900 mg BID FB formulation
  Rociletinib free base (FB) dose 900 mg twice a day (BID)
  Intervention: Drug: Rociletinib
• Experimental: Rociletinib 500 mg BID HBr formulation
  Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID)
  Intervention: Drug: Rociletinib
• Experimental: Rociletinib 625 mg BID HBr formulation
  Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID)
  Intervention: Drug: Rociletinib
• Experimental: Rociletinib 750 mg BID HBr formulation
  Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID)
  Intervention: Drug: Rociletinib
• Experimental: Rociletinib 1000 mg BID HBr formulation
  Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID)
  Intervention: Drug: Rociletinib

Publications *

• Krug AK, Enderle D, Karlovich C, Priewasser T, Bentink S, Spiel A, Brinkmann K, Emenegger J, Grimm DG, Castellanos-Rizaldos E, Goldman JW, Sequist LV, Soria JC, Camidge DR, Gadgeel SM, Wakelee HA, Raponi M, Noerholm M, Skog J. Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma. Ann Oncol. 2018 Mar 1;29(3):700-706. doi: 10.1093/annonc/mdx765.
• Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, Papadimitrakopoulou V, Solomon BJ, Oxnard GR, Dziadziuszko R, Aisner DL, Doebele RC, Galasso C, Garon EB, Heist RS, Logan J, Neal JW, Mendenhall MA, Nichols S, Piotrowska Z, Wozniak AJ, Raponi M, Karlovich CA, Jaw-Tsai S, Isaacson J, Despain D, Matheny SL, Rolfe L, Allen AR, Camidge DR. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1700-9. doi: 10.1056/NEJMoa1413654.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 9, 2019): 612
• Original Estimated Enrollment (submitted: February 2, 2012): 70
• Actual Study Completion Date: August 27, 2018
• Actual Primary Completion Date: July 3, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria -

All patients must meet the following inclusion criteria:

1. Metastatic or unresectable locally advanced NSCLC
2. Evidence of a tumor with one or more EGFR mutations excluding exon 20 insertion
3. Biopsy of either primary or metastatic tumor tissue within 60 days of dosing
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
5. Minimum age of 18 years
6. Adequate hematological and biological function
7. 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:

1. Documented evidence of an Exon 20 insertion activating mutation in the EGFR gene
2. Active second malignancy
3. Known pre-existing interstitial lung disease
4. 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).
5. Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib
6. 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
7. Prior treatment with rociletinib or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR
8. Certain cardiac abnormalities or history
9. Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib
10. Females who are pregnant or breastfeeding
11. Refusal to use adequate contraception for fertile patients (females and males) for 12 weeks after the last dose of rociletinib
12. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study
13. Any other reason the investigator considers the patient should not participate in the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Poland, United States

Administrative Information

• NCT Number: NCT01526928
• Other Study ID Numbers: CO-1686-008
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Clovis Oncology, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Clovis Oncology, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Clovis Oncology, Inc.
• Verification Date: July 2020