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)

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

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