TIGER-3: Open Label, Multicenter Study of Rociletinib (CO-1686) Mono Therapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR NSCLC Who Have Failed at Least One Previous EGFR-Directed TKI and Platinum-doublet Chemotherapy
Condition: Non-small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Rociletinib; Pemetrexed or gemcitabine or paclitaxel or docetaxel
Intervention MeSH terms: Paclitaxel; Docetaxel; Gemcitabine; Pemetrexed
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 149.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: cancer; metastatic; locally advanced; lung; non-small cell lung cancer; NSCLC; epidermal growth factor receptor; EGFR; T790M; CO-1686; unresectable; recurrent; EGFR-directed therapy; irreversible EGFR inhibitor; TIGER; Rociletinib

Summary:

      The purpose of this study is to compare the anti-tumor efficacy of oral single-agent
      rociletinib, as measured by investigator assessment of the PFS, with that of single-agent
      cytotoxic chemotherapy in patients with EGFR-mutated, advanced/metastatic NSCLC after failure
      of at least 1 previous EGFR-directed TKI and at least 1 line of platinum-containing doublet
      chemotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

        All patients must meet all of the following inclusion criteria:

          1. Histologically or cytologically confirmed metastatic or unresectable locally advanced
             NSCLC with radiological progression on the most recent therapy received

          2. Documented evidence of a tumor with 1 or more EGFR activating mutations excluding exon
             20 insertion

          3. Disease progression confirmed by radiological assessment while receiving treatment
             with single agent EGFR-TKI (e.g., erlotinib, gefitinib, afatinib, or dacomitinib) or
             EGFR-TKI in combination with other targeted therapy (e.g. bevacizumab, immunotherapy)

          4. Multiple lines of prior treatment are permitted and there is no specified order of
             treatment, but in the course of their treatment history, patients must have received
             and have radiologically documented disease progression following:

             At least 1 line of prior treatment with a single-agent EGFR-TKI (e.g., erlotinib,
             gefitinib, afatinib, or dacomitinib)

             If EGFR-TKI is a component of the most recent treatment line, the washout period for
             the EGFR-TKI is a minimum of 3 days before the start of study drug treatment

             AND

             A platinum-containing doublet chemotherapy (either progressed during therapy or
             completed at least 4 cycles without progression with subsequent progression after a
             treatment-free interval or after a maintenance treatment).

             If cytotoxic chemotherapy is a component of the most recent treatment line, treatment
             with chemotherapy should have been completed at least 14 days prior to start of study
             treatment. When an EGFR-TKI is given in combination with platinum-containing doublet
             chemotherapy, treatment with the EGFR-TKI may continue until at least 3 days before
             start of treatment.

          5. Have undergone a biopsy of either primary or metastatic tumor tissue within 60 days
             prior to start of treatment and have tissue sent to the central laboratory prior to
             randomization

          6. Measureable disease according to RECIST Version 1.1

          7. Life expectancy of at least 3 months

          8. ECOG performance status of 0 to 1

          9. Age ≥ 18 years (in certain territories, the minimum age requirement may be higher
             e.g., age ≥ 20 years in Japan and Taiwan, age ≥ 21 years in Singapore)

         10. Patients should have recovered to National Cancer Institute (NCI) Common Terminology
             Criteria for Adverse Events (CTCAE) Grade ≤ 1 from any significant
             chemotherapy-related toxicities

         11. Adequate hematological and biological function

         12. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee
             (IEC)-approved ICF before any study specific evaluation

        Exclusion Criteria:

        Any of the following criteria will exclude patients from study participation:

          1. Any other malignancy associated with a high mortality risk within the next 5 years and
             for which the patients may be (but not necessarily) currently receiving treatment

             Patients with a history of malignancy that has been completely treated, with no
             evidence of that cancer currently, are permitted to enroll in the trial provided all
             chemotherapy was completed > 6 months prior and/or bone marrow transplant > 2 years
             prior

          2. Known pre-existing interstitial lung disease

          3. Tumor small cell transformation by local assessment, irrespective of presence of
             T790M+ component

          4. Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system
             (CNS) metastases are only permitted if treated, asymptomatic, and stable (not
             requiring steroids for at least 2 weeks prior to randomization and the patient is
             neurologically stable i.e. free from new symptoms of brain metastases)

          5. Patients who are currently receiving treatment with any medications that have the
             potential to prolong the QT interval and that treatment cannot be either discontinued
             or switched to a different medication (known to have no effect on QT) before starting
             protocol-specified treatment (see http://crediblemeds.org/ for a list of QT-prolonging
             medications)

          6. Prior treatment with rociletinib, or other drugs that target T790M+ mutant EGFR with
             sparing of WT-EGFR including but not limited to osimertinib, HM61713, and TAS-121

          7. Any contraindications for therapy with pemetrexed, paclitaxel, gemcitabine or
             docetaxel unless a contraindication with respect to one of these drugs will not affect
             the use of any of the others as a comparator to rociletinib

          8. Any of the following cardiac abnormalities or history:

               1. Clinically significant abnormal 12-lead ECG, QT interval corrected using
                  Fridericia's method (QTCF) > 450 msec

               2. Inability to measure QT interval on ECG

               3. Personal or family history of long QT syndrome

               4. Implantable pacemaker or implantable cardioverter defibrillator

               5. Resting bradycardia < 55 beats/min

          9. Non-study related surgical procedures ≤ 7 days prior to randomization. In all cases,
             the patient must be sufficiently recovered and stable before treatment administration

         10. Females who are pregnant or breastfeeding

         11. Refusal to use adequate contraception for fertile patients (females and males) while
             on treatment and for 6 months after the last dose of study treatment (rociletinib and
             chemotherapy irrespective of single cytotoxic agent used)

         12. Presence of any serious or unstable concomitant systemic disorder incompatible with
             the clinical study (e.g., substance abuse, uncontrolled intercurrent illness including
             uncontrolled diabetes, active infection, arterial thrombosis, and symptomatic
             pulmonary embolism)

         13. Any other reason the investigator considers the patient should not participate in the
             study

         14. Treatment with live vaccines initiated less than 4 weeks prior to randomization