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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

NCT02322281

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: TIGER-3: A Phase 3, Open-label, Multicenter, Randomized Study of Oral Rociletinib (CO-1686) Monotherapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR Non-small Cell Lung Cancer (NSCLC) After Failure of at Least 1 Previous EGFR-directed Tyrosine Kinase Inhibitor (TKI) and Platinum-doublet Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: CO-1686-020 (TIGER-3)
  • NCT ID: NCT02322281

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
RociletinibCO-1686Rociletinib Monotherapy (500 mg BID)
Pemetrexed or gemcitabine or paclitaxel or docetaxelPemetrexed or gemcitabine or paclitaxel or docetaxel

Purpose

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.

Detailed Description

      This is a Phase 3, randomized, open-label, multicenter study evaluating the safety and
      efficacy of oral rociletinib at 500 mg BID and 625 mg BID compared with that of single-agent
      cytotoxic chemotherapy, in patients with previously treated mutant EGFR NSCLC. Eligible
      patients are those with mutant EGFR NSCLC previously treated with at least 1 EGFR inhibitor
      and at least 1 line of platinum-containing chemotherapy doublet for advanced/metastatic
      NSCLC.

      After providing informed consent to participate and screening to confirm eligibility,
      patients will be randomized 1:1:1 to receive either oral rociletinib 500 mg BID, oral
      rociletinib 625 mg BID, or single-agent cytotoxic chemotherapy (investigator choice of
      pemetrexed, gemcitabine, docetaxel, or paclitaxel; choice of chemotherapy agent must be
      specified before randomization).
    

Trial Arms

NameTypeDescriptionInterventions
Rociletinib Monotherapy (500 mg BID)ExperimentalDaily oral rociletinib at 500 mg BID with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Treatment with rociletinib is continuous and each cycle will comprise of 21 days.
  • Rociletinib
Rociletinib Monotherapy (625 mg BID)ExperimentalDaily oral rociletinib at 625 mg BID with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Treatment with rociletinib is continuous and each cycle will comprise of 21 days.
  • Rociletinib
Pemetrexed or gemcitabine or paclitaxel or docetaxelActive ComparatorPemetrexed 500 mg/m2 pemetrexed given intravenously on Day 1 of each 21-day cycle. Gemcitabine 1250 mg/m2 gemcitabine given intravenously on Day 1 and 8 of each 21-day cycle. Docetaxel 75 mg/m2 docetaxel (60 mg/m2 for patients residing in East-Asian territories) given intravenously on Day 1 of each 21-day cycle. or 35 mg/m2 docetaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel 80 mg/m2 paclitaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.
  • Pemetrexed or gemcitabine or paclitaxel or docetaxel

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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 35 months. This Time Frame includes the cross-over period, however, participants who crossed over to rociletinib were not analyzed for PFS.
Safety Issue:
Description:PFS was calculated as 1+ the number of days from the date of randomization to documented radiographic progression as determined by the investigator, or death due to any cause, whichever occurs first. 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 Outcome Measures

Measure:Percentage of Participants With Confirmed Response
Time Frame:Cycle 1 Day 1 to End of Treatment, up to approximately 35 months. This Time Frame includes the cross-over period, however, participants who crossed over to rociletinib were not analyzed for best overall confirmed response.
Safety Issue:
Description:Percentage of patients 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. Overall Response (OR),is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment was dependent on the achievement of both measurement and confirmation criteria.
Measure:Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment
Time Frame:Cycle 1 Day 1 to End of Treatment, up to approximately 35 months
Safety Issue:
Description:DOR in patients with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from date that any of these best responses is first recorded until 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. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. PR is at least a 30% decrease in sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response is the best response from start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Measure:Overall Survival (OS)
Time Frame:Cycle 1 Day 1 to date of death, assessed up to 3 years
Safety Issue:
Description:OS was calculated as 1+ the number of days from randomization 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.
Measure:Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling
Time Frame:Cycles 2 Day 1 to Cycle 7 Day 1, or approximately 6 months
Safety Issue:
Description:Blood samples were drawn for PK analysis at 21 ± 3 day intervals for the first 6 months (Day 1 of Cycles 2 to 7 inclusive). The sample could be taken predose or postdose. Plasma concentrations are presented for Rociletinib and 3 metabolites (M460, M502, M544).

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Clovis Oncology, Inc.

Trial 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

Last Updated

August 14, 2019