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

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

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.

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Rociletinib; Drug: Pemetrexed or gemcitabine or paclitaxel or docetaxel

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).

• Study Type: Interventional
• Enrollment (Actual): 149
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Saint Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
• France
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Alsace
    • Strasbourg, Alsace, France, 67091
      • Hopital Hautepierre (CHU) de Strasbourg
  • Basse-Normandie
    • Caen, Basse-Normandie, France, 14076
      • Centre Francois Baclesse
  • Bretagne
    • Rennes, Bretagne, France, 35033
      • Centre Hospitalier Universitaire de Rennes, Hôpital Pontchaillou
  • Ile-de-France
    • Créteil, Ile-de-France, France, 94010
      • Centre Hospitalier Intercommunal Creteil
    • Paris, Ile-de-France, France, 75018
      • Hopital Bichat-Claude Bernard
  • Limousin
    • Limoges, Limousin, France, 87042
      • CHRU de Limoges - Hôpital Dupuytren
  • Nord Pas-de-Calais
    • Lille, Nord Pas-de-Calais, France, 59037
      • CHRU de Lille - Hopital Calmette
  • Provence Alpes Cote D'Azur
    • Marseille, Provence Alpes Cote D'Azur, France, 13009
      • L'Assistance Publique - Hopitaux de Marseille
• Germany
  • Baden-Wuerttemberg
    • Gauting, Baden-Wuerttemberg, Germany, 82131
      • Asklepios Fachkliniken München-Gauting
    • Heidelberg, Baden-Wuerttemberg, Germany, 69126
      • Thoraxklinik Heidelberg gGmbH
  • Bayern
    • München, Bayern, Germany, 80336
      • LMU - Klinikum der Universität München
  • Niedersachen
    • Oldenburg, Niedersachen, Germany, 26121
      • Pius Hospital Oldenburg
  • Nordrhein-westfalen
    • Minden, Nordrhein-westfalen, Germany, 32429
      • Johannes-Wesling-Klinikum Minden
  • Schleswig-Holstein
    • Großhansdorf, Schleswig-Holstein, Germany, 22927
      • LungenClinic Grosshansdorf GmbH
• Italy
  • Firenze, Italy, 50139
    • Azienda Ospedaliero-Universitaria Careggi
  • Genova, Italy, 16132
    • IRCCS Azienda Ospedaliera Universitaria San Martino - IST
  • Livorno, Italy, 57124
    • Ospedale Civile di Livorno
  • Milano, Italy, 20141
    • Istituto Europeo di Oncologia
  • Perugia, Italy, 06132
    • Azienda Ospedaliera di Perugia
  • Torino
    • Orbassano, Torino, Italy, 10043
      • A.O.U. San Luigi Gonzaga di Orbassano
• Korea, Republic of
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Cheungcheongbuk-do
    • Cheongju-si, Cheungcheongbuk-do, Korea, Republic of, 361-712
      • Chungbuk National University Hospital
  • Gyeonggi
    • Suwon, Gyeonggi, Korea, Republic of, 442-723
      • The Catholic University of Korea Saint Vincent's Hospital
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, Korea, Republic of, 463-707
      • Seoul National University Bundang Hospital
  • Jeollanam-do
    • Hwasun-gun, Jeollanam-do, Korea, Republic of, 519-809
      • Chonnam National University Hwasun Hospital
• Netherlands
  • Groningen, Netherlands, 9700 RB
    • Universitair Medisch Centrum Groningen
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Academisch Ziekenhuis Maastricht
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1066 CX
      • Antoni van Leeuwenhoek Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08028
    • Institut Universitari Dexeus
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz (Clinica de la Concepcion) (UAM -FJD)
  • Málaga, Spain, 29010
    • Hospital Regional Universitario Carlos Haya
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol
    • Mataró, Barcelona, Spain, 08034
      • Hospital de Mataró
• Taiwan
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Tainan, Taiwan, 70403
    • National Cheng-Kung University Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
• United Kingdom
  • England
    • London, England, United Kingdom, SW3 6JJ
      • Royal Marsden NHS Trust
    • London, England, United Kingdom, NW1 2BU
      • University College London Hospitals
    • London, England, United Kingdom, SE1 9RT
      • Guy's and Saint Thomas NHS Foundation Trust
    • Manchester, England, United Kingdom, M20 4BX
      • The Christie Nhs Foundation Trust
• United States
  • California
    • Bakersfield, California, United States, 93309
      • Comprehensive Blood and Cancer Center
    • Duarte, California, United States, 91010
      • City of Hope Cancer Center
    • Fullerton, California, United States, 92835
      • Saint Joseph Heritage Healthcare
    • La Jolla, California, United States, 92093-0698
      • University of California San Diego Moores Cancer Center
    • Redondo Beach, California, United States, 90277
      • Cancer Care Associates Medical Group, Inc.
    • Sacramento, California, United States, 95816
      • Sutter Cancer center
    • San Francisco, California, United States, 94115
      • University of California, San Francisco Helen Diller Family Comprehensive Cancer Center
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corporation
    • Santa Monica, California, United States, 90404
      • University of California at Los Angeles
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
    • Whittier, California, United States, 90603
      • The Oncology Institute of Hope and Innovation
  • Florida
    • Deerfield Beach, Florida, United States, 33442
      • Sylvester Comprehensive Cancer Center (UMHC)
    • Gainesville, Florida, United States, 32608
      • University of Florida Health Science Center
    • Pembroke Pines, Florida, United States, 33028
      • Memorial Healthcare System
  • Georgia
    • Atlanta, Georgia, United States, 30341
      • Northside Hospital
  • Illinois
    • Evanston, Illinois, United States, 60201
      • North Shore University Health System
  • Maryland
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Saint Joseph Mercy Hospital
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute
  • New Jersey
    • East Brunswick, New Jersey, United States, 08816
      • Regional Cancer Care Associates, LLC
    • Morristown, New Jersey, United States, 07962
      • Regional Cancer Care Associates
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97223
      • Providence Health and Services
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University (OHSU) - Knight Cancer Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPMC)
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia
    • Richmond, Virginia, United States, 23230
      • Virginia Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rociletinib Monotherapy (500 mg BID); Daily 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.	Drug: Rociletinib; Other Names: CO-1686
EXPERIMENTAL: Rociletinib Monotherapy (625 mg BID); Daily 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.	Drug: Rociletinib; Other Names: CO-1686
ACTIVE_COMPARATOR: Pemetrexed or gemcitabine or paclitaxel or docetaxel; Pemetrexed 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.	Drug: Pemetrexed or gemcitabine or paclitaxel or docetaxel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)	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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Confirmed Response	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.	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.
Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment	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).	Cycle 1 Day 1 to End of Treatment, up to approximately 35 months
Overall Survival (OS)	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.	Cycle 1 Day 1 to date of death, assessed up to 3 years
Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling	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).	Cycles 2 Day 1 to Cycle 7 Day 1, or approximately 6 months

Collaborators and Investigators

• Sponsor: Clovis Oncology, Inc.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (ACTUAL): March 29, 2018
• Study Completion (ACTUAL): March 29, 2018

Study Registration Dates

• First Submitted: December 17, 2014
• First Submitted That Met QC Criteria: December 22, 2014
• First Posted (ESTIMATE): December 23, 2014

Study Record Updates

• Last Update Posted (ACTUAL): August 14, 2019
• Last Update Submitted That Met QC Criteria: July 31, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: lung; NSCLC; cancer; non-small cell lung cancer; EGFR; metastatic; recurrent; unresectable; locally advanced; T790M; epidermal growth factor receptor; irreversible EGFR inhibitor; CO-1686; EGFR-directed therapy; TIGER; Rociletinib
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Folic Acid Antagonists; Gemcitabine; Docetaxel; Paclitaxel; Pemetrexed
• Other Study ID Numbers: CO-1686-020 (TIGER-3)