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

Phase 3

Terminated

Conditions: Non-small Cell Lung Cancer

Interventions: Drug: Pemetrexed or gemcitabine or paclitaxel or docetaxel
Drug: Rociletinib

Registration Number: NCT02322281

Lead Sponsor: Clovis Oncology, Inc.

Brief 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.

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).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 149

Inclusion Criteria

All patients must meet all of the following inclusion criteria:

Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with radiological progression on the most recent therapy received
Documented evidence of a tumor with 1 or more EGFR activating mutations excluding exon 20 insertion
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)
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.
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
Measureable disease according to RECIST Version 1.1
Life expectancy of at least 3 months
ECOG performance status of 0 to 1
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)
Patients should have recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤ 1 from any significant chemotherapy-related toxicities
Adequate hematological and biological function
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:

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
Known pre-existing interstitial lung disease
Tumor small cell transformation by local assessment, irrespective of presence of T790M+ component
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)
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)
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
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
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
Non-study related surgical procedures ≤ 7 days prior to randomization. In all cases, the patient must be sufficiently recovered and stable before treatment administration
Females who are pregnant or breastfeeding
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)
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)
Any other reason the investigator considers the patient should not participate in the study
Treatment with live vaccines initiated less than 4 weeks prior to randomization

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pemetrexed or gemcitabine or paclitaxel or docetaxel	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.
Rociletinib Monotherapy (500 mg BID)	Rociletinib	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.
Rociletinib Monotherapy (625 mg BID)	Rociletinib	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.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)	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.	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

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

Trial Locations

Locations (80): Comprehensive Blood and Cancer Center
🇺🇸
Bakersfield, California, United States
Saint Joseph Heritage Healthcare
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Fullerton, California, United States
University of California at Los Angeles
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Santa Monica, California, United States
Sylvester Comprehensive Cancer Center (UMHC)
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Deerfield Beach, Florida, United States
Memorial Healthcare System
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Pembroke Pines, Florida, United States
Northside Hospital
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Atlanta, Georgia, United States
North Shore University Health System
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Evanston, Illinois, United States
The Ohio State University Comprehensive Cancer Center
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Columbus, Ohio, United States
University of Pittsburgh Cancer Institute (UPMC)
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Pittsburgh, Pennsylvania, United States
University of Texas Southwestern Medical Center
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Dallas, Texas, United States
Royal Marsden NHS Trust
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London, England, United Kingdom
Virginia Piper Cancer Institute
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Minneapolis, Minnesota, United States
LungenClinic Großhansdorf GmbH
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Großhansdorf, Schleswig-Holstein, Germany
City of Hope Cancer Center
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Duarte, California, United States
University of California San Diego Moores Cancer Center
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La Jolla, California, United States
Stanford University School of Medicine
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Stanford, California, United States
Cancer Care Associates Medical Group, Inc.
🇺🇸
Redondo Beach, California, United States
Central Coast Medical Oncology Corporation
🇺🇸
Santa Maria, California, United States
The Oncology Institute of Hope and Innovation
🇺🇸
Whittier, California, United States
Regional Cancer Care Associates, LLC
🇺🇸
East Brunswick, New Jersey, United States
Regional Cancer Care Associates
🇺🇸
Morristown, New Jersey, United States
Roswell Park Cancer Institute
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Buffalo, New York, United States
University of Virginia
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Charlottesville, Virginia, United States
Royal North Shore Hospital
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Saint Leonards, New South Wales, Australia
Westmead Hospital
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Westmead, New South Wales, Australia
Flinders Medical Centre
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Bedford Park, South Australia, Australia
Hopital Hautepierre (CHU) de Strasbourg
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Strasbourg, Alsace, France
Centre François Baclesse
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Caen, Basse-Normandie, France
CHRU de Limoges - Hôpital Dupuytren
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Limoges, Limousin, France
Centre Hospitalier Intercommunal Créteil
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Créteil, Ile-de-France, France
Centre Hospitalier Universitaire de Rennes, Hôpital Pontchaillou
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Rennes, Bretagne, France
Hôpital Bichat-Claude Bernard
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Paris, Ile-de-France, France
CHRU de Lille - Hôpital Calmette
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Lille, Nord Pas-de-Calais, France
Centre Léon Bérard
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Lyon, France
L'Assistance Publique - Hopitaux de Marseille
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Marseille, Provence Alpes Cote D'Azur, France
Asklepios Fachkliniken München-Gauting
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Gauting, Baden-Wuerttemberg, Germany
Thoraxklinik Heidelberg gGmbH
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Heidelberg, Baden-Wuerttemberg, Germany
LMU - Klinikum der Universität München
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München, Bayern, Germany
Pius Hospital Oldenburg
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Oldenburg, Niedersachen, Germany
Johannes-Wesling-Klinikum Minden
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Minden, Nordrhein-westfalen, Germany
A.O.U. San Luigi Gonzaga di Orbassano
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Orbassano, Torino, Italy
Azienda Ospedaliero-Universitaria Careggi
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Firenze, Italy
IRCCS Azienda Ospedaliera Universitaria San Martino - IST
🇮🇹
Genova, Italy
Istituto Europeo di Oncologia
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Milano, Italy
Ospedale Civile di Livorno
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Livorno, Italy
Azienda Ospedaliera di Perugia
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Perugia, Italy
Seoul National University Bundang Hospital
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Seongnam-si, Gyeonggi-do, Korea, Republic of
The Catholic University of Korea Saint Vincent's Hospital
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Suwon, Gyeonggi, Korea, Republic of
Chonnam National University Hwasun Hospital
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Hwasun-gun, Jeollanam-do, Korea, Republic of
Chungbuk National University Hospital
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Cheongju-si, Cheungcheongbuk-do, Korea, Republic of
Academisch Ziekenhuis Maastricht
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Maastricht, Limburg, Netherlands
Samsung Medical Center
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Seoul, Korea, Republic of
Antoni van Leeuwenhoek Hospital
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Amsterdam, Noord-Holland, Netherlands
Asan Medical Center
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Seoul, Korea, Republic of
Hospital Universitari Germans Trias i Pujol
🇪🇸
Badalona, Barcelona, Spain
Institut Universitari Dexeus
🇪🇸
Barcelona, Spain
Hospital de Mataró
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Mataró, Barcelona, Spain
Universitair Medisch Centrum Groningen
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Groningen, Netherlands
Hospital Universitari Vall D'Hebron
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Barcelona, Spain
Taichung Veterans General Hospital
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Taichung, Taiwan
Hospital Universitario Virgen del Rocio
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Sevilla, Spain
Hospital Regional Universitario Carlos Haya
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Málaga, Spain
Fundacion Jimenez Diaz (Clinica de la Concepcion) (UAM -FJD)
🇪🇸
Madrid, Spain
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
China Medical University Hospital
🇨🇳
Taichung, Taiwan
National Cheng-Kung University Hospital
🇨🇳
Tainan, Taiwan
Guy's and Saint Thomas NHS Foundation Trust
🇬🇧
London, England, United Kingdom
University College London Hospitals
🇬🇧
London, England, United Kingdom
Taipei Veterans General Hospital
🇨🇳
Taipei, Taiwan
The Christie NHS Foundation Trust
🇬🇧
Manchester, England, United Kingdom
Sutter Cancer Center
🇺🇸
Sacramento, California, United States
University of California, San Francisco Helen Diller Family Comprehensive Cancer Center
🇺🇸
San Francisco, California, United States
Saint Joseph Mercy Hospital
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Ann Arbor, Michigan, United States
Walter Reed National Military Medical Center
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Bethesda, Maryland, United States
Barbara Ann Karmanos Cancer Institute
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Detroit, Michigan, United States
Providence Health and Services
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Portland, Oregon, United States
Oregon Health & Science University (OHSU) - Knight Cancer Institute
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Portland, Oregon, United States
Huntsman Cancer Institute
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Salt Lake City, Utah, United States
Virginia Cancer Institute
🇺🇸
Richmond, Virginia, United States
University of Florida Health Science Center
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Gainesville, Florida, United States