Clinical trial NCT02322281: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
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
Lead sponsor: Clovis Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2014-12-23
Enrollment: 149
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)
timeFrame: 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 outcomes:
measure: Percentage of Participants With Confirmed Response
timeFrame: 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.
measure: Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment
timeFrame: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months
measure: Overall Survival (OS)
timeFrame: Cycle 1 Day 1 to date of death, assessed up to 3 years
measure: Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling
timeFrame: Cycles 2 Day 1 to Cycle 7 Day 1, or approximately 6 months
Other outcomes:
Locations:
city: Bakersfield
country: United States
facility: Comprehensive Blood and Cancer Center
state: California
city: Duarte
country: United States
facility: City of Hope Cancer Center
state: California
city: Fullerton
country: United States
facility: Saint Joseph Heritage Healthcare
state: California
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Redondo Beach
country: United States
facility: Cancer Care Associates Medical Group, Inc.
state: California
city: Sacramento
country: United States
facility: Sutter Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco Helen Diller Family Comprehensive Cancer Center
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology Corporation
state: California
city: Santa Monica
country: United States
facility: University of California at Los Angeles
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Deerfield Beach
country: United States
facility: Sylvester Comprehensive Cancer Center (UMHC)
state: Florida
city: Gainesville
country: United States
facility: University of Florida Health Science Center
state: Florida
city: Pembroke Pines
country: United States
facility: Memorial Healthcare System
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Evanston
country: United States
facility: North Shore University Health System
state: Illinois
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: Virginia Piper Cancer Institute
state: Minnesota
city: East Brunswick
country: United States
facility: Regional Cancer Care Associates, LLC
state: New Jersey
city: Morristown
country: United States
facility: Regional Cancer Care Associates
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Providence Health and Services
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University (OHSU) - Knight Cancer Institute
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPMC)
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Cancer Institute
state: Virginia
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Strasbourg
country: France
facility: Hopital Hautepierre (CHU) de Strasbourg
state: Alsace
city: Caen
country: France
facility: Centre François Baclesse
state: Basse-Normandie
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes, Hôpital Pontchaillou
state: Bretagne
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal Créteil
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Bichat-Claude Bernard
state: Ile-de-France
city: Limoges
country: France
facility: CHRU de Limoges - Hôpital Dupuytren
state: Limousin
city: Lille
country: France
facility: CHRU de Lille - Hôpital Calmette
state: Nord Pas-de-Calais
city: Marseille
country: France
facility: L'Assistance Publique - Hopitaux de Marseille
state: Provence Alpes Cote D'Azur
city: Lyon
country: France
facility: Centre Léon Bérard
city: Gauting
country: Germany
facility: Asklepios Fachkliniken München-Gauting
state: Baden-Wuerttemberg
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg gGmbH
state: Baden-Wuerttemberg
city: München
country: Germany
facility: LMU - Klinikum der Universität München
state: Bayern
city: Oldenburg
country: Germany
facility: Pius Hospital Oldenburg
state: Niedersachen
city: Minden
country: Germany
facility: Johannes-Wesling-Klinikum Minden
state: Nordrhein-westfalen
city: Großhansdorf
country: Germany
facility: LungenClinic Großhansdorf GmbH
state: Schleswig-Holstein
city: Orbassano
country: Italy
facility: A.O.U. San Luigi Gonzaga di Orbassano
state: Torino
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Genova
country: Italy
facility: IRCCS Azienda Ospedaliera Universitaria San Martino - IST
city: Livorno
country: Italy
facility: Ospedale Civile di Livorno
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Perugia
country: Italy
facility: Azienda Ospedaliera di Perugia
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Cheungcheongbuk-do
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea Saint Vincent's Hospital
state: Gyeonggi
city: Hwasun-gun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeollanam-do
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
state: Limburg
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek Hospital
state: Noord-Holland
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Mataró
country: Spain
facility: Hospital de Mataró
state: Barcelona
city: Barcelona
country: Spain
facility: Institut Universitari Dexeus
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D'Hebron
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz (Clinica de la Concepcion) (UAM -FJD)
city: Málaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng-Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: London
country: United Kingdom
facility: University College London Hospitals
state: England
city: London
country: United Kingdom
facility: Guy's and Saint Thomas NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: Royal Marsden NHS Trust
state: England
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: England
Study officials:
References: