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

Non-small Cell Lung Cancer Clinical Trial

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 Details — Status: Terminated

Administrative data

• NCT number: NCT02322281
• Other study ID #: CO-1686-020 (TIGER-3)
• Status: Terminated
• Phase: Phase 3
• Start date: February 2015
• Est. completion date: March 29, 2018

Study information

• Verified date: July 2019
• Source: Clovis Oncology, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 149
• Est. completion date: March 29, 2018
• Est. primary completion date: March 29, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• Rociletinib

• Pemetrexed or gemcitabine or paclitaxel or docetaxel

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Clovis Oncology, Inc.

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Italy,  Korea, Republic of,  Netherlands,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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
Secondary	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
Secondary	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