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
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|ClinicalTrials.gov Identifier: NCT02322281|
Recruitment Status : Terminated (Sponsor discontinued development of CO-1686 for NSCLC)
First Posted : December 23, 2014
Results First Posted : July 23, 2019
Last Update Posted : August 14, 2019
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|Condition or disease||Intervention/treatment||Phase|
|Non-small Cell Lung Cancer||Drug: Rociletinib Drug: Pemetrexed or gemcitabine or paclitaxel or docetaxel||Phase 3|
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 (Clinical Trial)|
|Actual Enrollment :||149 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|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 Start Date :||February 2015|
|Actual Primary Completion Date :||March 29, 2018|
|Actual Study Completion Date :||March 29, 2018|
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.
Other Name: 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.
Other Name: CO-1686
Active Comparator: Pemetrexed or gemcitabine or paclitaxel or docetaxel
500 mg/m2 pemetrexed given intravenously on Day 1 of each 21-day cycle.
1250 mg/m2 gemcitabine given intravenously on Day 1 and 8 of each 21-day cycle.
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.
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
- 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. ]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.
- 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. ]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 [ Time Frame: 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).
- Overall Survival (OS) [ Time Frame: 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 [ Time Frame: 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).
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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
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
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:
- Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTCF) > 450 msec
- Inability to measure QT interval on ECG
- Personal or family history of long QT syndrome
- Implantable pacemaker or implantable cardioverter defibrillator
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02322281
Documents provided by Clovis Oncology, Inc.:
|Responsible Party:||Clovis Oncology, Inc.|
|Other Study ID Numbers:||
|First Posted:||December 23, 2014 Key Record Dates|
|Results First Posted:||July 23, 2019|
|Last Update Posted:||August 14, 2019|
|Last Verified:||July 2019|
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