Non-Small Cell Lung Cancer
Conditions
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
Brief summary
The purpose of this study is to compare the safety and anti-tumor effect of rociletinib with erlotinib in patients whose tumors have specific EGFR mutations and who have not previously received any treatment for advanced/metastatic EGFR mutated NSCLC. This study is a 'Randomized' Study. This means that upon entering the study, patients will be randomly assigned to be dosed with either rociletinib twice a day or erlotinib once a day. Patients will continue to take either rociletinib or erlotinib until it is no longer beneficial.
Detailed description
This is a randomized, Phase 2/3 study of rociletinib versus erlotinib as a first-line treatment for patients with EGFR-mutant advanced/metastatic NSCLC whose tumors have EGFR-activating mutations. The study will consist of Phase 2 and Phase 3 parts which will use the same enrollment criteria and treatment assignment principles. Patients will be randomized 1:1 to erlotinib or rociletinib. The Phase 2 part is an open-label study. In the Phase 3 part, the sponsor will be blinded to the efficacy and safety results. The study will consist of a screening phase to establish study eligibility (including tumor genotype) and document baseline measurements, a treatment phase, in which patients will receive either rociletinib BID (twice a day) or erlotinib QD (once daily) to ascertain safety and efficacy until protocol-defined disease progression, and a follow-up phase, to monitor survival status and subsequent NSCLC cancer therapy. In the Phase 2 part only, patients initially randomized to erlotinib may be eligible to participate in an optional crossover phase to receive rociletinib if they demonstrate the T790M resistance mutation after radiographic progression on erlotinib treatment among other eligibility requirements. Patients eligible for this study must have EGFR-mutated NSCLC who have not been treated with an EGFR-directed therapy.Treatment with rociletinib or erlotinib is continuous. Each 28 day period of treatment will represent one cycle, with dosing initiated on Cycle 1 Day 1 (C1 D1).
Interventions
DRUGRociletinib Mono-Therapy
Rociletinib will be administered twice daily
DRUGErlotinib Mono-Therapy
Erlotinib will be administered once a day
Sponsors
Clovis Oncology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed metastatic or unresectable locally advanced/metastatic NSCLC 2. Documented evidence of a tumor with activating EGFR mutations by local testing. Patients with exon 20 insertions are not eligible with the exception of patients with documented evidence of the exon 20 insertion A763\_Y764insFQEA in the EGFR gene 3. Have undergone a biopsy or surgical resection of either primary or metastatic tumor tissue within 60 days of the first day of study treatment, C1D1, and have tissue available to send to sponsor laboratories or are able to undergo a biopsy during screening and provide tissue to sponsor laboratories 4. Measureable disease according to RECIST Version 1.1 5. Life expectancy of at least 3 months 6. ECOG (Eastern Cooperative Oncology Group) performance status of 0 to 1 7. Minimum age 18 years (in certain territories, the minimum age requirement may be higher (e.g. 20 years in Japan and Taiwan) 8. Adequate hematological and biological function, confirmed by defined laboratory values 9. Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study-specific evaluation
Exclusion criteria
1. Documented evidence of an exon 20 insertion activating mutation other than A763\_Y764insFQEA in the EGFR gene 2. Prior treatment with cytotoxic chemotherapy for advanced NSCLC; neoadjuvant/adjuvant chemotherapy is permitted if at least 6 months has elapsed between the end of chemotherapy and randomization 3. Active second malignancy; i.e., patient known to have potentially fatal cancer present for which he/she may be (but not necessarily) currently receiving treatment 4. Patients with a history of malignancy that has been completely treated, and currently with no evidence of that cancer, are permitted to enroll in the trial provided all chemotherapy was completed \> 6 months prior and/or bone marrow transplant \> 2 years prior to first day of study treatment 5. Known pre-existing interstitial lung disease 6. Brain metastases 7. Treatment with prohibited medications less than or equal to 14 days prior to first day of study treatment 8. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval if that treatment cannot be either discontinued or switched to a different medication prior to administration of study drug 9. Prior treatment with EGFR TKIs (e.g. erlotinib, gefitinib, neratinib, afatinib, AZD9291, or dacomitinib), rociletinib or other drugs that target mutant EGFR 10. Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTCF) \> 450 ms 11. Inability to measure QT interval on ECG 12. Personal or family history of long QT syndrome 13. Implantable pacemaker or implantable cardioverter defibrillator 14. Resting bradycardia \< 55 beats/min 15. Non-study related surgical procedures less than or equal to 7 days prior to administration of study drug. In all cases, the patient must be sufficiently recovered and stable before treatment administration. 16. Females who are pregnant or breastfeeding 17. Refusal to use adequate contraception for fertile patients (females and males) for 12 weeks after the last dose of rociletinib and 2 weeks after the last dose of erlotinib 18. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study 19. Any other reason the investigator considers the patient should not participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | To compare the antitumor efficacy of oral single-agent rociletinib with that of erlotinib as measured by progression-free survival (PFS), when administered as a first-line targeted treatment to patients with EGFR-mutated, advanced NSCLC.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
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Response Rate | Cycle 1 Day 1 to End of Treatment, up to approximately 35 months. | Proportion 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 | Cycle 1 Day 1 to End of Treatment, up to approximately 35 months | Duration of Response in Patients with Confirmed Response per Investigator |
Countries
Germany, Hong Kong, Italy, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
100 subjects recruited from 74 sites, in 7 countries and randomized (1:1) to treatment with rociletinib or erlotinib.Original protocol had rociletinib starting dose of 625mg. In global Amendment 2, starting dose reduced to 500mg. Crossover to rociletinib was permitted however, only 2 patients did so. Safety data for these 2 patients are reported.
Participants by arm
| Arm | Count |
|---|---|
| Rociletinib 500mg Tablets Starting dose of 500mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression. | 20 |
| Rociletinib 625mg Tablets Starting dose of 625mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression. | 30 |
| Erlotinib 150mg Tablets Starting dose of 150mg. Taken orally once daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression. | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 5 | 5 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Missing | 0 | 0 | 2 |
| Overall Study | Other | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Progressive Disease | 7 | 22 | 27 |
| Overall Study | Protocol Deviation | 0 | 2 | 0 |
| Overall Study | Study Terminated by Sponsor | 1 | 0 | 11 |
| Overall Study | Withdrawal by Subject | 5 | 1 | 3 |
Baseline characteristics
| Characteristic | Total | Erlotinib 150mg Tablets | Rociletinib 625mg Tablets | Rociletinib 500mg Tablets |
|---|---|---|---|---|
| Age, Customized | 65 years | 64 years | 67.0 years | 66.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 6 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 43 Participants | 27 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| History of CNS Metastases | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| Number of Previous Therapies | 0.0 units on a scale | 0.0 units on a scale | 0.0 units on a scale | 0.0 units on a scale |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 49 Participants | 25 Participants | 15 Participants | 9 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 1 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Missing | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-White, Non-Asian | 9 Participants | 4 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 42 Participants | 21 Participants | 12 Participants | 9 Participants |
| Sex: Female, Male Female | 67 Participants | 32 Participants | 18 Participants | 17 Participants |
| Sex: Female, Male Male | 33 Participants | 18 Participants | 12 Participants | 3 Participants |
| Time Since Diagnosis of NSCLC | 7.1 months STANDARD_DEVIATION 17.57 | 8.2 months STANDARD_DEVIATION 21.83 | 5.3 months STANDARD_DEVIATION 10.39 | 7.2 months STANDARD_DEVIATION 14.12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 19 | 1 / 30 | 2 / 50 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 19 / 19 | 30 / 30 | 50 / 50 | 0 / 1 | 1 / 1 |
| serious Total, serious adverse events | 10 / 19 | 15 / 30 | 7 / 50 | 0 / 1 | 1 / 1 |
Outcome results
Primary
Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)
To compare the antitumor efficacy of oral single-agent rociletinib with that of erlotinib as measured by progression-free survival (PFS), when administered as a first-line targeted treatment to patients with EGFR-mutated, advanced NSCLC.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.
Time frame: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months
Population: Intent-to-treat: All patients randomized.~1 patient was not included in analysis, due to discontinuation of study shortly after randomization and prior to first dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rociletinib 500mg Tablets | Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) | 274 Days |
| Rociletinib 625mg Tablets | Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) | 207 Days |
| Erlotinib 150mg Tablets | Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) | 390 Days |
95% CI: [112, 260]
95% CI: [282, 499]
Secondary
Confirmed Response Rate
Proportion 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.
Time frame: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months.
Population: Intent-to-treat: All patients randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rociletinib 500mg Tablets | Confirmed Response Rate | 25.0 percentage of participants |
| Rociletinib 625mg Tablets | Confirmed Response Rate | 40.0 percentage of participants |
| Erlotinib 150mg Tablets | Confirmed Response Rate | 78.0 percentage of participants |
95% CI: [8.7, 49.1]
95% CI: [22.7, 59.4]
95% CI: [64, 88.5]
Secondary
Duration of Response
Duration of Response in Patients with Confirmed Response per Investigator
Time frame: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rociletinib 500mg Tablets | Duration of Response | 225 Days |
| Rociletinib 625mg Tablets | Duration of Response | 195.5 Days |
| Erlotinib 150mg Tablets | Duration of Response | 335.0 Days |
95% CI: [143, 617]
95% CI: [282, 480]