LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-small Cell Lung Cancer
A single-arm, open-label, two-stage multicenter, phase II study. Patients will be pre-screened for ALK positive status. Treatment with LDK378 at 750 mg qd will continue until the patient experiences unacceptable toxicity that precludes further treatment, discontinues treatment at the discretion of the investigator or patient, starts a new anticancer therapy and/or dies. LDK378 may be continued beyond RECIST defined PD as assessed by the investigator, if in the judgment of the investigator, there is evidence of clinical benefit. Patients who discontinue the study medication in the absence of progression will continue to be followed for tumor assessment until the time of PD as assessed by the investigator. Male and female patients aged 18 or over with ALK-rearranged NSCLC will be screened for eligibility. Patients must have received no prior crizotinib, and must be chemotherapy-naïve or have been pretreated with cytotoxic chemotherapy (up to three prior lines)
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-small Cell Lung Cancer|
- Overall response rate (ORR) to LDK378 by investigator assessment [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: No ]ORR per RECIST 1.1 calculated as the proportion of patients with a best overall response (OR) defined as complete response (CR) or partial response (PR) as assessed by investigator.
- Duration of response (DOR) [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: No ]DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to underlying cancer, by investigator and BIRC (Blinded Independent Review Committee) assessment
- Disease control rate (DCR) [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: No ]DCR, calculated as the proportion of patients with best overall response of CR, PR, or SD, by investigator and BIRC assessment
- Time to Response (TTR) [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: No ]TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by investigator and BIRC assessment
- ORR by BIRC assessment [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: No ]ORR (CR+PR) per RECIST 1.1 as assessed by BIRC
- Safety profile [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: Yes ]Adverse events and laboratory abnormalities
- Progression-free survival (PFS) [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: No ]PFS, defined as time from first dose of LDK378 to progression or death due to any cause, as assessed by BIRC and investigator assessment
- Overall survival (OS) [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: No ]OS, defined as time from first dose of LDK378 to death due to any cause
- Overall intracranial response rate (OIRR) [ Time Frame: 6 cycles of 28 days up to 24 weeks ] [ Designated as safety issue: No ]OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline
|Study Start Date:||August 2012|
|Estimated Study Completion Date:||January 2016|
|Estimated Primary Completion Date:||January 2016 (Final data collection date for primary outcome measure)|
Oral LDK378 750 mg once daily
Oral LDK378 750 mg once daily
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This is a single-arm, open-label, two-stage, multicenter, phase II study in which the efficacy and safety of LDK378 will be evaluated in patients with stage IIIB or IV NSCLC harboring a confirmed ALK rearrangement, defined as 15% or more positive tumor cells as assessed by the FDA-approved FISH test (Abbott Molecular Inc.) using Vysis breakapart probes.
Patients will be pre-screened to test for ALK positivity. The test to confirm ALK rearrangement must be performed either using archival tissue or, preferably, using a fresh biopsy prior to study entry according to the above criteria, i.e. with an FDA-approved assay. The test will be performed at a Novartis designated central laboratory.
After confirmation of ALK positivity, the study begins with a screening period to assess eligibility, up to and including 28 days prior to the first dose of LDK378.
Patients must not have received prior crizotinib. Patients must be chemotherapy-naïve or have been pretreated with cytotoxic chemotherapy (up to three prior lines)
The study will use a Simon's optimal two-stage design. Stage 1 will consist of 43 patients and their data up to 6 cycles of treatment unless a patient has discontinued treatment earlier or a confirmed response to treatment has been observed prior to completing 6 cycles. The trial will be stopped at Stage 1 for futility if 16 or fewer responses are observed. If at the time that the last patient is enrolled to Stage 1 a minimum of 17 responses have not yet been observed, accrual may be temporarily suspended during the analysis of Stage 1. The Data Monitoring Committee will periodically review response data and will make the appropriate recommendation regarding transition into Stage 2 or stopping enrollment. Stage 2 will include an additional 62 patients. The primary analysis will occur when all 105 patients have completed 6 cycles of treatment or discontinued treatment earlier.
The treatment period begins on Day 1 of Cycle 1. All patients will be treated with LDK378, administered orally, at a starting dose of 750 mg. A total of approximately 105 patients will be enrolled in the study. Patients will take LDK378 once daily, at approximately the same time each day. On days when a PK sample is obtained, the patient will take LDK378 during the clinic visit as instructed by the study staff. Treatment with LDK378 will continue until the patient experiences unacceptable toxicity that precludes further treatment, discontinues treatment at the discretion of the patient or investigator, starts a new anti-cancer therapy or dies. If the patient experiences RECIST-defined progressive disease (PD) on LDK378 as assessed by the investigator, treatment with the study drug may be continued if, in the judgment of the investigator, there is still evidence of clinical benefit. These patients will be counted as PD for ORR, DOR, DCR and PFS calculations.
Assessments of tumor response and progression will be performed every 8 weeks (i.e. every 2 cycles), starting from the first day of treatment with LDK378. This schedule of tumor assessment every 8 weeks must continue regardless of dose interruptions. Tumor assessment should continue until:
- For patients who experience PD as assessed by the investigator, tumor assessments should continue every 8 weeks until LDK378 is permanently discontinued (i.e. if the patient continues treatment with LDK378 after PD, tumor assessments should continue until LDK378 is permanently discontinued).
- For patients who discontinue treatment in the absence of PD, tumor assessments should continue every 8 weeks from the EOT visit until PD is assessed by the investigator.
Tumor evaluations will always cease if the patient starts a new anti-cancer therapy, withdraws consent (unless the patient agrees to continue efficacy assessments in absence of dosing with LDK378, or dies.
All tumor imaging assessments will be submitted for independent radiological assessment of response by a Blinded Independent Review Committee (BIRC).
Clinical and laboratory assessments will be performed.
When the patient discontinues from study treatment an End of Treatment (EOT) visit must be performed as soon as possible and within 7 days of the last dose of LDK378. Patients will be contacted for the safety follow-up 30 days after their last dose of LDK378 to determine if they have experienced any new AEs and/or to follow resolution of ongoing AEs.
Following the end of tumor assessments, the Study Phase Completion Disposition eCRF must be completed. Patients will be contacted every 3 months to obtain information pertaining to survival status until death, loss to follow-up, withdrawal of consent to survival follow-up, or the end of the study. Patients do not need to visit the clinic during the survival follow-up.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01685138
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|Study Director:||Novartis Pharmaceuticals||Novartis Pharmaceuticals|