LDK378 in Adult Patients With ALK-activated NSCLC Previously Treated With Chemotherapy and Crizotinib

Non-Small Cell Lung Cancer Clinical Trial

Official title:

A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Adult Patients With ALK-activated Non-small Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01685060
• Other study ID #: CLDK378A2201
• Secondary ID: 2012-003432-24
• Status: Completed
• Phase: Phase 2
• First received: September 4, 2012
• Last updated: August 31, 2016
• Start date: November 2012
• Est. completion date: March 2016

Study information

• Verified date: August 2016
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: Department of Health and Ageing Therapeutic Goods AdministrationBelgium: Federal Agency for Medicinal Products and Health ProductsCanada: Health CanadaFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesHong Kong: Department of HealthItaly: Ministry of HealthJapan: Pharmaceuticals and Medical Devices AgencyKorea: Food and Drug AdministrationNetherlands: Medicines Evaluation Board (MEB)Singapore: Clinical Trials & Epidemiology Research Unit (CTERU)Spain: Spanish Agency of MedicinesSweden: Medical Products AgencyUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

A single-arm, open-label, multicenter, phase II study. Treatment with LDK378 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 anti-cancer 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. In these patients tumor assessment should continue as per the schedule of assessments until treatment with LDK378 is permanently discontinued. 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

Description:

This is a single-arm, open-label, 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 break-apart probes. If documentation of ALK rearrangement by the FDA-approved FISH test is available, no further ALK test is required for inclusion in the study. If such documentation is not available, a new test to assess ALK status by the FDA-approved Vysis ALK break-apart FISH test should be performed.

Patients must have been pretreated with cytotoxic chemotherapy (1 to 3 prior lines, of which 1 must have been a platinum doublet) and then with crizotinib. Patients may also have received first line treatment with crizotinib followed by cytotoxic chemotherapy and, subsequently, a rechallenge treatment with crizotinib. Patients must have demonstrated progression (regardless of initial response) on the last crizotinib treatment, i.e. the crizotinib regimen received as the last therapy prior to study entry.

The study begins with a screening period to assess eligibility, up to and including 28 days prior to the first dose of LDK378.

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 137 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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 141
• Est. completion date: March 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion critieria:

• Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that carries an ALK rearrangement, as per the FDA-approved FISH assay (Abbott Molecular Inc.).

• Age 18 years or older at the time of informed consent.

• Patients must have NSCLC that has progressed during therapy with crizotinib or within 30 days of the last dose

• Patients must have received 1-3 lines of cytotoxic chemotherapy (of which 1 must have been a platinum doublet) to treat their locally advanced or metastatic NSCLC

• Patients must have a tumor tissue sample available, collected either at the time of diagnosis of NSCLC or any time since.

• Patients must have recovered from all toxicities related to prior anticancer therapies to grade = 2, except for patients with grade 2 nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who will not be allowed to participate in the study.

Exclusion criteria:

• Patients with known hypersensitivity to any of the excipients of LDK378.

• Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.

• History of carcinomatous meningitis.

• Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years.

• Clinically significant, uncontrolled heart disease

• Systemic anti-cancer therapy given after the last dose of crizotinib and prior to starting study drug.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• LDK378

Locations

Country	Name	City	State
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Oshawa	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
France	Novartis Investigative Site	Marseille cedex 20
France	Novartis Investigative Site	Paris
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Hong Kong	Novartis Investigative Site	Hong Kong
Italy	Novartis Investigative Site	Avellino	AV
Italy	Novartis Investigative Site	Livorno	LI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Parma	PR
Italy	Novartis Investigative Site	Perugia	PG
Japan	Novartis Investigative Site	Akashi	Hyogo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Koto	Tokyo
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Okayama-city	Okayama
Japan	Novartis Investigative Site	OsakaSayama	Osaka
Japan	Novartis Investigative Site	Sunto-gun	Shizuoka
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Maastricht
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Sevilla	Andalucia
United Kingdom	Novartis Investigative Site	London
United States	Emory University School of Medicine/Winship Cancer Institute Dept of Oncology	Atlanta	Georgia
United States	University of Colorado Hospital SC	Aurora	Colorado
United States	Massachusetts General Hospital Mass General	Boston	Massachusetts
United States	Levine Cancer Institute SC 1	Charlotte	North Carolina
United States	University of Chicago Medical Center SC	Chicago	Illinois
United States	U of TX Southwestern Medical Center - SimmonsCompCancerCtr Clinical Research Office	Dallas	Texas
United States	City of Hope National Medical Center Dept of Oncology 2	Duarte	California
United States	Highlands Oncology Group Dept of Highlands Oncology Grp	Fayetteville	Arkansas
United States	University of Kansas Cancer Center DeptofUofKansas CancerCenter-2	Kansas City	Kansas
United States	University of California at Los Angeles UCLA - Santa Monica 2	Los Angeles	California
United States	University of Wisconsin Univ Wisc 2	Madison	Wisconsin
United States	Sarah Cannon Research Institute Drug Ship - 4	Nashville	Tennessee
United States	Maryland Oncology Hematology, P.A. SC	Rockville	Maryland
United States	University of California at San Diego, Moores Cancer Ctr SC	San Diego	California
United States	Seattle Cancer Care Alliance SC-1	Seattle	Washington
United States	Stanford University Medical Center Stanford Cancer Center(2)	Stanford	California
United States	Cancer Center of Kansas Dept of CCK	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Hong Kong,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Singapore,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response rate (ORR) to LDK378 by investigator assessment	ORR per RECIST 1.1 calculated as the proportion of patients with a best overall response defined as complete response or partial response (CR+PR) as assessed by investigator	6 cycles of 28 days up to 24 weeks	No
Secondary	Duration of response (DOR)	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 Imaging Review Committee)	6 cycles of 28 days up to 24 weeks	No
Secondary	Disease control rate (DCR)	DCR, calculated as the proportion of patients with best overall response of CR, PR, or SD, by investigator and BIRC	6 cycles of 28 days up to 24 weeks	No
Secondary	Time to Response (TTR)	TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by investigator and BIRC	6 cycles of 28 days up to 24 weeks	No
Secondary	ORR by BIRC assessment	ORR (CR+PR) per RECIST 1.1 as assessed by BIRC	6 cycles of 28 days up to 24 weeks	No
Secondary	Safety profile	Adverse events and laboratory abnormalities	6 cycles of 28 days up to 24 weeks	Yes
Secondary	Progression-free survival (PFS)	PFS, defined as time from first dose of LDK378 to progression or death due to any cause, as assessed by BIRC and investigator assessment	6 cycles of 28 days up to 24 weeks	No
Secondary	Overall survival (OS)	OS, defined as time from first dose of LDK378 to death due to any cause	6 cycles of 28 days up to 24 weeks	No
Secondary	Overall intracranial response rate (OIRR)	OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline	6 cycles of 28 days up to 24 weeks	No