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

Phase 2
18 Years
Open (Enrolling)
Non-Small Cell Lung Cancer

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Trial Information

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

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

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 have been pretreated with
cytotoxic chemotherapy (1 to 3 prior lines, of which 1 must have been a platinum doublet).

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

Inclusion Criteria

Inclusion criteria:

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

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

- Patients must have NSCLC that has progressed during or after prior the last
chemotherapy regimen received prior to the first dose of LDK378.

- 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 archival 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:

- Prior treatment with crizotinib, or any other ALK inhibitor investigational agent,

- 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.

Type of Study:


Study Design:

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

Outcome Measure:

Overall response rate (ORR) to LDK378 by investigator assessment

Outcome Description:

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.

Outcome Time Frame:

6 cycles of 28 days up to 24 weeks

Safety Issue:


Principal Investigator

Novartis Pharmaceuticals

Investigator Role:

Study Director

Investigator Affiliation:

Novartis Pharmaceuticals


United States: Food and Drug Administration

Study ID:




Start Date:

December 2012

Completion Date:

July 2014

Related Keywords:

  • Non-Small Cell Lung Cancer
  • Non-Small Cell Lung Cancer, ALK, LDK378
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



Highlands Oncology Group Dept of Highlands Oncology Grp Fayetteville, Arkansas  72703
Washington University School Of Medicine-Siteman Cancer Ctr Wash Uni St. Louis, Missouri  63110
U of TX Southwestern Medical Center - SimmonsCompCancerCtr Clinical Research Office Dallas, Texas  75390-9151
University of Miami SC Miami, Florida  33136
University of California Irvine Dept of Hematology/Oncology Orange, California  92868
University of California at Los Angeles UCLA - Santa Monica 2 Los Angeles, California  90095
Rush University Medical Center SC-3 Chicago, Illinois  60612
Levine Cancer Institute SC 1 Charlotte, North Carolina  28203
University of Pennsylvania Medical Center SC Philadephia, Pennsylvania  19104
Sarah Cannon Research Institute Dept of Oncology Nashville, Tennessee  37203
University of Utah / Huntsman Cancer Institute SC Salt Lake City, Utah  84103
Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research SC-1 Seattle, Washington  98109-1023
University of California at San Diego, Moores Cancer Ctr Dept. of MooresCancerCenter(2) San Diego, California  92103
H. Lee Moffitt Cancer Center & Research Institute SC-3 Tampa, Florida  33612
University of Iowa Hospitals & Clinics SC-2 Iowa City, Iowa  52242
Massachusetts General Hospital Mass Gen 5 Boston, Massachusetts  02114
Case Western Reserve SC - 2 Cleveland, Ohio  44106-5000
MD Anderson Cancer Center/University of Texas SC-9 Houston, Texas  77030-4009
University of Wisconsin / Paul P. Carbone Comp Cancer Center SC Madison, Wisconsin  53792-6164