A Phase I study to assess the systemic exposure efficacy and safety of 450mg ceritinib taken with a lowfat meal and 600mg ceritinib taken with a lowfat meal as compared with that of 750mg ceritinib taken in the fasted state in adult patients with ALK rearranged metastatic nonsmall cell lung cancer

• Register: CTRI
• Last refreshed on: 24 November 2021
• Main ID: CTRI/2016/09/007234
• Date of registration: 05-09-2016
• Prospective Registration: Yes
• Primary sponsor: Novartis Healthcare Pvt Ltd
• Public title: A Phase I study to assess the systemic exposure efficacy and safety of 450mg ceritinib taken with a lowfat meal and 600mg ceritinib taken with a lowfat meal as compared with that of 750mg ceritinib taken in the fasted state in adult patients with ALK rearranged metastatic nonsmall cell lung cancer
• Scientific title: A multi-center, randomized open label study to assess the systemic exposure, efficacy, and safety of 450 mg ceritinib taken with a low-fat meal and 600 mg ceritinib taken with a low-fat meal as compared with that of 750 mg ceritinib taken in the fasted state in adult patients with ALK rearranged (ALK-positive) metastatic non-small cell lung cancer (NSCLC) - Ascend 8 - CLDK378A2112
• Date of first enrolment: 15-09-2016
• Target sample size: 300
• Recruitment status: Other (Terminated)
• URL: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=14531
• Study type: Interventional
• Study design: Randomized, Parallel Group, Multiple Arm Trial; Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:On-site computer system Blinding and masking:Open Label
• Phase: Phase 1

Countries of recruitment

Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Colombia, Czech Republic, France, Germany, Greece, Hungary, India, Italy, Lebanon, Malaysia, Netherlands, New Zealand, Poland, Portugal, Republic of Korea, Romania, Russian Federation, Spain, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States of America

Contacts

• Name: Murugananthan K
• Affiliation: Novartis Healthcare Pvt Limited

• Name: Murugananthan K
• Affiliation: Novartis Healthcare Pvt Limited

Key inclusion & exclusion criteria

Inclusion criteria: 1. Histologically or cytologically confirmed diagnosis of stage IIIB and is not a candidate for definitive multimodality therapy or IV ALK positive NSCLC.

Eligible patients include those who are either previously treated with systemic anticancer therapy for advanced disease, either experimental or not, or treatment naive with the exception of neo adjuvant or adjuvant therapy excluding regimens containing an ALK inhibitor as depicted in the inclusion criterion No. 13. For AJCC stage groupings and TNM definitions, refer to NCI 2014 guidelines.

For patients previously treated with systemic anti-cancer therapy (including crizotinib), ALK-positive status can be determined locally by using the FDA approved Vysis ALK Break Apart FISH Probe Kit Abbott Molecular Inc. test and scoring algorithm including positivity criteria. Locally confirmed results of ALK positive status must be available prior to randomization. In instances where a local ALK positive result is not available as described above, a central test to confirm ALK positivity must be performed at a Novartis designated central laboratory using either archival tumor obtained at or since the time of diagnosis or a newly obtained tumor sample taken prior to randomization.

For patients who are treatment-naive, ALK-positivity must be determined prospectively at a Novartis central laboratory using the Ventana anti ALK D5F3 IHC test Ventana IHC prior to randomization. The Ventana IHC test must be performed on a biopsy obtained prior to randomization or on archival tumor obtained at or since the time of initial diagnosis.

Note Patients with clinically and neurologically stable central nervous system CNSmetastases who have not required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms are eligible

2. Retired from protocol version 00

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

4. Patients who are previously treated may have received one prior treatment regimen with crizotinib. all other ALK inhibitors are excluded.

Patients previously treated with crizotinib must have discontinued treatment with crizotinib at least 1 week prior to the first dose of study drug

5. Patients who are previously treated may have received prior chemotherapy, biologic therapy, or other investigational agents. ALK inhibitors other than crizotinib are excluded.

Patients who have been treated with chemotherapy, biological therapy, or other investigational agents must have discontinued the treatment at least 2 weeks prior to starting study drug. In case last chemotherapy contains nitroso urea or mitomycin C, the treatment must be discontinued at least 6 weeks prior to the first dose of study drug.

6. Patients who have received prior chemotherapy, crizotinib, biologic therapy, or other investigational agents must have recovered from all toxicities related to prior anticancer therapies to grade less than 1 CTCAE v 4. 03 prior to starting study drug. Patients with grade less than 2 peripheral neuropathy or any grade of alopecia, nail changes, or skin changes are allowed to enter the study.

7. Patient must meet the following laboratory values at the screening visit:

Absolute Neutrophil Count greater than 1.5 x 10 raised to 9 per L

Platelets greater than 75 x 10 raised to 9 per L

Hemoglobin Hgb greater than 8 g per dL

Serum creatinine less than 1.5 mg per dL and or
Exclusion criteria: Patients eligible for this study must not meet any of the following criteria

1. Prior treatment with an ALK inhibitor other than crizotinib.

2. Patients with known hypersensitivity to any of the excipients of ceritinib microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate.

3. History of carcinomatous meningitis.

4. Presence or history of a malignant disease other than an ALK positive advanced tumor that has been diagnosed and or required therapy within the past 3 years. Exceptions to this exclusion include the following completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.

5. Patient who has received thoracic radiotherapy to lung fields less than 4 weeks prior to starting the study treatment or patients who have not recovered from radiotherapy related toxicities.

For all other anatomic sites including radiotherapy to thoracic vertebrae and ribs radiotherapy less than 2 weeks prior to starting the study treatment or has not recovered from radiotherapy related toxicities. Palliative radiotherapy for bone lesions less than 2 weeks prior to starting study treatment is allowed.

6. Clinically significant, uncontrolled heart disease and or recent cardiac event within 6 months, such as

Unstable angina within 6 months prior to screening.

Myocardial infarction within 6 months prior to screening.

History of documented congestive heart failure New York Heart Association

functional classification III to IV.

Uncontrolled hypertension defined by a Systolic Blood Pressure SBP greater than 160 mm Hg andor Diastolic Blood Pressure DBP greater than 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication is allowed prior to screening.

Ventricular arrhythmias.

Supraventricular and nodal arrhythmias not controlled with medication.

Other cardiac arrhythmia not controlled with medication.

Corrected QT QTcF greater than 470 ms using Fridericias correction on the screening ECG as mean of triplicate ECGs. Patient has history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis i.e., affecting activities of daily living or

requiring therapeutic intervention.

8. Patient has other severe, acute, or chronic medical conditions including uncontrolled diabetes mellitus or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results.

9. Patient has impairment of GI function or GI disease that may significantly alter the absorption of ceritinib e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,or malabsorption syndrome.

10. Patient receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with ceritinib and for the duration of the study

Strong inhibitors or strong inducers of CYP3A4 or 5. Medications with a low therapeutic index that are primarily metabolized by CYP3A4 or 5 and or CYP2C9.

Medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.

11. Patient is currently receiving treatment with

Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Health Condition 1: C399- Malignant neoplasm of lower respiratory tract, part unspecified Health Condition 2: null- previously treated and treatment-naive adult patients with metastatic ALK-positive NSCLC.

Intervention(s)

Intervention1: LDK378: Investigational Arm 1 oral ceritinib once daily at a dose of 450 mg administered in the
morning immediately within 30 minutes following a lowfat meal. Patients should
refrain from eating one hour after dosing.

Intervention2: LDK378: Investigational Arm 2 oral ceritinib once daily at a dose of 600 mg administered in the morning immediately within 30 minutes following a lowfat meal. Patients should refrain from eating one hour after dosing.
Intervention3: LDK378: Control arm oral ceritinib once daily at a dose of 750 mg administered in the morning on an empty stomach i.e., fast from food and drink except water at least one hour before or two hours after a meal.
Control Intervention1: Not Applicable: Not Applicable
Control Intervention2: Not Applicable: Not Applicable

Primary Outcome(s)

To assess the steady state PK of 450 mg or 600 mg ceritinib

taken daily with a lowfat meal as compared with that of 750

mg ceritinib taken daily in the fasted state in patients with

metastatic ALK positive NSCLC

Timepoint: Plasma concentration of ceritinib and PK parameters,

including but not limited to AUClast, AUC0 24h, Cmax, Tmax,

Tlast, Racc, and CLssF

Secondary Outcome(s)

To assess the safety profile including frequency of

patients with GI AEs by severity and overall of 450 mg or 600 mg ceritinib taken daily with a lowfat meal as

compared with that of 750 mg ceritinib taken daily in the

fasted state in patients with metastatic ALKpositive

NSCLCTimepoint: GI AEs, all AEs, vital signs, ECGs and laboratory

abnormalities

To assess the antitumor activity as measured by overall response rate and duration of response based

on Blinded Independent Review Committee. assessment of 450 mg or 600 mg ceritinib taken daily with a lowfat meal as compared with that of 750 mg ceritinib taken daily in the fasted state in treatment naive patients with metastatic ALK positive NSCLC who have had ALKpositive

status determined prospectively at a Novartis central laboratory using the Ventana anti ALK D5F3 IHC test

Ventana IHC

Timepoint: The following endpoints will be evaluated by BIRC per

RECIST v1.1 for treatment-naive patients with ALK positive

NSCLC who have had ALK positive status determined

centrally by Ventana IHC

ï? ORR, defined as the proportion of patients with a best

overall response of complete response CR or partial

response PR

DOR defined as the time from the date of the first

documented CR or PR to the first documented

progression or all cause death

To assess the antitumor activity of ceritinib as measuredby ORR and DOR by Investigator assessment. TTR, DCR and PFS by BIRC and by Investigator assessment in treatmentnaive patients with metastatic ALKpositive NSCLC who have had ALKpositive status determinedcentrally by Ventana IHC following oral dosing of 450 mg or 600 mg ceritinib taken daily with a lowfat meal and750 mg ceritinib taken daily in the fasted stateTimepoint: The endpoints will be evaluated byinvestigator assessment perRECISTfor treatmentnaive patients with metastaticALKpositiveNSCLC. ORR DOR and by investigator and BIRC assessment for treatmentnaive patients with metastatic ALKpositive NSCLC. TTR defined as the time from randomization to first documented response for patients with PR,CR. DCR defined as proportion of patients with best overall response of CR PR SD. PFS defined as time from randomization to progression or death due to any cause

To assess overall survival in treatmentnaive patients with metastatic ALKpositive NSCLC who have had ALKpositive status determined centrally by Ventana IHC following oral dosing of 450 mg or 600 mg ceritinib taken daily with a low-fat meal and 750 mg ceritinib taken daily in the fasted stateTimepoint: OS defined as time from randomization to death due to

any cause, for treatmentnaive patients with metastatic

ALKpositive metastatic NSCLC determined centrally by

Ventana IHC

To assess the single dose PK of 450 mg or 600 mg

ceritinib taken with a low fat meal as compared with that

of 750 mg ceritinib taken in the fasted state in patients

with metastatic ALKpositive NSCLCTimepoint: Plasma concentration of ceritinib and PK parameters,

including but not limited to AUClast, AUC0 24h, Cmax,

Tmax, and Tlast

Secondary ID(s)

CLDK378A2112 Version 02 dated 16-Oct-15

NCT02299505

Source(s) of Monetary Support

Novartis Healthcare Private Limited Trial Monitoring â?? GDO, GDD India Inspire- BKC, 7th floor, G Block, BKC Main Road Bandra Kurla Complex Bandra (East) Mumbai-400051, Maharashtra

Ethics review

Status: Approved
Approval date: 22/04/2016
Contact:

Institutional Ethics Commitee

Status: Approved
Approval date: 08/09/2016
Contact:

Institutional Review Board RGCI

Status: Approved
Approval date: 16/09/2016
Contact:

Institutional Ethics Committee,Saroj Gupta Cancer Centre & Research Institute

Status: Approved
Approval date: 06/12/2016
Contact:

HCG Triesta Institutional Ethics Committee

Status: Approved
Approval date: 23/02/2017
Contact:

Institutional Ethics Committee, Basavatarakam Indo American Cancer Hospital and research institute

Results

• Date Completed: 19/06/2019