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Study of Safety and Efficacy of LEE011 and Ceritinib in Patients With ALK-positive Non-small Cell Lung Cancer.

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ClinicalTrials.gov Identifier: NCT02292550
Recruitment Status : Completed
First Posted : November 17, 2014
Last Update Posted : July 26, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:

This was a Phase Ib/II study of the ALK inhibitor ceritinib in combination with the CDK4/6 inhibitor LEE011 in patients with ALK-positive non-small cell lung cancer.

The purpose of the study was to determine the MTD/RP2D of the LEE011 and ceritinib combination and evaluate whether the combination was safe and had beneficial effects in ALK-positive advanced non-small cell lung cancer patients.

This trial did not progress to Phase II. Trial population terminated before reaching Phase II


Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Drug: Ribociclib Drug: Ceritinib Phase 1

Detailed Description:
In Sep-2016, Novartis made a decision not to move into phase ll after the primary objective for this study was met. Because the study never made it to phase ll, the study phase has been changed from a phase l/ll to a phase l.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This was a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the maximum tolerated doses (MTD(s))
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of the ALK Inhibitor Ceritinib in Combination With the CDK4/6 Inhibitor LEE011 in Patients With ALK-positive Non-Small Cell Lung Cancer
Actual Study Start Date : May 14, 2015
Actual Primary Completion Date : September 26, 2018
Actual Study Completion Date : September 26, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Ribociclib 100 mg + Ceritinib 300 mg
LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use
Drug: Ribociclib
CDK 4/6 inhibitor
Other Name: LEE011

Drug: Ceritinib
ALK inhibitor
Other Name: LDK378, Zykadia

Experimental: Ribociclib 100 mg + Ceritinib 450 mg
LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use
Drug: Ribociclib
CDK 4/6 inhibitor
Other Name: LEE011

Drug: Ceritinib
ALK inhibitor
Other Name: LDK378, Zykadia

Experimental: Ribociclib 200 mg + Ceritinib 300 mg
LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use
Drug: Ribociclib
CDK 4/6 inhibitor
Other Name: LEE011

Drug: Ceritinib
ALK inhibitor
Other Name: LDK378, Zykadia

Experimental: Ribociclib 200 mg + Ceritinib 450 mg
LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use
Drug: Ribociclib
CDK 4/6 inhibitor
Other Name: LEE011

Drug: Ceritinib
ALK inhibitor
Other Name: LDK378, Zykadia

Experimental: Ribociclib 300 mg + Ceritinib 450 mg
LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use
Drug: Ribociclib
CDK 4/6 inhibitor
Other Name: LEE011

Drug: Ceritinib
ALK inhibitor
Other Name: LDK378, Zykadia




Primary Outcome Measures :
  1. Incidence rate of dose limiting toxicities (DLTs) during the first cycle of treatment (Phase Ib ) [ Time Frame: 1 month ]

    Maximum Tolerated Dose(s) (MTD(s)) and/or recommended phase 2 dose (RP2D(s)) and schedule of LEE011 in combination with ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients.

    Cycle = 28 days


  2. Overall Response Rate (ORR) as per RECIST v1.1 [ Time Frame: Up to 24 months ]
    Preliminary anti-tumor activity of the LEE011 and ceritinib combination

  3. Exposure to LEE011 and ceritinib (Phase Ib ) [ Time Frame: Up to 6 months ]
    Measurement of pharmacokinetics (PK) parameters (AUC0-24h at C1D15)


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) - Phase Ib & II [ Time Frame: Up to 24 months ]
    Preliminary measure of anti-tumor activity of LEE011 and ceritinib combination

  2. Frequency of adverse events/serious adverse events [ Time Frame: Up to 24 months ]
    Characterization of the safety and tolerability of the LEE011 and ceritinib combination as determined by changes in laboratory values and electrocardiograms

  3. PK parameters of LEE011 and ceritinib [ Time Frame: Up to 6 months ]
    Characterization of the PK of LEE011 and ceritinib

  4. Frequency of dose interruptions and dose reductions (phase lb & ll) [ Time Frame: Up to 24 months ]
    Characterization of tolerability

  5. Progression free survival (PFS) per RECIST v1.1 - Phase Ib & II [ Time Frame: Up to 24 months ]
    Preliminary measures of anti-tumor activity of LEE011 and ceritinib combination

  6. Duration of response (DOR) [ Time Frame: Up to 24 months ]
    Preliminary measure of anti-tumor activity of LEE011 and ceritinib combination

  7. Time to response (TTR) - Phase Ib & II [ Time Frame: Up to 24 months ]
    Preliminary measures of anti-tumor activity of LEE011 and ceritinib combination

  8. Disease Control Rate (DCR) - Phase Ib & II [ Time Frame: Up to 24 months ]
    Preliminary measures of anti-tumor activity of LEE011 and ceritinib combination

  9. Overall survival (OS) - Phase Ib & II [ Time Frame: Up to 24 months ]
    Preliminary measures of anti-tumor activity of LEE011 and ceritinib combination

  10. Severity of adverse events/serious adverse events [ Time Frame: Up to 24 months ]
    Characterization of the safety and tolerability of the LEE011 and ceritinib combination as determined by changes in laboratory values and electrocardiograms.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be diagnosed with ALK-positive advanced NSCLC. The tumor must be ALK-positive as determined by ALK rearrangement in ≥15% of cells (as measured by FISH using the Vysis break-apart ALK probe) or by using the Ventana ALK IHC test. The analysis may be performed locally.
  • Eastern cooperative oncology group (ECOG) performance status ≤ 2.
  • Measurable disease as per RECIST v1.1
  • Availability of tumor sample:

For ALK inhibitor naïve patients:

o A representative tumor sample must be submitted. An archival tumor specimen is acceptable

For patients after progression on an ALK inhibitor:

o A new tumor biopsy is required unless a biopsy performed after progression on the patient's most recent ALK inhibitor is available for submission For all patients a newly obtained tumor specimen must be submitted if no appropriate archival sample is available. In the event that no sample is available and a new biopsy cannot be obtained, enrollment may be considered after discussion with the sponsor.

Exclusion Criteria:

  • For Phase I part:

    o Patients who have not previously received at least one line of therapy for ALK-positive NSCLC

  • For Phase II part:

    • Group A: prior therapy with any ALK inhibitor is not permitted.
    • Group B: progression following any ALK inhibitor(s) other than ceritinib is required and the last dose of the ALK inhibitor must be no more than 60 days prior to the first dose of study drug. Prior ceritinib is not permitted.
    • Group C: progression following ceritinib is required and the last dose of ceritinib must be no more than 60 days prior to the first dose of study drug.
  • Patients who have previously been unable to tolerate ceritinib, in the opinion of the investigator. Exceptions to this exclusion include nausea, vomiting and diarrhea in patients taking ceritinib under fasted conditions.
  • Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of steroids or local CNS-directed therapy to control their CNS disease
  • Patients with abnormal laboratory values during screening and on day 1 of pre-dose
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ceritinib or LEE011
  • Patients who are currently receiving treatment (that cannot be discontinued at least 1 week prior to the initiation of the study) with agents that are known to be any of the following: strong inducers or inhibitors of CYP3A4/5; sensitive substrates of CYP3A; substrates of CYP3A4/5 or CYP2C9 with a narrow therapeutic index.
  • Patient has a history of pancreatitis or history of increased amylase or lipase that was due to pancreatic disease.
  • Patient with impaired cardiac function or any clinically significant uncontrolled cardiac disease, and/or, cardiac repolarization abnormality, including any of the following:

Clinically significant heart disease such as CHF requiring treatment (NYH grade ≥ 2), history of angina pectoris, myocardial infarction, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry, documented cardiomyopathy, or left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO).

Uncontrolled systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is allowed prior to screening, Systolic blood pressure (SBP) <90 mmHg Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by central laboratory

  • QTcF interval at screening >450 msec (using Fridericia's correction)
  • Resting heart rate <50 bpm or > 90 bpm

Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

  • Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
  • Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study drug)
  • Inability to determine the QTcF interval Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).

Other protocol-defined inclusion/exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02292550


Locations
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United States, Massachusetts
Novartis Investigative Site
Boston, Massachusetts, United States, 02114
France
Novartis Investigative Site
Marseille cedex 05, France, 13385
Italy
Novartis Investigative Site
Bologna, BO, Italy, 40138
Novartis Investigative Site
Rozzano, MI, Italy, 20089
Korea, Republic of
Novartis Investigative Site
Seoul, Seocho Gu, Korea, Republic of, 06591
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Taiwan
Novartis Investigative Site
Tainan, Taiwan ROC, Taiwan, 70403
Novartis Investigative Site
Taipei, Taiwan, 10002
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02292550     History of Changes
Other Study ID Numbers: CLEE011X2110C
First Posted: November 17, 2014    Key Record Dates
Last Update Posted: July 26, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Non-small cell lung cancer
ALK translocation
ALK-positive
NSCLC
LEE011
CDK4/6 inhibitor
EML4-ALK
cancer
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Ceritinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action