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

Study Overview
=================
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

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.

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

Conditions
-----------------
Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Ribociclib
* Drug: Ceritinib


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ribociclib 100 mg + Ceritinib 300 mg<br>LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use | Drug: Ribociclib<br>* CDK 4/6 inhibitor<br>* Other names: LEE011;Drug: Ceritinib<br>* ALK inhibitor<br>* Other names: LDK378, Zykadia;|
| Experimental: Ribociclib 100 mg + Ceritinib 450 mg<br>LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use | Drug: Ribociclib<br>* CDK 4/6 inhibitor<br>* Other names: LEE011;Drug: Ceritinib<br>* ALK inhibitor<br>* Other names: LDK378, Zykadia;|
| Experimental: Ribociclib 200 mg + Ceritinib 300 mg<br>LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use | Drug: Ribociclib<br>* CDK 4/6 inhibitor<br>* Other names: LEE011;Drug: Ceritinib<br>* ALK inhibitor<br>* Other names: LDK378, Zykadia;|
| Experimental: Ribociclib 200 mg + Ceritinib 450 mg<br>LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use | Drug: Ribociclib<br>* CDK 4/6 inhibitor<br>* Other names: LEE011;Drug: Ceritinib<br>* ALK inhibitor<br>* Other names: LDK378, Zykadia;|
| Experimental: Ribociclib 300 mg + Ceritinib 450 mg<br>LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use | Drug: Ribociclib<br>* CDK 4/6 inhibitor<br>* Other names: LEE011;Drug: Ceritinib<br>* ALK inhibitor<br>* Other names: LDK378, Zykadia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of dose limiting toxicities (DLTs) during the first cycle of treatment (Phase Ib ) | 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 | 1 month | 
| Overall Response Rate (ORR) as per RECIST v1.1 | Preliminary anti-tumor activity of the LEE011 and ceritinib combination | Up to 24 months | 
| Exposure to LEE011 and ceritinib (Phase Ib ) | Measurement of pharmacokinetics (PK) parameters (AUC0-24h at C1D15) | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) - Phase Ib & II | Preliminary measure of anti-tumor activity of LEE011 and ceritinib combination | Up to 24 months | 
| Frequency of adverse events/serious adverse events | Characterization of the safety and tolerability of the LEE011 and ceritinib combination as determined by changes in laboratory values and electrocardiograms | Up to 24 months | 
| PK parameters of LEE011 and ceritinib | Characterization of the PK of LEE011 and ceritinib | Up to 6 months | 
| Frequency of dose interruptions and dose reductions (phase lb & ll) | Characterization of tolerability | Up to 24 months | 
| Progression free survival (PFS) per RECIST v1.1 - Phase Ib & II | Preliminary measures of anti-tumor activity of LEE011 and ceritinib combination | Up to 24 months | 
| Duration of response (DOR) | Preliminary measure of anti-tumor activity of LEE011 and ceritinib combination | Up to 24 months | 
| Time to response (TTR) - Phase Ib & II | Preliminary measures of anti-tumor activity of LEE011 and ceritinib combination | Up to 24 months | 
| Disease Control Rate (DCR) - Phase Ib & II | Preliminary measures of anti-tumor activity of LEE011 and ceritinib combination | Up to 24 months | 
| Overall survival (OS) - Phase Ib & II | Preliminary measures of anti-tumor activity of LEE011 and ceritinib combination | Up to 24 months | 
| Severity of adverse events/serious adverse events | Characterization of the safety and tolerability of the LEE011 and ceritinib combination as determined by changes in laboratory values and electrocardiograms. | Up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-small cell lung cancer, ALK translocation, ALK-positive, NSCLC, LEE011, CDK4/6 inhibitor, EML4-ALK, cancer