| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
•Phase Ib: To estimate the MTD(s) and/or RP2D(s) of LEE011 in combination with ceritinib in ALK-positive NSCLC patients as measured by the incidence of DLTs in Cycle 1 and by exposure to LEE011 and ceritinib as measured by PK parameters
•Phase II: To assess preliminary anti-tumor activity of the LEE011 and ceritinib combination as measured by Overall Response Rate (ORR) as per RECIST v1.1 |
|
| E.2.2 | Secondary objectives of the trial |
•To characterize the safety and tolerability of the LEE011 and ceritinib combination as measured by the frequency and severity of adverse events and serious adverse events, changes in laboratory values, and electrocardiograms, and by the frequency of dose interruptions and dose reductions.
•To characterize the PK profile of LEE011 and ceritinib combination as measured by concentration-time profiles and derived PK parameters.
•To assess additional clinical activity of the LEE011 and ceritinib combination as measured by Progression free survival, duration of response, time to response, disease Control Rate, and overall survival. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Male or female aged ≥ 18 years
•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:
oFor ALK inhibitor naïve patients:
A representative tumor sample must be submitted. An archival tumor specimen is acceptable
oFor patients after progression on an ALK inhibitor:
A new tumor biopsy is required unless a biopsy performed after progression on the patient’s most recent ALK inhibitor is available for submission
oFor 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. |
|
| E.4 | Principal exclusion criteria |
•For dose escalation part:
oPatients who have received prior treatment with ceritinib cannot be enrolled in the escalation part of the study until a combination drug dose with appropriate ceritinib exposure is determined. Prior therapy with other ALK inhibitors is allowed.
•For Phase II part:
oGroup A: prior therapy with any ALK inhibitor is not permitted.
oGroup 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.
oGroup 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 must have tolerated a dose of ceritinib of 600 mg QD, or greater.
•Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of steroids or local CNS-directed therapy (such as radiotherapy, surgery or intrathecal chemotherapy) to control their CNS disease
•Impaired cardiac function or any clinically significant cardiac disease, including any of the following:
oClinically significant heart disease such as CHF requiring treatment (NYH grade ≥ 2), unstable angina pectoris or myocardial infarction within the past 3 months, or left ventricular ejection fraction (LVEF) < 45% or less than the institution lower limit of normal as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO).
oQT corrected with Fridericia’s (QTcF) >450 ms screening ECG or congenital long QT syndrome or family history of unexpected sudden cardiac death.
oAny other clinically significant heart disease such as unstable arrhythmia, resting bradycardia, left bundle branch block, bifascicular block, or any heart disease that requires the use of a cardiac pacemaker ≤ 3 months prior to starting study drug
•Patients with the following laboratory values during screening and on day 1 of pre-dose:
oHematology
-Absolute neutrophil count (ANC) < 1.5 x 109/L
-Platelet count < 100 x 109/L
-Hemoglobin (Hgb) < 9 g/dL
oBiochemistry
-Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min
-Total bilirubin > 1.5 x ULN, except for patients with known Gilbert syndrome, who are excluded if total bilirubin is > 3.0 x ULN or direct bilirubin is > 1.5 x ULN
-Alanine aminotransferase (ALT) > 3 x ULN, except for patients that have tumor involvement of the liver, who must have a value ≤ 5 x ULN
-Aspartate aminotransferase (AST) > 3 x ULN, except for patients that have tumor involvement of the liver, who must have a value ≤ 5 x ULN
-Potassium, magnesium or calcium abnormality > CTCAE grade 1 (despite oral supplementation)
-Phosphate abnormality > CTCAE grade 2 (despite oral supplementation)
•Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ceritinib or LEE011 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
•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:
oStrong inducers or inhibitors of CYP3A4/5
oPrimarily metabolized by CYP3A4/5 or CYP2C9
oSubstrates of CYP3A4/5 or CYP2C9 with a narrow therapeutic index |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib:
1.Incidence rate of DLTs during the first cycle of treatment
2.Exposure to LEE011 and ceritinib as measured by PK parameters (AUC0-24h at C1D15)
Phase II:
3.Overall Response Rate (ORR) as per RECIST v1.1
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. 28 days
2. C1D15
3. 30 months |
|
| E.5.2 | Secondary end point(s) |
Phase Ib
1.Overall Response Rate (ORR)
Phase Ib + II
2.Progression free survival (PFS) per RECIST v1.1
3.Duration of response (DOR)
4.Time to response (TTR)
5.Disease Control Rate (DCR)
6.Overall survival (OS)
7.Safety: Frequency and severity of adverse events and serious adverse events, changes in laboratory values, and electrocardiograms.
8.Tolerability: Frequency of dose interruptions and dose reductions
9.PK parameters of LEE011 and ceritinib
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. end of phase Ib
2. to 9. 30 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Hong Kong |
| Italy |
| Korea, Republic of |
| Netherlands |
| Singapore |
| Spain |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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