E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
locally advanced or metastatic BRAF mutant melanoma |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 determine
the RP2D of oral LEE011 in combination with oral
LGX818 in patients with BRAF mutant melanoma.
Phase II:
Part 1: To assess the anti-tumor activity of LEE011 in
combination with LGX818 vs. LGX818 alone in
patients with metastatic BRAF mutant melanoma who are naïve to prior selective BRAFi treatment
Part 2: To assess the anti-tumor activity of LEE011 in
combination with LGX818 in patients with metastatic
BRAF mutant melanoma who are resistant to prior
selective BRAFi treatment |
|
E.2.2 | Secondary objectives of the trial |
- To characterize the safety and tolerability of LEE011 in combination with LGX818.
- To characterize the PK profiles of LEE011 and LGX818 as well as evaluate any other clinically significant metabolites that may be identified.
- To assess preliminary clinical anti-tumor activity of the LEE011 and LGX818 combination. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >18 years.
- Diagnosis of locally advanced or metastatic melanoma along with written documentation of BRAF V600 mutation.
- ECOG performance status of 0 – 2.
- Patients enrolled into Phase Ib must have evidence of evaluable and/or measurable disease as determined by RECIST v1.1.
- Patients enrolled into Phase II (BRAFi naïve and resistant) must have evidence of measurable
disease as determined by RECIST v1.1.
- Archival tumor tissue must be obtained for patients enrolled in Phase Ib and Phase II arm 1a/b- BRAFi naïve patients. If an archival tumor tissue is
not available, a fresh tumor sample is acceptable.
- For patients enrolled in the phase II arm 2, patients must agree to undergo a fresh tumor biopsy unless one was collected prior to study entry
but at the time of disease relapse from the most recent BRAFi treatment.
Other, protocol related inclusion criteria may apply. |
|
E.4 | Principal exclusion criteria |
- Symptomatic brain metastases.
- Symptomatic or untreated leptomeningeal disease.
- Patients with inadequate laboratory values during screening.
- In the phase II BRAFi naïve arms (1a/b), prior exposure to CDK4/6 inhibitor (e.g., PD 0332991)
- Impaired cardiac function or clinically significant cardiac diseases.
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LEE011 or LGX818.
- Patients with concurrent severe and/or uncontrolled concurrent medical conditions.
- Previous or concurrent malignancy.
- Major surgery < 2 weeks before starting study treatment
- Known diagnosis of human immunodeficiency virus (HIV) or hepatitis
Other protocol-defined exclusion criteria may apply. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Incidence of Dose Limiting Toxicities (Phase Ib)
2. Progression Free Survival (PFS) - Phase II
3. Objective Response Rate (ORR) - Phase II |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. cycle 1 = 28 days
2-3. 23 months after FPFV |
|
E.5.2 | Secondary end point(s) |
1. Number of Adverse Events
2. Number of Serious Adverse Events
3. Plasma concentration-time profiles
4. Overall Response Rate (ORR)
5. Progression Free Survival (PFS)
6. Duration Of Response (DOR)
7. Overall Survival (OS) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2 and 4-7. approx. 23 months
3. 28 days |
|
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 | No |
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 | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Canada |
France |
Italy |
Netherlands |
Argentina |
Australia |
Brazil |
Germany |
Spain |
Taiwan |
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
|
Phase Ib and II of the study will end when the treatment period, safety follow-up, disease follow-up and survival follow-up (only for phase II) have ended for all patients or when the study is terminated early. |
|
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 | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |