Safety and Efficacy of LEE011 and LGX818 in Patients With BRAF Mutant Melanoma.
This study is not yet open for participant recruitment.
Verified January 2013 by Novartis
Sponsor:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01777776
First received: January 22, 2013
Last updated: January 28, 2013
Last verified: January 2013
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Purpose
To evaluate the safety, tolerability and efficacy of LEE011 and LGX818 when administered orally to patients with BRAF mutant melanoma.
| Condition | Intervention | Phase |
|---|---|---|
|
Locally Advanced or Metastatic BRAF Mutant Melanoma |
Drug: LEE011 Drug: LGX818 |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase Ib/II, Mulicenter, Study of LEE011 in Combination With LGX818 in Adult Patients With BRAF Mutant Melanoma. |
Resource links provided by NLM:
Further study details as provided by Novartis:
Primary Outcome Measures:
- Incidence of Dose Limiting Toxicities (Phase Ib) [ Time Frame: Cycle 1 = 28 days ] [ Designated as safety issue: Yes ]Dose Limiting Toxicities (DLTs) during the first 28 days of the combination treatment of LEE011 and LGX818.
- Progression Free Survival (PFS) - Phase II Arms 1 a/b [ Time Frame: 23 months after FPFV ] [ Designated as safety issue: No ]As per RECIST v1.1. PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.
- Objective Response Rate (ORR) - Phase II Arm 2 [ Time Frame: 23 months after FPFV ] [ Designated as safety issue: No ]As per RECIST v1.1. ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
Secondary Outcome Measures:
- Number of Adverse Events - Phase Ib/II [ Time Frame: Approximately 23 months after FPF ] [ Designated as safety issue: Yes ]To assess the safety and tolerability of LEE011 and LGX818 in these patients which includes changes in hematology and chemistry values, vital signs and elctrocardiograms (ECG's) assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
- Number of Serious Adverse Events - Phase Ib/II [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: Yes ]To assess the safety and tolerability of LEE011 and LGX818 in patients which includes changes in hematology and chemistry values, vital signs and electrocardiograms (ECGs) assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
- Plasma concentration-time profiles - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).
- Overall Response Rate (ORR) - Phase Ib and Phase II arms 1a/b [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: No ]ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
- Progression Free Survival (PFS) - Phase Ib and Phase II Arm 2 [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: No ]PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.
- Duration Of Response (DOR) - Phase Ib, Phase II arms 1a/1b/2 [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: No ]DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer.
- Overall Survival (OS) - Phase II arms 1a/1b/2 [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: No ]OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.
- Plasma concentration-time profiles: AUCtau - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).
- Plasma concentration-time profiles: Cmin - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).
- Plasma concentration-time profiles: Cmax - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).
- Plasma concentration-time profiles: Tmax - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).
- Plasma concentration-time profiles: Racc - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).
| Estimated Enrollment: | 150 |
| Study Start Date: | May 2013 |
| Estimated Study Completion Date: | December 2015 |
| Estimated Primary Completion Date: | December 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Phase Ib
Pahse Ib will randomize 18 patients with BRAF mutant melanoma, who are naive or who have progressed on prior therapy tyo evaluate the safety and tolerability of the combination of LEE011 and LGX818.
|
Drug: LEE011
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
|
|
Experimental: Phase II arm 1a
Phase II arm 1a will randomize 60 patients that are naïve to prior BRAF inhibitor therapy to LGX818+LEE011 to evaluate the effect of adding LEE011 to a BRAFi in this population.
|
Drug: LEE011
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
|
|
Experimental: Phase II arm 1b
Phase II arm 1b will randomize 30 patients to LGX818. Single agent anti-tumor activity of LGX818 is comparable to other BRAFi that are either approved or in clinical trials. This single agent anti-tumor activity will be compared to that of the combination (LEE011 + LGX818) in the BRAFi naïve patient population.
|
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
|
|
Experimental: Phase II arm 2
Phase II arm 2 will evaluate a single arm LEE011+LGX818 in 40 patients resistant to prior BRAF inhibitor therapy. Single agent LGX818 has shown limited activity in patients with melanoma who have failed prior BRAF inhibitor treatment; the contribution of LEE011 in this combination will be evaluated.
|
Drug: LEE011
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
|
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Criteria
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.
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 gastro-intestinal (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 C.
Other protocol-defined inclusion/exclusion criteria may apply.
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01777776
Contacts
| Contact: Novartis Pharmaceuticals | 1-888-669-6682 | |
| Contact: Novartis Pharmaceuticals |
Locations
| United States, California | |
| University of California San Diego Dept of Onc | Not yet recruiting |
| La Jolla, California, United States, 92093-0658 | |
| Contact: Guia Rodriguez 858-822-4171 G1rodriguez@ucsd.edu | |
| Principal Investigator: Gregory Daniels | |
| University of California at Los Angeles UCLA 3 | Not yet recruiting |
| Los Angeles, California, United States, 90095 | |
| Contact: Christy Palodichuk 310-794-6913 cpalodichuk@mednet.ucla.edu | |
| Principal Investigator: Bartosz Chmielowski | |
| United States, Colorado | |
| University of Colorado Dept of Oncology | Not yet recruiting |
| Aurora, Colorado, United States, 80045 | |
| Contact: Laurie Draheim 720-848-0632 Laurie.draheim@ucdenver.edu | |
| Principal Investigator: Rene Gonzalez | |
| United States, Connecticut | |
| Yale University School of Medicine dept of Onc | Not yet recruiting |
| New Haven, Connecticut, United States, 06520 | |
| Contact: Geraldine Tomassi 203-737-5381 Geraldine.tomassi@yale.edu | |
| Principal Investigator: Harriet Kluger | |
| United States, Florida | |
| Cancer Centers of Florida PA Cancer Centers of South Florid | Not yet recruiting |
| Ocoee, Florida, United States, *see dep* | |
| Contact: Donna McCallie 561-253-3979 dmccallie@cancersf.com | |
| Principal Investigator: Abraham Schwarzberg | |
| United States, Illinois | |
| Northwestern University Clinical Research Office (2) | Not yet recruiting |
| Chicago, Illinois, United States, 60611 | |
| Contact: Anne McDermott 312-695-1005 a-mcdermott@northwestern.edu | |
| Principal Investigator: Timothy Kunzel | |
| United States, New Hampshire | |
| Dartmouth Hitchcock Medical Center Dept Onc | Not yet recruiting |
| Lebanon, New Hampshire, United States, 03756 | |
| Contact: Eryn Bagley 603-650-4035 Eryn.M.Bagley@hitchcock.org | |
| Principal Investigator: Marc S. Ernstoff | |
| United States, New York | |
| Memorial Sloan Kettering Cancer Center Dept Oncology | Not yet recruiting |
| New York, New York, United States, 10021 | |
| Contact: Natasha Martin 646-888-4339 martinn@mskcc.org | |
| Principal Investigator: Gary K. Schwartz | |
| United States, North Carolina | |
| Duke University Medical Center SC-6 | Not yet recruiting |
| Durham, North Carolina, United States, 27710 | |
| Contact: Kristen Linney 919-684-8239 k.linney@duke.edu | |
| Principal Investigator: April Salama | |
| United States, Ohio | |
| Ohio State Comprehensive Cancer Center/James Cancer Hospital Ohio State University | Not yet recruiting |
| Columbus, Ohio, United States, 43210 | |
| Contact: Caitlin Spontelli 614-293-2268 caitlin.spontelli@osumc.edu | |
| Principal Investigator: Kari Kendra | |
| United States, Oregon | |
| Oregon Health & Science University Dept. of OHSU (3) | Not yet recruiting |
| Portland, Oregon, United States, 97239 | |
| Contact: Alisa Claeys 503-346-0792 claeys@ohsu.edu | |
| Principal Investigator: Matthew Taylor | |
| United States, South Carolina | |
| Cancer Centers of the Carolinas CCC Faris | Not yet recruiting |
| Greenville, South Carolina, United States, 29605 | |
| Contact: Jill Cantrell 864-455-3735 jcantrell@ghs.org | |
| Principal Investigator: Joe J. Stephenson, Jr. | |
| United States, Washington | |
| Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Dept of Oncology | Not yet recruiting |
| Seattle, Washington, United States, 98109-1023 | |
| Contact: Daniel Leatham 206-288-7370 dleatham@u.washington.edu | |
| Principal Investigator: Kim Margolin | |
| France | |
| Novartis Investigative Site | Not yet recruiting |
| Lyon Cedex, France, 69373 | |
| Novartis Investigative Site | Not yet recruiting |
| Villejuif Cedex, France, 94805 | |
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
More Information
No publications provided
| Responsible Party: | Novartis ( Novartis Pharmaceuticals ) |
| ClinicalTrials.gov Identifier: | NCT01777776 History of Changes |
| Other Study ID Numbers: | CLEE011X2105 |
| Study First Received: | January 22, 2013 |
| Last Updated: | January 28, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Novartis:
|
Open-label dose escalation; BRAF inhibitor; LEE011; CDK4/6; LGX818; RAF kinase inhibitor; metastatic melanoma; BRAF; V600 |
Additional relevant MeSH terms:
|
Melanoma Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal |
Neoplasms by Histologic Type Neoplasms Neoplasms, Nerve Tissue Nevi and Melanomas |
ClinicalTrials.gov processed this record on May 22, 2013