Locally Advanced Metastatic BRAF Mutant Melanoma
Conditions
Keywords
Open-label dose escalation, BRAF inhibitor, LEE011, CDK4/6, LGX818, RAF kinase inhibitor, Metastatic melanoma, BRAF, V600
Brief summary
To evaluate the safety, tolerability and efficacy of LEE011 and LGX818 when administered orally to patients with BRAF mutant melanoma.
Detailed description
In response to developments in the treatment of melanoma, the sponsor reviewed the data from the ongoing study and decided to halt further enrollment of patients in the Phase Ib part of the study. Consequently, the Phase II part of the study was not performed. Early termination of the study was not due to any safety concerns.
Interventions
DRUGLEE011
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
DRUGLGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
Sponsors
Array BioPharma
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Cycle 1 (approximately 28 days) | Dose Limiting Toxicities (DLTs) during the first 28 days of the combination treatment of LEE011 and LGX818. Due to the halt of enrollment, no Maximum Tolerated Dose (MTD) was formally declared during the study. |
| Phase II - Progression Free Survival (PFS) | Approximately 23 months after enrollment | 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. Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed. |
| Phase II - Objective Response Rate (ORR) | Approximately 23 months after enrollment | As per RECIST v1.1, ORR is defined as the proportion of patients with a best overall response of complete response or partial response. Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib/II - Overall Response Rate (ORR) | Approximately 23 months after enrollment | ORR is defined as the proportion of patients with a best overall response of complete response or partial response. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed. |
| Phase Ib/II - Progression Free Survival (PFS) | Approximately 23 months after enrollment | 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. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed. |
| Phase Ib/II - Duration Of Response (DOR) | Approximately 23 months after enrollment | 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. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed. |
| Phase II - Overall Survival (OS) | Approximately 23 months after enrollment | 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. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed. |
| Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE). | Approximately 23 months after enrollment | — |
| Phase Ib/II - Pharmacokinetic Parameters: Cmin | 28-day cycles | Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. |
| Phase Ib/II - Pharmacokinetic Parameters: Cmax | 28-day cycles | Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. |
| Phase Ib/II - Pharmacokinetic Parameters: Tmax | 28-day cycles | Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. |
| Phase Ib/II - Pharmacokinetic Parameters: Racc | 28-day cycles | Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. |
| Phase Ib/II - Pharmacokinetic Parameters: AUCtau | 28-day cycles | Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. |
| Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE). | Approximately 23 months after enrollment | — |
| Phase Ib/II - Plasma Concentration-time Profiles | 28-day cycles | Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to plasma concentration time profiles were not performed. |
Countries
Australia, Canada, Netherlands, United States
Participant flow
Recruitment details
Recruitment to CLEE011X2105 began on 10-July-2013. The study concluded on 13-April-2015. Participant Flow data is comprised of the Full Analysis Set (FAS), which is all patients who received at least one dose of LGX818 or LEE011. Not completed subjects represents subjects that stopped treatment early, due to the corresponding reason.
Pre-assignment details
In response to developments in the treatment of melanoma, the sponsor reviewed the data from the ongoing study and decided to halt further enrollment of patients in the Phase Ib part of the study. Consequently, the Phase II part of the study was not performed. Early termination of the study was not due to any safety concerns.
Participants by arm
| Arm | Count |
|---|---|
| Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) Ribociclib (LEE011) was provided in capsule form for oral use and was to be taken orally, once a day for 21 consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment.
Encorafenib (LGX818) was to be provided in capsule form for oral use and taken orally, once a day for 28 consecutive days as part of each 28-day cycle of treatment. | 6 |
| Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort) Ribociclib (LEE011) was provided in capsule form for oral use and was to be taken orally, once a day for 21 consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment.
Encorafenib (LGX818) was to be provided in capsule form for oral use and taken orally, once a day for 28 consecutive days as part of each 28-day cycle of treatment. | 12 |
| Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) Ribociclib (LEE011) was provided in capsule form for oral use and was to be taken orally, once a day for 21 consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment.
Encorafenib (LGX818) was to be provided in capsule form for oral use and taken orally, once a day for 28 consecutive days as part of each 28-day cycle of treatment. | 6 |
| Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) Ribociclib (LEE011) was provided in capsule form for oral use and was to be taken orally, once a day for 21 consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment.
Encorafenib (LGX818) was to be provided in capsule form for oral use and taken orally, once a day for 28 consecutive days as part of each 28-day cycle of treatment. | 4 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 | 0 | 0 |
| Overall Study | Disease Progression | 4 | 8 | 6 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) | Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort) | Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) | Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 2 Participants | 2 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 10 Participants | 4 Participants | 2 Participants | 18 Participants |
| Age, Continuous | 65.0 years STANDARD_DEVIATION 10.71 | 49.8 years STANDARD_DEVIATION 13.66 | 58.0 years STANDARD_DEVIATION 10.55 | 62.0 years STANDARD_DEVIATION 17.63 | 56.6 years STANDARD_DEVIATION 13.9 |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 1 Participants | 0 Participants | 11 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 5 Participants | 4 Participants | 17 Participants |
| Weight | 84.60 kilograms STANDARD_DEVIATION 12.793 | 78.08 kilograms STANDARD_DEVIATION 17.069 | 80.17 kilograms STANDARD_DEVIATION 10.308 | 74.70 kilograms STANDARD_DEVIATION 16.415 | 79.44 kilograms STANDARD_DEVIATION 14.45 |
| WHO/ECOG performance status 0 | 2 participants | 4 participants | 1 participants | 1 participants | 8 participants |
| WHO/ECOG performance status 1 | 4 participants | 7 participants | 5 participants | 3 participants | 19 participants |
| WHO/ECOG performance status 2 | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 12 / 12 | 6 / 6 | 4 / 4 |
| serious Total, serious adverse events | 3 / 6 | 5 / 12 | 3 / 6 | 1 / 4 |
Outcome results
Primary
Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1
Dose Limiting Toxicities (DLTs) during the first 28 days of the combination treatment of LEE011 and LGX818. Due to the halt of enrollment, no Maximum Tolerated Dose (MTD) was formally declared during the study.
Time frame: Cycle 1 (approximately 28 days)
Population: Analysis group is comprised of the Safety Set (SS), which includes all patients who received at least one dose of LEE011 or LGX818, and have at least one valid post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Myalagia | 1 participants with DLTs |
| Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Elevated Bilirubin | 1 participants with DLTs |
| Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Neuralgia | 0 participants with DLTs |
| Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Maculopapular Rash | 0 participants with DLTs |
| Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Elevated Bilirubin | 0 participants with DLTs |
| Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Neuralgia | 0 participants with DLTs |
| Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Maculopapular Rash | 0 participants with DLTs |
| Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Myalagia | 0 participants with DLTs |
| Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Neuralgia | 1 participants with DLTs |
| Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Elevated Bilirubin | 0 participants with DLTs |
| Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Maculopapular Rash | 0 participants with DLTs |
| Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Myalagia | 0 participants with DLTs |
| Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Maculopapular Rash | 1 participants with DLTs |
| Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Elevated Bilirubin | 0 participants with DLTs |
| Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Myalagia | 0 participants with DLTs |
| Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) | Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 | Neuralgia | 0 participants with DLTs |
Primary
Phase II - Objective Response Rate (ORR)
As per RECIST v1.1, ORR is defined as the proportion of patients with a best overall response of complete response or partial response. Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed.
Time frame: Approximately 23 months after enrollment
Population: This analysis set would have been the Full Analysis (FAS), which included all patients who received at least one dose of encorafenib or ribociclib.
Primary
Phase II - Progression Free Survival (PFS)
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. Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed.
Time frame: Approximately 23 months after enrollment
Population: This analysis set would have been the Full Analysis (FAS), which included all patients who received at least one dose of encorafenib or ribociclib.
Secondary
Phase Ib/II - Duration Of Response (DOR)
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. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.
Time frame: Approximately 23 months after enrollment
Population: This analysis set would have been the Full Analysis (FAS), which included all patients who received at least one dose of encorafenib or ribociclib.
Secondary
Phase Ib/II - Overall Response Rate (ORR)
ORR is defined as the proportion of patients with a best overall response of complete response or partial response. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.
Time frame: Approximately 23 months after enrollment
Population: This analysis set would have been the Full Analysis (FAS), which included all patients who received at least one dose of encorafenib or ribociclib.
Secondary
Phase Ib/II - Pharmacokinetic Parameters: AUCtau
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time frame: 28-day cycles
Population: This analysis group would have been the PK analysis set (PAS), which would have consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
Secondary
Phase Ib/II - Pharmacokinetic Parameters: Cmax
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time frame: 28-day cycles
Population: This analysis group would have been the PK analysis set (PAS), which would have consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
Secondary
Phase Ib/II - Pharmacokinetic Parameters: Cmin
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time frame: 28-day cycles
Population: This analysis group would have been the PK analysis set (PAS), which would have consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
Secondary
Phase Ib/II - Pharmacokinetic Parameters: Racc
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time frame: 28-day cycles
Population: This analysis group would have been the PK analysis set (PAS), which would have consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
Secondary
Phase Ib/II - Pharmacokinetic Parameters: Tmax
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time frame: 28-day cycles
Population: This analysis group would have been the PK analysis set (PAS), which would have consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
Secondary
Phase Ib/II - Plasma Concentration-time Profiles
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to plasma concentration time profiles were not performed.
Time frame: 28-day cycles
Population: This analysis group would have been the PK analysis set (PAS), which would have consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
Secondary
Phase Ib/II - Progression Free Survival (PFS)
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. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.
Time frame: Approximately 23 months after enrollment
Population: This analysis set would have been the Full Analysis (FAS), which included all patients who received at least one dose of encorafenib or ribociclib.
Secondary
Phase II - Overall Survival (OS)
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. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.
Time frame: Approximately 23 months after enrollment
Population: This analysis set would have been the Full Analysis (FAS), which included all patients who received at least one dose of encorafenib or ribociclib.
Secondary
Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE).
Time frame: Approximately 23 months after enrollment
Population: Analysis group is comprised of the Safety Set (SS), which includes all patients who received at least one dose of LEE011 or LGX818, and have at least one valid post-baseline safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) | Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE). | 6 participants |
| Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort) | Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE). | 12 participants |
| Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) | Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE). | 6 participants |
| Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) | Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE). | 4 participants |
Secondary
Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE).
Time frame: Approximately 23 months after enrollment
Population: Analysis group is comprised of the Safety Set (SS), which is all patients who received at least one dose of LEE011 or LGX818, and have at least one valid post-baseline safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) | Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE). | 3 participants |
| Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort) | Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE). | 5 participants |
| Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) | Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE). | 3 participants |
| Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) | Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE). | 1 participants |