Melanoma
Conditions
Keywords
open-label study, BRAF inhibitor, LGX818, MEK1620, MAPK1/2 inhibitor, Pi3K inhibitor, FGFR, c-Met, CDK4/6, metastatic melanoma, BRAF, V600
Brief summary
The primary purpose of the Phase II CLGX818X2102 study is to assess the anti-tumor activity of LGX818 in combination with selected agents.
Detailed description
This is a phase II two part multi-center, open-label study. Part I: LGX818 single agent treatment until progression Part II: Combination treatments of LGX818 + MEK162, or BKM120, or BGJ398, or INC280, or LEE01 to assess the clinical efficacy, to further evaluate the safety of the drug combinations in patients with locally advanced or metastatic BRAF mutant melanoma after relapse on LGX818, and to determine the maximum tolerated dose of the combinations (when not established previously). These drug combinations are selected and assigned to patients based on documentation of molecular resistance mechanism. Patients with BRAF mutant melanoma treated by LGX818 single agent in other studies can be enrolled directly in Part II of CLGX818X2102 after relapse. Dose-escalations in the combination arms for which no MTD has been established will be based on the recommendations of a Bayesian logistic regression model guided by an escalation with overdose control criterion. After careful evaluation of slow enrollment and the BRAF-mutant melanoma treatment landscape, recruitment was permanently halted on 26-Jul-2014. This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.
Interventions
DRUGLGX818
BRAF inhibitor. LGX818 was administered QD orally on a daily schedule (21-day cycles) as a flat-fixed dose and not by body weight or body surface area. LGX818 100 mg capsules and 50 mg capsules.
Sponsors
Array BioPharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* locally advanced or metastatic melanoma * confirmed BRAF V600 mutation * patients naïve to a selective BRAF inhibitor * fresh tumor biopsy at baseline, and patient agrees for a mandatory biopsy at the time of relapse * life expectancy ≥ 3 months * World Health Organization (WHO) Performance Status ≤ 2.
Exclusion criteria
* Previous treatment with RAF-inhibitor * Symptomatic or untreated leptomeningeal disease * Symptomatic brain metastases. * Known acute or chronic pancreatitis * Clinically significant cardiac disease * AST/SGOT and ALT/SGPT \> 2.5 x ULN, or \> 5 x ULN if liver metastases are present * Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral interventional drug * Previous or concurrent malignancy. * Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Baseline through study completion (approximately 2 years) | Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: * Complete Response (CR) is the Disappearance of all target lesions. * Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. * Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. * Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose Limiting Toxicities (DLTs) (Part II) | Baseline through study completion (approximately 2 years) | Incidence of DLTs in Part II of the study was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. |
| Plasma Concentration and Derived Pharmacokinetic Parameters | Baseline through study completion (approximately 2 years) | Assessment of pharmacokinetic (PK) parameters and plasma concentration was not done due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. |
| Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) | Baseline through completion of Part I of the study (approximately 2 years) | Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: * Complete Response (CR) is the Disappearance of all target lesions. * Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. * Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. * Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
| Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) | Entry to Part II of the study through study completion (approximately 22 days) | Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: * Complete Response (CR) is the Disappearance of all target lesions. * Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. * Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. * Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study. |
| Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways | Baseline and at progression with LGX818 single agent treatment | Molecular status was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. |
Countries
Australia, Canada, Germany, Spain, Switzerland, United States
Participant flow
Recruitment details
The study began on 04-Nov-2013 (First Subject First Visit) to the CLGX818X2102 (LOGIC 1) study. A total of 15 subjects were enrolled. The last subject's last visit occurred on 23-Mar-2015. Not completed subjects represents subjects that stopped treatment early, due to the corresponding reason.
Pre-assignment details
After careful evaluation of slow enrollment and the BRAF-mutant melanoma treatment landscape, recruitment was permanently halted on 26-Jul-2014. This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.
Participants by arm
| Arm | Count |
|---|---|
| Part I: LGX818 - Single Agent Subjects in Part I of the study received LGX818 as a single agent. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part II: LGX818 + MEK162 | Study Termination | 0 | 1 |
| Part I: LGX818 | Administrative Problems | 3 | 0 |
| Part I: LGX818 | Adverse Event | 6 | 0 |
| Part I: LGX818 | Death | 1 | 0 |
| Part I: LGX818 | Disease Progression | 4 | 0 |
Baseline characteristics
| Characteristic | Part I: LGX818 - Single Agent |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 52.3 years STANDARD_DEVIATION 16.53 |
| Gender Female | 7 Participants |
| Gender Male | 8 Participants |
| Height | 171.8 centimeters STANDARD_DEVIATION 9.51 |
| Region of Enrollment Australia | 3 participants |
| Region of Enrollment Germany | 1 participants |
| Region of Enrollment Spain | 3 participants |
| Region of Enrollment Switzerland | 6 participants |
| Region of Enrollment United States | 2 participants |
| Weight | 80.3 kilograms STANDARD_DEVIATION 19.11 |
| WHO/ ECOG performance status 0 | 14 participants |
| WHO/ ECOG performance status 1 | 1 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 3 / 15 |
Outcome results
Primary
Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II)
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: * Complete Response (CR) is the Disappearance of all target lesions. * Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. * Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. * Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Baseline through study completion (approximately 2 years)
Population: This analysis is comprised of the Full Analysis Set, which consists of all patients who received at least one dose of LGX818.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Partial Response | 8 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Stable Disease | 2 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Progressive Disease | 1 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Unknown | 3 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Complete Response | 1 participants |
| Part II: CLGX818 + MEK162 | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Unknown | 0 participants |
| Part II: CLGX818 + MEK162 | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Complete Response | 0 participants |
| Part II: CLGX818 + MEK162 | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Partial Response | 0 participants |
| Part II: CLGX818 + MEK162 | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Progressive Disease | 1 participants |
| Part II: CLGX818 + MEK162 | Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Stable Disease | 0 participants |
Secondary
Incidence of Dose Limiting Toxicities (DLTs) (Part II)
Incidence of DLTs in Part II of the study was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time frame: Baseline through study completion (approximately 2 years)
Secondary
Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways
Molecular status was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time frame: Baseline and at progression with LGX818 single agent treatment
Secondary
Plasma Concentration and Derived Pharmacokinetic Parameters
Assessment of pharmacokinetic (PK) parameters and plasma concentration was not done due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time frame: Baseline through study completion (approximately 2 years)
Secondary
Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I)
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: * Complete Response (CR) is the Disappearance of all target lesions. * Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. * Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. * Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Baseline through completion of Part I of the study (approximately 2 years)
Population: This analysis is comprised of the Full Analysis Set, which consists of all patients who received at least one dose of LGX818.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) | Complete Response | 1 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) | Partial Response | 8 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) | Progressive Disease | 1 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) | Stable Disease | 2 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) | Unknown | 3 participants |
Secondary
Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II)
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: * Complete Response (CR) is the Disappearance of all target lesions. * Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. * Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. * Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study.
Time frame: Entry to Part II of the study through study completion (approximately 22 days)
Population: This analysis group is comprised of the Full Analysis Set, which consists of all patients who received at least one dose of LGX818.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) | Complete Response | 0 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) | Partial Response | 0 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) | Progressive Disease | 1 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) | Stable Disease | 0 participants |
| Part I: LGX818 - Single Agent | Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) | Unknown | 0 participants |