A Phase Ib/II Study of AEB071 and MEK162 in Adult Patients With Metastatic Uveal Melanoma

Study Overview
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Brief Summary
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A phase Ib dose-escalation study of the AEB071 and MEK162 combination in adult patients with confirmed metastatic uveal melanoma. Cohorts of 3-6 patients will be assessed for dose limiting toxicities (DLTs) during Cycle 1 until the maximum tolerated dose (MTD) of the combination therapy is determined. The MTD or Phase 2 Recommended Dose (P2RD) will be used in a Phase II part of the study, which will enrol 55 patients each into two randomized groups: the combination therapy or MEK162 alone. The Phase II part will continue until proof of concept is established. Patients will continue treatment as long as clinical benefit is seen and no limiting adverse toxicity is observed

Detailed Description
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Due to halted enrollment, the Phase II part of the study was not conducted. The Sponsor decided to permanently stop recruitment for the study prior to MTD determination. Remaining patients on treatment with binimetinib and sotrastaurin who were considered by the Investigator to be benefiting from their treatment could have continued treatment and were to be followed up as per protocol. No patients were ongoing as of the data cut-off date. After the last patient last visit (LPLV) was declared, the study was terminated.

Official Title
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A Phase Ib/II, Open-label, Multicenter Study of AEB071 and MEK162 in Adult Patients With Metastatic Uveal Melanoma

Conditions
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Uveal Melanoma

Intervention / Treatment
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* Drug: AEB071
* Drug: MEK162


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Male and female patients aged 18 years or older A history of uveal (ocular) melanoma with biopsy-confirmed metastatic disease Consent to providing 3 tumor biopsy samples throughout the course of the study Presence of measurable disease A WHO performance status of less than or equal to 1 Exclusion Criteria: Presence of CNS lesions (stable lesions may be acceptable) Previous or concurrent malignancy, other than basal cell or squamous cell carcinoma of the skin: in situ carcinoma of the cervix, without evidence of recurrence for at least 3 years; a primary malignancy completely resected and no evidence of recurrence for at least 3 years Adverse event from prior chemotherapy, radiotherapy or surgery that has not recovered to CTCAE v4.03 Grade 1 or less, except for alopecia/sensory peripheral neuropathy, which must be less than Grade 2 History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO Impaired cardiac function or clinically significant cardiac disease Impaired GI function or disease that could interfere with the absorption of AEB071 and/or MEK162 Treatment with medicines or herbal supplements that are known inhibitors or inducers of CYP3A4/5 and cannot be withdrawn prior to study treatment Females of child-bearing potential who are unwilling or unable to use highly effective means of contraception Males who are unwilling or unable to use a condom during sexual intercourse Prior exposure to a MEK or PKC inhibitor Other inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>AEB071 and MEK162 combined | Drug: AEB071<br>* Twice-daily doses of AEB071 for a cycle of 28-days, given without interruption (continuous cycles)<br>* Other names: Sotrastaurin;Drug: MEK162<br>* Twice-daily doses of MEK162 for a cycle of 28-days, given without interruption (continuous cycles)<br>|
| Experimental: Arm B<br>MEK162 alone | Drug: MEK162<br>* Twice-daily doses of MEK162 for a cycle of 28-days, given without interruption (continuous cycles)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Incidence of Dose Limiting Toxicities (DLT) During the First Cycle | A DLT is defined as an adverse event or abnormal laboratory value as defined in the protocol that is assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment with AEB071 and MEK162. | Cycle 1 (up to 28 days) | 
| Phase II: Progression Free Survival (PFS) | The time from date of randomization to the date of event defined as the first documented progression or death due to any cause. Due to an enrollment halt, the Phase II part of the study was not conducted. The sponsor decided to permanently stop recruitment for the study prior to MTD determination. | From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib/II: The Number of Subjects Experiencing At Least One Adverse Event (AE) | An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient's signed informed consent has been obtained. | From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) | 
| Phase Ib/II: The Number of Subjects Experiencing At Least One Serious Adverse Event (SAE) | Serious adverse event (SAE) is defined as one of the following: Is fatal or life-threatening Results in persistent or significant disability/incapacity Constitutes a congenital anomaly/birth defect Is medically significant Requires inpatient hospitalization or prolongation of existing hospitalization Note that hospitalizations for the following reasons should not be reported as serious adverse events: Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition Elective or pre-planned treatment for a pre-existing condition that is unrelated to metastatic uveal melanoma and has not worsened since signing the informed consent Social reasons and respite care in the absence of any deterioration in the patient's general condition | From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) | 
| Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Best Overall Response (BOR) | Assessment of the preliminary anti-tumor activity of AEB071 and MEK162 in combination. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. | Cycle 1 (up to 28 days) | 
| Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Duration of Response (DOR) | Assessment of the preliminary anti-tumor activity of AEB071 and MEK162 in combination. Duration of Response (DOR) is not reported, since there were no responses of Complete Response (CR) or Partial Response (PR) at any time during the study. | Cycle 1 (up to 28 days) | 
| Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Progression Free Survival (PFS) | Assessment of the preliminary anti-tumor activity of AEB071 and MEK162 in combination. 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. | Cycle 1 (up to 28 days) | 
| Phase II: Evaluation of Preliminary Anti-tumor Activity - Overall Response Rate (CR+PR) | Evaluation of the preliminary anti-tumor activity at the RP2D for AEB071 and MEK162 and at 45 mg BID for MEK162 alone. Overall response rate (ORR) is the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR). This is also referred to as 'Objective response rate' in some protocols or publications. Due to an enrollment halt, the Phase II part of the study was not conducted. | From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) | 
| Phase II: Evaluation of Preliminary Anti-tumor Activity - Best Overall Response (BOR) | Evaluation of the preliminary anti-tumor activity at the RP2D for AEB071 and MEK162 and at 45 mg BID for MEK162 alone. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for Progressive Disease (PD) the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. Due to an enrollment halt, the Phase II part of the study was not conducted. | From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) | 
| Phase II: Evaluation of Preliminary Anti-tumor Activity - Duration of Response (DOR) | Evaluation of the preliminary anti-tumor activity at the RP2D for AEB071 and MEK162 and at 45 mg BID for MEK162 alone. Duration of Response is not reported, due to the enrollment halt, which occurred prior to Phase II of the study. | From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) | 
| Phase II: Evaluation of Preliminary Anti-tumor Activity - Overall Survival (OS) | Evaluation of the preliminary anti-tumor activity at the RP2D for AEB071 and MEK162 and at 45 mg BID for MEK162 alone. Overall survival (OS) is defined as the time from date of randomization/start of treatment to date of death due to any cause. Due to an enrollment halt, the Phase II part of the study was not conducted. | From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) | 
| Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 1) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 1) | 
| Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 1) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 1) | 
| Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 1) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 1) | 
| Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 15) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 15) | 
| Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 15) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 15) | 
| Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 15) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 15) | 
| Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 1) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 1) | 
| Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 1) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 1) | 
| Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 1) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 1) | 
| Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 15) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 15) | 
| Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 15) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 15) | 
| Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 15) | Blood samples were collected from all patients during Cycle 1 (Days 1 and 15) for pharmacokinetic profiling. On Days 8 and 22 of Cycle 1, trough samples were collected. Additionally, pre-dose samples were collected on Day 1 of Cycle 2 through Cycle 6. | Cycle 1 (Day 15) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma,, melanoma of the eye,, uveal,, MEK162,, AEB071