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
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
38
Dana Farber Cancer Institute Dept. Onc
Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center Dept of Onc..
New York, New York, United States
Pfizer Investigative Site
Paris, France
Pfizer Investigative Site
Essen, Germany
Pfizer Investigative Site
Leiden, Netherlands
Pfizer Investigative Site
Madrid, Spain
Pfizer Investigative Site
London, United Kingdom
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.
Time frame: 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.
Time frame: 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 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Cycle 1 (Day 15)
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