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

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

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

Brief Summary: 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 Summary:

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.


Sponsor: Array BioPharma

Current Primary Outcome:

  • Phase Ib: Incidence of Dose Limiting Toxicities (DLT) During the First Cycle [ Time Frame: Cycle 1 (up to 28 days) ]
    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.
  • Phase II: Progression Free Survival (PFS) [ Time Frame: From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) ]

    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.



Original Primary Outcome:

  • Phase I: dose limiting toxicity (DLT) [ Time Frame: Up to 28 days of treatment with AEB071 and MEK162 ]
    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.
  • Phase II: Objective Response Rate (ORR) [ Time Frame: From first dose cycle 1, day 1 (C1D1) to time to progression up to 24 months ]
    The proportion of patients that have a best overall response of complete response (CR) or partial response (PR), as assessed by RECIST 1.1. cycle 1 = 28 days


Current Secondary Outcome:

  • Phase Ib/II: The Number of Subjects Experiencing At Least One Adverse Event (AE) [ Time Frame: From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) ]
    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.
  • Phase Ib/II: The Number of Subjects Experiencing At Least One Serious Adverse Event (SAE) [ Time Frame: From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) ]

    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
  • Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Best Overall Response (BOR) [ Time Frame: Cycle 1 (up to 28 days) ]

    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.

  • Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Duration of Response (DOR) [ Time Frame: Cycle 1 (up to 28 days) ]

    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.

  • Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Progression Free Survival (PFS) [ Time Frame: Cycle 1 (up to 28 days) ]

    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.

  • Phase II: Evaluation of Preliminary Anti-tumor Activity - Overall Response Rate (CR+PR) [ Time Frame: From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) ]

    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.

  • Phase II: Evaluation of Preliminary Anti-tumor Activity - Best Overall Response (BOR) [ Time Frame: From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) ]

    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 enro

    Original Secondary Outcome:

    • Phase Ib: Disease control rate (DCR) [ Time Frame: From first dose cycle 1 day 1 (C1D1) to time to progression up to 24 months ]
      Disease status for all patients according to RECIST 1.1. DCR is defined as all patients that have stable disease (SD), partial response (PR) or complete response (CR). cycle = 28 days
    • Phase II: Disease control rate (DCR) [ Time Frame: at 4 months of treatment ]
      Disease status for all patients according to RECIST 1.1. DCR is defined as all patients that have stable disease (SD), PR or CR at 4 months of treatment
    • Duration of Response [ Time Frame: From first dose (C1D1) to time to progression up to 24 months ]
      Duration from best response to confirmed disease progression
    • Best Overall Response [ Time Frame: From first dose (C1D1) to time to progression up to 24 months ]
      Maximum response at any time during treatment (response is SD, PR or CR)
    • Progression free survival [ Time Frame: From first dose (C1D1) to time to progression up to 24 months ]
      Duration of treatment from Cycle 1 Day 1 to confirmed disease progression or withdrawal
    • Overall survival [ Time Frame: From C1D1 to death or lost to follow-up up to 24 months ]
      The duration of survival from first treatment (C1D1) until confirmed death due to any cause, whether on treatment or not
    • Safety and tolerability of AEB071 and MEK162 [ Time Frame: From consent to 30-days post-end-of-treatment ]
      Frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs), as well as changes in laboratory values and electrocardiograms, dose interruptions, reductions and dose intensity
    • Blood concentrations of AEB071, MEK162 and their active metabolites (Phase Ib) [ Time Frame: up to 28 days ]
      Determine blood concentrations and fit to standard PK parameters


    Information By: Array BioPharma

    Dates:
    Date Received: February 21, 2013
    Date Started: August 2013
    Date Completion:
    Last Updated: August 29, 2016
    Last Verified: August 2016