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

This study has been terminated.
(The trial was terminated for scientific reasons.)
Sponsor:
Information provided by (Responsible Party):
Array BioPharma
ClinicalTrials.gov Identifier:
NCT01801358
First received: February 21, 2013
Last updated: August 29, 2016
Last verified: August 2016

February 21, 2013
August 29, 2016
August 2013
May 2015   (final data collection date for primary outcome measure)
  • Phase Ib: Incidence of Dose Limiting Toxicities (DLT) During the First Cycle [ Time Frame: Cycle 1 (up to 28 days) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]

    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.

  • Phase I: dose limiting toxicity (DLT) [ Time Frame: Up to 28 days of treatment with AEB071 and MEK162 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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
Complete list of historical versions of study NCT01801358 on ClinicalTrials.gov Archive Site
  • 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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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.

  • Phase II: Evaluation of Preliminary Anti-tumor Activity - Duration of Response (DOR) [ Time Frame: From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) ] [ Designated as safety issue: No ]

    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.

  • Phase II: Evaluation of Preliminary Anti-tumor Activity - Overall Survival (OS) [ Time Frame: From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit) ] [ Designated as safety issue: No ]

    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.

  • Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 1) [ Time Frame: Cycle 1 (Day 1) ] [ Designated as safety issue: No ]
    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.
  • Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 1) [ Time Frame: Cycle 1 (Day 1) ] [ Designated as safety issue: No ]
    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.
  • Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 1) [ Time Frame: Cycle 1 (Day 1) ] [ Designated as safety issue: No ]
    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.
  • Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 15) [ Time Frame: Cycle 1 (Day 15) ] [ Designated as safety issue: No ]
    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.
  • Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 15) [ Time Frame: Cycle 1 (Day 15) ] [ Designated as safety issue: No ]
    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.
  • Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 15) [ Time Frame: Cycle 1 (Day 15) ] [ Designated as safety issue: No ]
    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.
  • Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 1) [ Time Frame: Cycle 1 (Day 1) ] [ Designated as safety issue: No ]
    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.
  • Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 1) [ Time Frame: Cycle 1 (Day 1) ] [ Designated as safety issue: No ]
    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.
  • Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 1) [ Time Frame: Cycle 1 (Day 1) ] [ Designated as safety issue: No ]
    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.
  • Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 15) [ Time Frame: Cycle 1 (Day 15) ] [ Designated as safety issue: No ]
    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.
  • Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 15) [ Time Frame: Cycle 1 (Day 15) ] [ Designated as safety issue: No ]
    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.
  • Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 15) [ Time Frame: Cycle 1 (Day 15) ] [ Designated as safety issue: No ]
    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.
  • Phase Ib: Disease control rate (DCR) [ Time Frame: From first dose cycle 1 day 1 (C1D1) to time to progression up to 24 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    Determine blood concentrations and fit to standard PK parameters
Not Provided
Not Provided
 
A Phase Ib/II Study of AEB071 and MEK162 in Adult Patients With Metastatic Uveal Melanoma
A Phase Ib/II, Open-label, Multicenter Study of AEB071 and MEK162 in Adult Patients With Metastatic Uveal Melanoma
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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Uveal Melanoma
  • Drug: AEB071
    Twice-daily doses of AEB071 for a cycle of 28-days, given without interruption (continuous cycles)
    Other Name: Sotrastaurin
  • Drug: MEK162
    Twice-daily doses of MEK162 for a cycle of 28-days, given without interruption (continuous cycles)
  • Experimental: Arm A
    AEB071 and MEK162 combined
    Interventions:
    • Drug: AEB071
    • Drug: MEK162
  • Experimental: Arm B
    MEK162 alone
    Intervention: Drug: MEK162
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
38
May 2015
May 2015   (final data collection date for primary outcome measure)

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
Both
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States,   France,   Germany,   Netherlands,   Spain,   United Kingdom
Australia,   Canada,   Italy,   Norway
 
NCT01801358
CMEK162X2203
No
Not Provided
Not Provided
Array BioPharma
Array BioPharma
Not Provided
Study Director: Array BioPharma 303-381-6604
Array BioPharma
August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP