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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
  Purpose
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

Condition Intervention Phase
Uveal Melanoma
Drug: AEB071
Drug: MEK162
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II, Open-label, Multicenter Study of AEB071 and MEK162 in Adult Patients With Metastatic Uveal Melanoma

Resource links provided by NLM:


Further study details as provided by Array BioPharma:

Primary Outcome Measures:
  • 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.



Secondary Outcome Measures:
  • 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.


Enrollment: 38
Study Start Date: August 2013
Study Completion Date: May 2015
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
AEB071 and MEK162 combined
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 B
MEK162 alone
Drug: MEK162
Twice-daily doses of MEK162 for a cycle of 28-days, given without interruption (continuous cycles)

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01801358

Locations
United States, Massachusetts
Dana Farber Cancer Institute Dept. Onc
Boston, Massachusetts, United States, 02215
United States, New York
Memorial Sloan Kettering Cancer Center Dept of Onc..
NY, New York, United States, 90033
France
Novartis Investigative Site
Paris, France, 75231
Germany
Novartis Investigative Site
Essen, Germany, 45147
Netherlands
Novartis Investigative Site
Leiden, Netherlands, 2300 RC
Spain
Novartis Investigative Site
Madrid, Spain, 28050
United Kingdom
Novartis Investigative Site
London, United Kingdom, SW3 6JJ
Sponsors and Collaborators
Array BioPharma
Investigators
Study Director: Array BioPharma 303-381-6604
  More Information

Responsible Party: Array BioPharma
ClinicalTrials.gov Identifier: NCT01801358     History of Changes
Other Study ID Numbers: CMEK162X2203 
Study First Received: February 21, 2013
Results First Received: May 12, 2016
Last Updated: August 29, 2016
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Canada: Health Canada
France: L'Agence nationale de sécurité du médicament et des produits de santé (ANSM)
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Norway: Norwegian Medicines Agency
Spain: Spanish Agency of Medicines
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Array BioPharma:
Melanoma,
melanoma of the eye,
uveal,
MEK162,
AEB071

Additional relevant MeSH terms:
Melanoma
Uveal Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Eye Neoplasms
Neoplasms by Site
Eye Diseases
Uveal Diseases

ClinicalTrials.gov processed this record on December 02, 2016