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

• ClinicalTrials.gov Identifier: NCT01801358
• Recruitment Status: Terminated
• First Posted: February 28, 2013
• Results First Posted: October 20, 2016
• Last Update Posted: September 16, 2020
• Sponsor: Array Biopharma, now a wholly owned subsidiary of Pfizer
• Information provided by (Responsible Party): Array BioPharma ( Array Biopharma, now a wholly owned subsidiary of Pfizer )

Study Description

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

Condition or disease	Intervention/treatment	Phase
Uveal Melanoma	Drug: AEB071; Drug: MEK162	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Study Start Date: August 2013
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: May 2015

Arms and Interventions

Arm	Intervention/treatment
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)

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.

Secondary Outcome Measures :

1. 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.
2. 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
3. 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.

4. 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.

5. 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.

6. 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.

7. 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 enrollment halt, the Phase II part of the study was not conducted.

8. 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) ]

   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.

9. 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) ]

   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.

10. Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 1) [ Time Frame: 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.
11. Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 1) [ Time Frame: 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.
12. Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 1) [ Time Frame: 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.
13. Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 15) [ Time Frame: 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.
14. Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 15) [ Time Frame: 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.
15. Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 15) [ Time Frame: 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.
16. Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 1) [ Time Frame: 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.
17. Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 1) [ Time Frame: 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.
18. Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 1) [ Time Frame: 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.
19. Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 15) [ Time Frame: 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.
20. Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 15) [ Time Frame: 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.
21. Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 15) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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..

New York, New York, United States, 90033

France

Pfizer Investigative Site

Paris, France, 75231

Germany

Pfizer Investigative Site

Essen, Germany, 45147

Netherlands

Pfizer Investigative Site

Leiden, Netherlands, 2300 RC

Spain

Pfizer Investigative Site

Madrid, Spain, 28050

United Kingdom

Pfizer Investigative Site

London, United Kingdom, SW3 6JJ

Sponsors and Collaborators

Array Biopharma, now a wholly owned subsidiary of Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

• Responsible Party: Array Biopharma, now a wholly owned subsidiary of Pfizer
• ClinicalTrials.gov Identifier: NCT01801358
• Other Study ID Numbers: CMEK162X2203
• First Posted: February 28, 2013
• Results First Posted: October 20, 2016
• Last Update Posted: September 16, 2020
• Last Verified: September 2020

Keywords provided by Array BioPharma ( Array Biopharma, now a wholly owned subsidiary of Pfizer ):

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