Trial of AEB071 in Combination With BYL719 in Patients With Melanoma

Brief Title

Trial of AEB071 in Combination With BYL719 in Patients With Melanoma

Official Title

Phase Ib Trial of AEB071, a PKC Inhibitor, in Combination With BYL719, a PI3Kα Inhibitor, in Patients With Metastatic Uveal Melanoma

Brief Summary

      Primary objective is to define the maximum tolerated dose (MTD) for the combination of AEB071
      and BYL719. Secondary objectives are to define the safety and tolerability of AEB071 and
      BYL719.
    

Detailed Description

      Uveal melanoma is the most common primary intraocular malignancy in adults and is thought to
      be particularly resistant to systemic treatment, and no systemic therapy has yet been
      demonstrated to improve survival. Drugs commonly used to treat advanced cutaneous melanoma
      rarely achieve durable responses in patients with uveal melanoma. Because of the lack of
      effective systemic treatment options, outcomes are poor once metastatic disease occurs, and
      the median survival from the time of the development of distant metastatic disease is 6 to 12
      months. Although it is clear that novel effective therapies are desperately needed for this
      disease, the development of such therapies has been hampered by the rarity of uveal melanoma.
    

Study Phase

Phase 1

Study Type

Interventional

Primary Outcome

Total maximum tolerated dose (in milligrams) of AEB071 in combination with BYL719

Secondary Outcome

 Number of participants with adverse events

Condition

Uveal Melanoma

Intervention

AEB071

Study Arms / Comparison Groups

 AEB071 and BYL719

Description:  AEB071, oral, 100-400 mg twice daily BYL719, oral, 200-350 mg daily

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

30

Start Date

November 2014

Completion Date

December 2018

Primary Completion Date

March 2018

Eligibility Criteria

        Inclusion Criteria:

          -  Metastatic histologically or cytologically confirmed uveal melanoma with pathologic
             confirmation at a participating center that is judged to be progressive in the opinion
             of the treating physician.

          -  Measurable disease. Patients with biopsy-proven metastatic disease that do not meet
             criteria for measurable disease may be eligible at the discretion of the principal
             investigator.

          -  Prior cytotoxic therapy and immunotherapy are allowed. For the dose escalation, prior
             targeted therapy with a MEK inhibitor, Protein Kinase C inhibitor, Akt, or mechanistic
             target of rapamycin (mTOR) inhibitor are allowed. For the dose expansion cohort, no
             prior PKC, Akt, or mTOR inhibitors are allowed. Local therapies such as radiofrequency
             ablation or cryotherapy for metastatic disease are permitted but must have been
             performed at least 21 days prior to initiation of study therapy.

          -  Age greater than or equal to 18 years

          -  Willingness to undergo core biopsies at baseline, mid-Cycle 1, and/or at progression
             unless contraindicated by medical risk in the opinion of the treating physician.

          -  Easter Cooperative Oncology Group (ECOG) performance status less than or equal to 2
             (Karnofsky greater than or equal to 60 percent).

          -  Life expectancy of greater than 3 months.

          -  Able to swallow and retain medication and does not have any clinically significant
             gastrointestinal abnormalities that may alter absorption such as malabsorption
             syndrome or major resection of the stomach or bowels.

          -  Fasting plasma glucose (FPG) less than 140 mg/dL / 7.8 mmol/L.

          -  All prior treatment-related toxicities must be grade less than or equal to 1 (except
             alopecia).

          -  Patients must have adequate organ and marrow function within 14 days of starting Cycle
             1, Day 1 of therapy

          -  Women of child-bearing potential and men must agree to use adequate contraception
             prior to study entry and for the duration of study participation. Women of
             child-bearing potential must have a negative serum pregnancy test within 14 days prior
             to registration.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  History of another malignancy except for those who have been disease-free for 24
             months. Patients with a history of completely resected non-melanoma skin cancer and/or
             patients with indolent secondary malignancies not requiring active therapy are
             eligible.

          -  Any major surgery or extensive radiotherapy within 28 days prior to screening

          -  Use of other investigational drugs within 28 days (or five half-lives, whichever is
             longer) preceding the first dose of AEB071 and BYL719.

          -  Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
             compression. Treated brain metastases must have been stable for at least 1 month.

          -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to AEB071 or BYL719.

          -  Current use of a prohibited medication.

          -  Type I Diabetes Mellitus (DM), Type II DM patients requiring insulin for chronic blood
             glucose control, and any patients with a fasting blood glucose greater than 140 mg/dL
             at screening.

          -  History or evidence of cardiovascular risk.

          -  Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
             Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection,
             which will be allowed).

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection and psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Patients with impairment of gastrointestinal function or gastrointestinal disease that
             could interfere with the absorption of AEB071 or BYL719 (e.g. ulcerative disease,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
             resection).

          -  Patients who have received prior systemic anti-cancer treatment, such as cyclical
             chemotherapy or biological therapy within a period of time that is shorter than the
             cycle length used for that treatment (e.g. 6 weeks for nitrosourea, mitomycin-C) prior
             to starting study treatment.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Richard Carvajal, MD, , 

Location Countries

United States

Location Countries

United States

NCT ID

NCT02273219

Organization ID

AAAN4901

Secondary IDs

CAEB071AUS01T

Responsible Party

Sponsor-Investigator

Study Sponsor

Richard D. Carvajal

Study Sponsor

Richard Carvajal, MD, Principal Investigator, Columbia University

Verification Date

June 2018