Trial of AEB071 in Combination With BYL719 in Patients With Melanoma

August 11, 2023 updated by: Columbia University

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
30

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Miami, Florida, United States, 33136
        • Bascom Palmer Eye Institute of University Of Miami Medical Center
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Dose 1: AEB071 and BYL719
AEB071, oral, 100 mg twice daily BYL719, oral, 200 mg daily
Drug: AEB071
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
  • Sotrastaurin
Drug: BYL719
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
  • NVP-BYL719
Experimental: Dose 2: AEB071 and BYL719
AEB071, oral, 200 mg twice daily BYL719, oral, 250 mg daily
Drug: AEB071
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
  • Sotrastaurin
Drug: BYL719
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
  • NVP-BYL719
Experimental: Dose 3: AEB071 and BYL719
AEB071, oral, 200 mg twice daily BYL719, oral, 300 mg daily
Drug: AEB071
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
  • Sotrastaurin
Drug: BYL719
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
  • NVP-BYL719
Experimental: Dose 4: AEB071 and BYL719
AEB071, oral, 200 mg twice daily BYL719, oral, 350 mg daily
Drug: AEB071
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
  • Sotrastaurin
Drug: BYL719
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
  • NVP-BYL719
Experimental: Dose 5: AEB071 and BYL719
AEB071, oral, 300 mg twice daily BYL719, oral, 350 mg daily
Drug: AEB071
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
  • Sotrastaurin
Drug: BYL719
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
  • NVP-BYL719

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Total maximum tolerated dose (in milligrams) of AEB071 in combination with BYL719
Time Frame: 4 years (approximately)
Establish the maximum tolerated dose (up to 400 mg twice daily) for AEB071 and up to 350 mg daily for BYL719
4 years (approximately)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of participants with adverse events
Time Frame: 4 years (approximately)
Obtain safety data of the combination therapy of AEB071 with BYL719
4 years (approximately)
Change in area under the curve (AUC) for the combination of AEB071 and BYL719
Time Frame: Cycle 1 Day 1, pre-dose, .5, 1, 2, 4, 6, 8, and 24 hours post dose, Cycle 1, Day 8, pre-dose, .5, 1, 2, 4, 6, and 8 hours post dose, Cycle 1 Day 15, pre-dose, Cycle 2-3-4-5-6 Day 1, pre-dose
To evaluate the pharmacokinetic properties of the combination of AEB071 and BYL719 at varying dose levels utilizing standard pharmacokinetic parameters such as peak concentration (Cmax) and area under the curve (AUC) of AEB071 and BYL719 in plasma samples.
Cycle 1 Day 1, pre-dose, .5, 1, 2, 4, 6, 8, and 24 hours post dose, Cycle 1, Day 8, pre-dose, .5, 1, 2, 4, 6, and 8 hours post dose, Cycle 1 Day 15, pre-dose, Cycle 2-3-4-5-6 Day 1, pre-dose
Change in peak concentration (Cmax) for the combination of AEB071 and BYL719
Time Frame: Cycle 1 Day 1, pre-dose, .5, 1, 2, 4, 6, 8, and 24 hours post dose, Cycle 1, Day 8, pre-dose, .5, 1, 2, 4, 6, and 8 hours post dose, Cycle 1 Day 15, pre-dose, Cycle 2-3-4-5-6 Day 1, pre-dose
To evaluate the pharmacokinetic properties of the combination of AEB071 and BYL719 at varying dose levels utilizing standard pharmacokinetic parameters such as peak concentration (Cmax) and area under the curve (AUC) of AEB071 and BYL719 in plasma samples.
Cycle 1 Day 1, pre-dose, .5, 1, 2, 4, 6, 8, and 24 hours post dose, Cycle 1, Day 8, pre-dose, .5, 1, 2, 4, 6, and 8 hours post dose, Cycle 1 Day 15, pre-dose, Cycle 2-3-4-5-6 Day 1, pre-dose
Number participants who respond to therapy
Time Frame: 4 years (approximately)
Clinical benefit rate will be assessed as overall object response rate, using metric measurements on imaging scans.
4 years (approximately)
Change in numerically calculated toxicity burden (0-10)
Time Frame: baseline, Cycle 1 Day 8, Day 15, and Day 22, Cycle 2 and above, End of Treatment, 28 day Follow-Up visit
To explore the toxicity burden on the patient during treatment as perceived by the patient and the physician.
baseline, Cycle 1 Day 8, Day 15, and Day 22, Cycle 2 and above, End of Treatment, 28 day Follow-Up visit
Mean months of overall survival
Time Frame: 4 years (approximately)
Overall survival will be calculated in months, starting at time of enrollment.
4 years (approximately)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Columbia University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Richard Carvajal, MD, Columbia University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 19, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 18, 2017

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 2, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 17, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 21, 2014

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 23, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 15, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 11, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • AAAN4901
  • CAEB071AUS01T (Other Identifier: Novartis)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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