- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02273219
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
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
Interventional
Enrollment (Actual)
30
Phase
- 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
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Florida
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Miami, Florida, United States, 33136
- Bascom Palmer Eye Institute of University Of Miami Medical Center
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New York
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New York, New York, United States, 10032
- Columbia University Medical Center
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New York, New York, United States, 10065
- Memorial Sloan Kettering Cancer Center
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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
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 |
Intervention / Treatment |
---|---|
Experimental: Dose 1: AEB071 and BYL719
AEB071, oral, 100 mg twice daily BYL719, oral, 200 mg daily
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Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
|
Experimental: Dose 2: AEB071 and BYL719
AEB071, oral, 200 mg twice daily BYL719, oral, 250 mg daily
|
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
|
Experimental: Dose 3: AEB071 and BYL719
AEB071, oral, 200 mg twice daily BYL719, oral, 300 mg daily
|
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
|
Experimental: Dose 4: AEB071 and BYL719
AEB071, oral, 200 mg twice daily BYL719, oral, 350 mg daily
|
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
|
Experimental: Dose 5: AEB071 and BYL719
AEB071, oral, 300 mg twice daily BYL719, oral, 350 mg daily
|
Oral, 100-400 mg twice daily A potent, oral, selective inhibitor of the classical Protein Kinase C (PKC)
Other Names:
Oral, 200-350 mg daily An oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Total maximum tolerated dose (in milligrams) of AEB071 in combination with BYL719
Time Frame: 4 years (approximately)
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Establish the maximum tolerated dose (up to 400 mg twice daily) for AEB071 and up to 350 mg daily for BYL719
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4 years (approximately)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of participants with adverse events
Time Frame: 4 years (approximately)
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Obtain safety data of the combination therapy of AEB071 with BYL719
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4 years (approximately)
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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
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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.
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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
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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
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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
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Number participants who respond to therapy
Time Frame: 4 years (approximately)
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Clinical benefit rate will be assessed as overall object response rate, using metric measurements on imaging scans.
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4 years (approximately)
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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
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To explore the toxicity burden on the patient during treatment as perceived by the patient and the physician.
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baseline, Cycle 1 Day 8, Day 15, and Day 22, Cycle 2 and above, End of Treatment, 28 day Follow-Up visit
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Mean months of overall survival
Time Frame: 4 years (approximately)
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Overall survival will be calculated in months, starting at time of enrollment.
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4 years (approximately)
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- 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)
November 19, 2014
Primary Completion (Actual)
October 18, 2017
Study Completion (Actual)
July 2, 2018
Study Registration Dates
First Submitted
October 17, 2014
First Submitted That Met QC Criteria
October 21, 2014
First Posted (Estimated)
October 23, 2014
Study Record Updates
Last Update Posted (Actual)
August 15, 2023
Last Update Submitted That Met QC Criteria
August 11, 2023
Last Verified
August 1, 2023
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID 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.
Clinical Trials on Uveal Melanoma
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Jonsson Comprehensive Cancer CenterNational Cancer Institute (NCI)TerminatedIris Melanoma | Medium/Large Size Posterior Uveal Melanoma | Stage IIA Uveal Melanoma | Stage IIB Uveal Melanoma | Stage IIIA Uveal Melanoma | Stage IIIB Uveal Melanoma | Stage IIIC Uveal MelanomaUnited States
-
National Cancer Institute (NCI)ExelisisCompletedStage IV Uveal Melanoma AJCC v7 | Recurrent Uveal Melanoma | Stage III Uveal Melanoma AJCC v7 | Stage IIIA Uveal Melanoma AJCC v7 | Stage IIIB Uveal Melanoma AJCC v7 | Stage IIIC Uveal Melanoma AJCC v7United States, Canada
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Vanderbilt-Ingram Cancer CenterNational Cancer Institute (NCI)TerminatedStage IV Uveal Melanoma | Stage IIIA Uveal Melanoma | Stage IIIB Uveal Melanoma | Stage IIIC Uveal MelanomaUnited States
-
National Cancer Institute (NCI)CompletedIris Melanoma | Stage IV Uveal Melanoma | Medium/Large Size Posterior Uveal Melanoma | Recurrent Uveal Melanoma | Ocular Melanoma With Extraocular Extension | Small Size Posterior Uveal MelanomaUnited States, Canada
-
Alliance for Clinical Trials in OncologyWithdrawnMetastatic Uveal Melanoma | Advanced Uveal Melanoma | Unresectable Uveal Melanoma
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Fred Hutchinson Cancer CenterNational Cancer Institute (NCI); Incyte Corporation; University of VirginiaCompletedStage IV Skin Melanoma | Recurrent Melanoma | Stage IIIB Skin Melanoma | Stage IIIC Skin Melanoma | Mucosal Melanoma | Stage IV Uveal Melanoma | Stage IIIA Skin Melanoma | Stage IIIA Uveal Melanoma | Stage IIIB Uveal Melanoma | Stage IIIC Uveal Melanoma | Recurrent Uveal MelanomaUnited States
-
National Cancer Institute (NCI)CompletedStage IV Cutaneous Melanoma AJCC v6 and v7 | Recurrent Melanoma | Stage IIIC Cutaneous Melanoma AJCC v7 | Mucosal Melanoma | Iris Melanoma | Stage IIIA Cutaneous Melanoma AJCC v7 | Stage IIIB Cutaneous Melanoma AJCC v7 | Stage IV Uveal Melanoma AJCC v7 | Medium/Large Size Posterior Uveal Melanoma | Recurrent... and other conditionsUnited States
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National Cancer Institute (NCI)Memorial Sloan Kettering Cancer Center; Institut Curie Paris; Moffitt Cancer...Active, not recruitingMetastatic Uveal Melanoma | Stage IV Uveal Melanoma AJCC v7United States
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National Cancer Institute (NCI)CompletedStage IV Uveal Melanoma AJCC v7 | Recurrent Uveal MelanomaUnited States
-
National Cancer Institute (NCI)CompletedStage IV Uveal Melanoma AJCC v7 | Recurrent Uveal MelanomaUnited States, France, United Kingdom
Clinical Trials on AEB071
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Novartis PharmaceuticalsCompletedUveal MelanomaUnited Kingdom, France, Netherlands, United States
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Novartis PharmaceuticalsTerminatedDiffuse Large B-Cell LymphomaTaiwan, Netherlands, Hong Kong, Italy, Germany, United States, Spain, France, United Kingdom, Korea, Republic of
-
NovartisCompletedPanuveitis | Uveitis | Posterior UveitisUnited States
-
NovartisCompleted
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Novartis PharmaceuticalsCompletedModerate and Severe Plaque PsoriasisUnited States, Argentina, Germany, Belgium, Italy, United Kingdom, Turkey, Guatemala, Australia
-
Array Biopharma, now a wholly owned subsidiary...TerminatedUveal MelanomaUnited States, France, Germany, Netherlands, Spain, United Kingdom
-
Novartis PharmaceuticalsCompletedUlcerative ColitisGermany, United States, Denmark, Poland
-
NovartisCompletedde Novo Liver TransplantationGermany, Italy, Switzerland
-
Novartis PharmaceuticalsCompletedKidney TransplantationUnited States, United Kingdom, Germany, Belgium, Spain, Canada, Sweden