This is an open-label, dose-escalation study of the proviral integration site of Moloney murine leukemia virus (PIM) kinase inhibitor INCB053914 in subjects with advanced malignancies. The study will be conducted in 4 parts. Part 1 (monotherapy dose escalation) will evaluate safety and determine the maximum tolerated dose of INCB053914 monotherapy and the recommended phase 2 dose(s) (a tolerated pharmacologically active dose that will be taken forward into the remaining parts of the study). Part 2 (monotherapy dose expansion) will further evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the recommended Phase 2 dose(s). Part 3 (combination dose finding) will evaluate safety of INCB053914 in combination with select standard of care (SOC) agents and will identify the optimal INCB053914 dose in combination with conventional SOC regimens to take forward into Part 4. Part 4 (combination dose expansion) will further evaluate the safety, efficacy and pharmacokinetics of the recommended Phase 2 dose combination(s).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
97
Initial cohort dose of INCB053914 at the protocol-specified starting dose in two treatment groups in dose escalation, with subsequent expansion in up to five cohorts based on protocol-specific criteria. INCB053914 tablets to be administered by mouth.
Cytarabine dose will be 1 g/m\^2. Cytarabine will be administered as an intravenous (IV) infusion.
Azacitidine dose will be 75 mg/m\^2. Azacitidine will be administered either sub-cutaneously (SC) or intravenously (IV).
Starting dose of ruxolitinib will be the dose the subject was on at study entry Ruxolitinib will be administered by mouth.
The University of Arizona Cancer Center
Tucson, Arizona, United States
UC Davis comprehensive Cancer Center
Sacramento, California, United States
UCLA Medical Hematology & Oncology
Santa Monica, California, United States
Yale University
New Haven, Connecticut, United States
Mayo Clinic Florida
Jacksonville, Florida, United States
Florida Cancer Specialists & Research Institute
Sarasota, Florida, United States
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, United States
Emory University-Winship Cancer Institute
Atlanta, Georgia, United States
University of Maryland
Baltimore, Maryland, United States
Dana-Farber Cancer Center
Boston, Massachusetts, United States
...and 9 more locations
Determination of the Safety and Tolerability of INCB053914 as Measured by the Number of Participants With Adverse Events
Time frame: Approximately 7 months
Part 4 Only : Determination of the Efficacy of INCB053914 in Combination With the Intermediate-dose Cytarabine (I DAC) in Subjects With Relapsed or Refractory Acute Myeloid Leukemia (AML) Based on Objective Remission Rate (ORR)
The primary efficacy endpoint of ORR in patients with AML who received INCB053914 in combination with cytarabine in Part 4 was not assessed because Part 4 was not opened for enrollment owing to this combination regimen not being tolerated in Part 3.
Time frame: Approximately 2 months
Part 4 Only : Determination of the Efficacy of INCB053914 in Combination With Azacitidine in Subjects With Newly Diagnosed AML Who Are 65 Years or Older and Unfit for Intensive Chemotherapy Based on ORR
The primary efficacy endpoint of ORR in patients with AML who received INCB053914 plus azacitidine in Part 4 was not performed due to limited enrollment as a result of early study termination.
Time frame: Approximately 6 months
Evaluation of Phosphorylated BCL--2 Associated Death Promoter Protein (pBAD)
Percent Inhibition of pBAD at the C1D15 trough from the pBAD at pre-dose by ex vivo cellular assay
Time frame: 1 month
Pharmacokinetics: Tmax of Combination Treatment Group A INCB053914 50 mg + Cytarabine
Time frame: Cycle 1 Day 5
Pharmacokinetics: AUCtau of Combination Treatment Group A INCB053914 50 mg + Cytarabine
Time frame: Cycle 1 Day 5
Pharmacokinetics: Cl/F of Combination Treatment Group A INCB053914 50 mg + Cytarabine
Time frame: Cycle 1 Day 5
Pharmacokinetics: Cmax of Combination Treatment Group A INCB053914 50 mg + Cytarabine
Time frame: Cycle 1 Day 5
Pharmacokinetics: Cmin of Combination Treatment Group A INCB053914 50 mg + Cytarabine
Time frame: Cycle 1 Day 5
Pharmacokinetics: Tmax of Combination Group B INCB053914 80 mg + Azatcitidine
Time frame: Cycle 1 Day 8
Pharmacokinetics: AUCtau of Combination Group B INCB053914 80 mg + Azatcitidine
Time frame: Cycle 1 Day 8
Pharmacokinetics: Cl/F of Combination Group B INCB053914 80 mg + Azatcitidine
Time frame: Cycle 1 Day 8
Pharmacokinetics: Cmax of Combination Group B INCB053914 80 mg + Azatcitidine
Time frame: Cycle 1 Day 8
Pharmacokinetics: Cmin of Combination Group B INCB053914 80 mg + Azatcitidine
Time frame: Cycle 1 Day 8
Pharmacokinetics: Tmax of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib
Time frame: Regimen 2 Week 4
Pharmacokinetics: AUCtau of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib
Time frame: Regimen 2 Week 4
Pharmacokinetics: Cl/F of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib
Time frame: Regimen 2 Week 4
Pharmacokinetics: Cmax of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib
Time frame: Regimen 2 Week 4
Pharmacokinetics: Cmin of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib
Time frame: Regimen 2 Week 4
Pharmacokinetics: Tmax of INCB053914 Monotherapy
Time frame: Cycle 1 Day 8
Pharmacokinetics: AUCtau of INCB053914 Monotherapy
Time frame: Cycle 1 Day 8
Pharmacokinetics: CL/F of INCB053914 Monotherapy
Time frame: Cycle 1 Day 8
Pharmacokinetics: Cmax of INCB053914 Monotherapy
Time frame: Cycle 1 Day 8
Pharmacokinetics: Ctau of INCB053914 Monotherapy
Time frame: Cycle 1 Day 8
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