Study of INCB053914 in Subjects With Advanced Malignancies

A Phase 1/2 Study of INCB053914 in Subjects With Advanced Malignancies

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 Overview

• Status: Terminated
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: INCB053914; Drug: Azacitidine; Drug: I-DAC (Intermediate dose cytarabine); Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 2; Phase 1

Expanded Access

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Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • The University of Arizona Cancer Center
  • California
    • Sacramento, California, United States, 95817
      • UC Davis Comprehensive Cancer Center
    • Santa Monica, California, United States, 90095
      • UCLA Medical Hematology & Oncology
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale University
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Sarasota, Florida, United States, 33916
      • Florida Cancer Specialists & Research Institute
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University-Winship Cancer Institute
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Nebraska
    • Omaha, Nebraska, United States, 69198
      • University of Nebraska Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Oncology Hematology Care Clinical Trials LLC
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology
    • Tyler, Texas, United States, 75702
      • Texas Oncology
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged 18 years or older
• Confirmed diagnosis of select advanced malignancy

• Parts 1 and 2:

  • Unresponsive to currently available therapy and there is no standard-of-care therapy available in the judgment of the investigator.
  • Not currently a candidate for curative treatment

• Parts 3 and 4:

  • Subjects with relapsed/refractory AML must have received either induction chemotherapy for AML or hypomethylating agents for hematologic disease before AML.
  • Elderly subjects (≥ 65 years) with newly diagnosed AML must be treatment naive and unfit for intensive chemotherapy.
  • Myelofibrosis subjects must have been treated with ruxolitinib for ≥ 6 months with a stable dose for ≥ 8 weeks (acceptable doses are 5 mg twice daily [BID] to 25 mg BID).
• Willingness to undergo a pretreatment bone marrow biopsy and/or aspirate, or archival sample obtained since completion of most recent therapy (as appropriate to subjects with existing bone marrow disease or for whom bone marrow examination is a component of disease status assessment)

• Eastern Cooperative Oncology Group (ECOG) performance status

  • Part 1: 0 or 1
  • Parts 2, 3 and 4: 0, 1, or 2
• Life expectancy > 12 weeks or ≥ 24 weeks for Part 3 and Part 4 MF subjects.

Exclusion Criteria:

• Inadequate bone marrow or organ function
• Received an investigational agent within 5 half-lives or 14 days, whichever is longer, prior to receiving the first dose of study drug
• Received non-biologic anticancer medication within 5 half-lives prior to receiving the first dose of study drug (within 6 weeks for mitomycin-C or nitrosoureas), within 28 days for any antibodies or biological therapies
• Prior receipt of a PIM inhibitor
• Any history of disease involving the central nervous system (Part 1). Known active disease involving the central nervous system (Part 2).
• Screening corrected QT interval (QTc) interval > 470 milliseconds
• Radiotherapy within the 2 weeks prior to initiation of treatment
• Chronic or current active infection requiring systemic antibiotic, antifungal, or antiviral treatment

Study Plan

How is the study designed?

Design Details

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

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Parts 1 and 2: INCB053914 100 mg QD; INCB053914 will be self-administered orally once a day in as a 100mg immediate release tablet as a monotherapy.	Drug: INCB053914; 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.
Experimental: Parts 3 and 4: INCB053914 + Azacitidine; Azacitidine will be administered at a dose of 75 mg/m2 subcutaneously or via IV per day, as a combination therapy with INCB053914.	Drug: INCB053914; 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.; Drug: Azacitidine; Azacitidine dose will be 75 mg/m^2. Azacitidine will be administered either sub-cutaneously (SC) or intravenously (IV).; Other Names: Vidaza®
Experimental: Parts 3 and 4: INCB053914 + I-DAC (Intermediate dose cytarabine); I-DAC (intermediate dose cytarabine) will be administered at a dose of 1 g/m2 per day as an infusion as a combination therapy with INCB053914.	Drug: INCB053914; 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.; Drug: I-DAC (Intermediate dose cytarabine); Cytarabine dose will be 1 g/m^2. Cytarabine will be administered as an intravenous (IV) infusion.
Experimental: Parts 3 and 4: INCB053914 + Ruxolitinib; Ruxolitinib will be administered as an oral dose between 5 mg to 25 mg twice per day, as a combination therapy with INCB053914.	Drug: INCB053914; 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.; Drug: Ruxolitinib; Starting dose of ruxolitinib will be the dose the subject was on at study entry Ruxolitinib will be administered by mouth.
Experimental: Parts 1 and 2: INCB053914 50 mg; INCB053914 will be self-administered orally twice day in as a 50mg immediate release tablet as a monotherapy.	Drug: INCB053914; 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.
Experimental: Parts 1 and 2: INB053914 65 mg; INCB053914 will be self-administered orally twice day in as a 65mg immediate release tablet as a monotherapy.	Drug: INCB053914; 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.
Experimental: Parts 1 and 2: INB053914 80 mg; INCB053914 will be self-administered orally twice day in as a 80mg immediate release tablet as a monotherapy.	Drug: INCB053914; 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.
Experimental: Parts 1 and 2: INB053914 100 mg BID; INCB053914 will be self-administered orally twice day in as a 100mg immediate release tablet as a monotherapy.	Drug: INCB053914; 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.
Experimental: Parts 1 and 2: INB053914 115 mg; INCB053914 will be self-administered orally twice day in as a 115mg immediate release tablet as a monotherapy.	Drug: INCB053914; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the Safety and Tolerability of INCB053914 as Measured by the Number of Participants With Adverse Events		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.	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.	Approximately 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	1 month
Pharmacokinetics: Tmax of Combination Treatment Group A INCB053914 50 mg + Cytarabine		Cycle 1 Day 5
Pharmacokinetics: AUCtau of Combination Treatment Group A INCB053914 50 mg + Cytarabine		Cycle 1 Day 5
Pharmacokinetics: Cl/F of Combination Treatment Group A INCB053914 50 mg + Cytarabine		Cycle 1 Day 5
Pharmacokinetics: Cmax of Combination Treatment Group A INCB053914 50 mg + Cytarabine		Cycle 1 Day 5
Pharmacokinetics: Cmin of Combination Treatment Group A INCB053914 50 mg + Cytarabine		Cycle 1 Day 5
Pharmacokinetics: Tmax of Combination Group B INCB053914 80 mg + Azatcitidine		Cycle 1 Day 8
Pharmacokinetics: AUCtau of Combination Group B INCB053914 80 mg + Azatcitidine		Cycle 1 Day 8
Pharmacokinetics: Cl/F of Combination Group B INCB053914 80 mg + Azatcitidine		Cycle 1 Day 8
Pharmacokinetics: Cmax of Combination Group B INCB053914 80 mg + Azatcitidine		Cycle 1 Day 8
Pharmacokinetics: Cmin of Combination Group B INCB053914 80 mg + Azatcitidine		Cycle 1 Day 8
Pharmacokinetics: Tmax of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib		Regimen 2 Week 4
Pharmacokinetics: AUCtau of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib		Regimen 2 Week 4
Pharmacokinetics: Cl/F of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib		Regimen 2 Week 4
Pharmacokinetics: Cmax of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib		Regimen 2 Week 4
Pharmacokinetics: Cmin of Combination Treatment Group C INCB053914 80 mg + Ruxolitinib		Regimen 2 Week 4
Pharmacokinetics: Tmax of INCB053914 Monotherapy		Cycle 1 Day 8
Pharmacokinetics: AUCtau of INCB053914 Monotherapy		Cycle 1 Day 8
Pharmacokinetics: CL/F of INCB053914 Monotherapy		Cycle 1 Day 8
Pharmacokinetics: Cmax of INCB053914 Monotherapy		Cycle 1 Day 8
Pharmacokinetics: Ctau of INCB053914 Monotherapy		Cycle 1 Day 8

Collaborators and Investigators

• Sponsor: Incyte Corporation

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2015
• Primary Completion (Actual): August 11, 2020
• Study Completion (Actual): August 11, 2020

Study Registration Dates

• First Submitted: October 26, 2015
• First Submitted That Met QC Criteria: October 26, 2015
• First Posted (Estimate): October 27, 2015

Study Record Updates

• Last Update Posted (Actual): December 8, 2021
• Last Update Submitted That Met QC Criteria: November 9, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: leukemia; acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); PIM kinases; myelofibrosis (MF); lymphomas; lymphoproliferative disorders; multiple myeloma (MM); myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Azacitidine; Cytarabine
• Other Study ID Numbers: INCB 53914-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No