Study of INCB053914 in Subjects With Advanced Malignancies

Study Overview
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Brief Summary
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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).

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

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: INCB053914
* Drug: I-DAC (Intermediate dose cytarabine)
* Drug: Azacitidine
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Parts 1 and 2: INCB053914 100 mg QD<br>INCB053914 will be self-administered orally once a day in as a 100mg immediate release tablet as a monotherapy. | Drug: INCB053914<br>* 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.<br>|
| Experimental: Parts 3 and 4: INCB053914 + Azacitidine<br>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<br>* 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.<br>Drug: Azacitidine<br>* Azacitidine dose will be 75 mg/m^2. Azacitidine will be administered either sub-cutaneously (SC) or intravenously (IV).<br>* Other names: Vidaza®;|
| Experimental: Parts 3 and 4: INCB053914 + I-DAC (Intermediate dose cytarabine)<br>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<br>* 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.<br>Drug: I-DAC (Intermediate dose cytarabine)<br>* Cytarabine dose will be 1 g/m^2. Cytarabine will be administered as an intravenous (IV) infusion.<br>|
| Experimental: Parts 3 and 4: INCB053914 + Ruxolitinib<br>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<br>* 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.<br>Drug: Ruxolitinib<br>* Starting dose of ruxolitinib will be the dose the subject was on at study entry Ruxolitinib will be administered by mouth.<br>|
| Experimental: Parts 1 and 2: INCB053914 50 mg<br>INCB053914 will be self-administered orally twice day in as a 50mg immediate release tablet as a monotherapy. | Drug: INCB053914<br>* 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.<br>|
| Experimental: Parts 1 and 2: INB053914 65 mg<br>INCB053914 will be self-administered orally twice day in as a 65mg immediate release tablet as a monotherapy. | Drug: INCB053914<br>* 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.<br>|
| Experimental: Parts 1 and 2: INB053914 80 mg<br>INCB053914 will be self-administered orally twice day in as a 80mg immediate release tablet as a monotherapy. | Drug: INCB053914<br>* 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.<br>|
| Experimental: Parts 1 and 2: INB053914 100 mg BID<br>INCB053914 will be self-administered orally twice day in as a 100mg immediate release tablet as a monotherapy. | Drug: INCB053914<br>* 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.<br>|
| Experimental: Parts 1 and 2: INB053914 115 mg<br>INCB053914 will be self-administered orally twice day in as a 115mg immediate release tablet as a monotherapy. | Drug: INCB053914<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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leukemia, myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), myelofibrosis (MF), lymphoproliferative disorders, acute myeloid leukemia (AML), lymphomas, multiple myeloma (MM), PIM kinases