An Open-Label, Dose-Escalation Study of INCB054329 in Patients With Advanced Malignancies

Study Overview
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Brief Summary
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This was a study of INCB054329 given to patients with advanced malignancies that were conducted in three treatment groups. Each treatment group had a dose escalation (Part 1) and a dose expansion (Part 3), two of the treatment groups also had an intra-patient dose titration (Part 2).

Official Title
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A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of INCB054329 in Subjects With Advanced Malignancies

Conditions
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Solid Tumors and Hematologic Malignancy

Intervention / Treatment
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* Drug: INCB054329 Monotherapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Confirmed diagnosis of advanced malignancy: Treatment Group A (TGA): Part 1 and Part 2: Any advanced solid tumor or lymphoma; Part 3: Histologically confirmed disease in specific solid tumors and lymphomas Treatment Group B (TGB): Acute Leukemia (Part 3 - acute myeloid leukemia [AML] only), myelodysplastic syndrome (MDS), myelodysplastic /myeloproliferative neoplasms (MDS/MPN) and myelofibrosis (MF) Treatment Group C (TGC): Multiple myeloma Progressed following at least 1 line of prior therapy and there is no further approved therapy available that has been demonstrated to prolong survival (including subjects who are intolerant to the approved therapy) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 in Parts 1 and 2 dose escalation and titration, and 0, 1, 2 in Part 3 dose expansion Key Exclusion Criteria: Inadequate hematopoietic, liver, endocrine or renal function Receipt of anticancer medications or investigational drugs within the following interval before the first administration of study drug: < 6 weeks for mitomycin-C or nitrosoureas < 5 half-lives or 14 days, whichever is longer, for any investigational agent (for any indication) < 28 days for any antibodies or biological therapies < 5 half-lives for all other anticancer medications, or sponsor approval Prior radiotherapy within 2 weeks prior to first dose of study drug Untreated brain or central nervous system (CNS) metastases Type 1 diabetes or uncontrolled Type 2 diabetes Any sign of clinically significant bleeding

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INCB054329 Monotherapy<br> | Drug: INCB054329 Monotherapy<br>* Initial cohort dose of INCB054329 monotherapy at the protocol-specified starting dose in the treatment group A (TGA), with subsequent cohort escalations in the three treatment groups (TGA, TGB, and TGC) based on protocol-specific criteria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Treatment-emergent Adverse Event (TEAE) | TEAE is defined as an adverse event reported for the first time or worsening of a pre-existing event after the first dose of study treatment. | up to 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) Analysis of INCB054329 | Cmax is defined as the maximum observed serum concentration measured at steady state (Day 15). Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen. | Summary of steady-state PK parameters by dosing regimen at Day 15 | 
| Time to Maximum Plasma Concentration (Tmax) Analysis of INCB054329 | Tmax is the time to maximum (peak) drug serum concentration. Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen. | Summary of steady-state PK parameters by dosing regimen at Day 15 | 
| Minimum Observed Plasma Concentration Over the Dose Interval (Cmin) Analysis of INCB054329 | Minimum observed plasma concentration measured at steady state (Day 15). Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen. | Summary of steady-state PK parameters by dosing regimen at Day 15 | 
| AUC0-t Analysis of INCB054329 | AUC0-t is the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t measured at steady state (Day 15). Study drug was administered with 240 mL of water. | Summary of steady-state PK parameters by dosing regimen at Day 15 | 
| Cl/F Analysis of INCB054329 | Cl/F is the apparent oral dose clearance measured at steady state (Day 15). Study drug was administered with 240 mL of water. | Summary of steady-state PK parameters by dosing regimen at Day 15 | 
| Pharmacodynamics (PD) Analysis - Total c-Myc % Inhibition Versus INCB054329 | The half maximal inhibitory concentration (IC50) of INCB054329 was measured. The maximal inhibition of total c-Myc was correlated to the level of drug exposure and demonstrated a high degree of interparticipant variability, parallel to the PK data. The measure was performed as a value across all cohorts. The entire dose escalation data set was used to create the relationship curve. Analysis of individual cohorts contained too few subjects and was biased toward one region of the curve so that the relationship was poorly defined. Individual data points from all subjects were subjected to a nonlinear least squares regression analysis with no weighting, resulting in a sigmoidal dose response curve defining the relationship. The numerical value given is the projected INCB0054329 concentration in nM that produced 50% inhibition of c-myc expression. | Day 15 in all cohorts | 
| Objective Response Rate (ORR) | Defined as the percentage of subjects having complete response (CR) or partial response (PR). The best overall response was defined as the best response recorded before and including the first event of Progressive disease (PD). | Baseline through end of study, up to 6 months | 
| Duration of Response (DOR) | Defined as the time from earliest date of disease response until earliest date of disease progression or death. | Baseline through end of study, up to 6 months | 
| Progression Free Survival (PFS) | PFS is the time from start of study treatment to first documentation of progression, or to death due to any cause, whichever comes first | Baseline through end of study, up to 6 months | 
| Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of the participant's death. | Baseline through end of study, up to 6 months for participants in Part 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumor, lymphoma, BET bromodomain inhibitor, BRD, Diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, c-MYC, colorectal cancer, Non-small cell lung cancer, Pancreatic adenocarcinoma, castration-resistant prostate cancer, breast cancer, NUT midline carcinoma, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms, myelofibrosis (MF), multiple myeloma (MM), MDS/MPN