Preliminary Results from an Ongoing Phase 1/2 Study of INCB057643, a Bromodomain and Extraterminal (BET) Protein Inhibitor, in Patients (pts) with Advanced Malignancies

Introduction: BET proteins regulate gene transcription through epigenetic interactions. BET inhibition has been shown to suppress oncogenic pathways (including MYC pathway downregulation), growth, and survival in models of solid and hematologic malignancies. INCB057643 is a potent and selective small-molecule BET inhibitor. We report the safety, pharmacokinetics (PK), and efficacy from an ongoing, phase 1/2 study of INCB057643 in pts with advanced malignancies (NCT02711137).

Methods: Eligible adults with relapsed and/or refractory advanced malignancies, ≥1 prior therapy, and ECOG performance status ≤1 (Part 1 [dose escalation]) or ≤2 (Part 2 [dose expansion]), received oral INCB057643 continuously once daily (QD), in 21-d cycles. Dose escalation followed a 3+3 design. Primary endpoints were safety and tolerability; secondary included PK, pharmacodynamics (PD), and efficacy.

Results: At data cut-off, 16 pts each in Part 1 (solid tumors, n=13; lymphoma, n=3 [all follicular lymphoma (FL)]) and Part 2 (solid tumors, n=14; lymphoma, n=2 [FL, n=1; diffuse large B-cell lymphoma, n=1]) were enrolled. Doses of 8, 12, 16 mg QD were explored in Part 1. At 16 mg QD, 1 DLT was observed (grade [Gr] 3 increased INR), which resolved with dose interruption and standard of care; 5 of 8 pts required dose interruption due to AEs during cycle 1 and 2. 16 mg QD was determined to be non-tolerated; 12 mg QD was the MTD and the recommended phase 2 dose for Part 2. The mean terminal elimination half-life ranged from 10.3-15.3 h. The 12 mg QD dose met the target PD activity level (MYC protein expression).

In Part 1 (median age [range], 59 [44-81] y; men, 50%), median exposure was 59.5 (range, 6-282) d. Treatment-related AEs (TRAEs; any Gr and Gr ≥3) are shown in Table 1. 2 serious TRAEs were reported (hyperglycemia, increased INR; each n=1 [6%]). TRAEs led to dose interruption in 5 pts: increased conjugated bilirubin, increased INR, thrombocytopenia, decreased appetite, and dyspnea (each n=1 [6%]); and dose reduction in 1 pt: increased conjugated bilirubin [6%]). 13 pts (81%) discontinued treatment: disease progression (n=8 [50%]), AEs (n=4 [25%]; upper abdominal pain/confusional state, decreased performance status, hyperglycemia, and increased INR), or loss to follow-up (n=1 [6%]). There were 5 deaths, all after study drug discontinuation and during survival follow-up (all caused by disease progression, unrelated to study treatment). Of these 5 pts, 3 reported fatal AEs (hepatic failure, pneumonia, and new metastasis of the central nervous system [brain metastasis]; each n=1) that occurred 14, 22, and 0 d post study drug discontinuation, respectively, and died 25, 8, and 41 d post onset of the fatal AE, respectively (all unrelated to study treatment). 11 of 13 pts with solid tumors were evaluable for efficacy: 1 pt had stable disease (SD) ≥6 mo (cholangiocarcinoma, ongoing at 9 mo), 2 pts had SD <6 mo (discontinued at 3 mo due to decreased performance status, and progressed at 2 mo, respectively), 6 pts had radiographic progression as best response, and 2 pts had clinical progression; 2 pts were not evaluable for efficacy (discontinued treatment due to AEs before first assessment). 3 pts with lymphoma were evaluable for efficacy: 1 pt with FL had a complete response (CR, ongoing at 8 mo) and 2 pts had SD <6mo (ongoing at 5.5 mo, and progressed at 4 mo, respectively).

In Part 2 (median age [range], 66 [45-79] y; men, 38%), median INCB057643 exposure was 21.5 (range, 2-43) d. TRAEs (any Gr and Gr ≥3) are shown in Table 1. 1 serious TRAE was reported (thrombocytopenia [6%]). TRAEs led to dose interruption in 2 pts, primarily due to decreased appetite (n=2 [13%]); there were no dose reductions. 3 pts (19%) discontinued treatment (disease progression, n=2 [13%]; other, n=1 [6%]). No pts died. Of 14 pts with solid tumors, 2 pts (both pancreatic cancer) were evaluable for efficacy and had progressive disease; 12 pts were not evaluable for efficacy: 1 pt discontinued due to AE before first assessment and 11 pts had not reached first assessment. Neither of the 2 pts with lymphoma in Part 2 were evaluable for efficacy (had not yet reached first assessment).

Conclusion: Early results from this ongoing first-in-human trial of INCB057643 indicate preliminary activity and a tolerable safety profile; increased INR was the only DLT reported. A CR was observed in 1 pt with FL. Updated data in all enrolled cohorts, with an emphasis on efficacy in pts with lymphoma, will be presented.

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