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TPS7068 Background: For patients (pts) with acute myeloid leukemia (AML) who cannot undergo intensive chemotherapy (IC), lower-intensity treatment (Tx) regimens, including low-dose cytarabine (LDAC) and hypomethylating agents (HMAs; azacitidine [AZA], decitabine), are generally well tolerated but are associated with lower response rates than IC [Vey 2020]. Similarly, the BCL2 inhibitor, venetoclax (VEN), has shown antileukemic activity, although only modest clinical benefit as monotherapy [Konopleva 2016]. VEN + AZA shows synergistic activity in preclinical models, enhancing leukemic cell apoptosis in vitro and anti-tumor activity in vivo [Jin 2020]. In IC-ineligible pts with ND AML, VEN + injectable AZA significantly increased complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates ( P < 0.001) and prolonged overall survival (OS; P < 0.001) vs AZA only [DiNardo 2020]. VEN, in combination with an HMA or LDAC, is approved in the US for Tx of pts with ND AML ≥ 75 years (y) of age or who cannot undergo IC due to comorbidities. Oral-AZA (CC-486) is approved for Tx of pts with newly diagnosed (ND) AML in first CR or CRi after IC who cannot receive curative therapy (eg, HSCT). In the phase 3 QUAZAR AML-001 trial, maintenance Tx with Oral-AZA 300 mg QD for 14 days (d)/28-d Tx cycle improved OS and relapse-free survival vs placebo in older pts in CR/CRi after IC [Wei 2020]. Incorporation of AZA into DNA is S-phase-restricted; thus, extending AZA exposure over a longer duration by using an oral formulation increases the opportunity for cycling tumor cells to incorporate the drug to sustain therapeutic activity [Laille 2015]. Additionally, an all-oral combination regimen allows for outpatient administration to optimize pt convenience and reduce resource utilization. Methods: OMNIVERSE (NCT04887857) is an open-label, multicenter, 2-part phase 1b trial. The main goals are to evaluate safety and establish the maximum tolerated dose of Oral-AZA + VEN in pts ≥ 18 y of age with relapsed/refractory AML who are ineligible for further IC ( part 1), and subsequently, in pts with ND AML ≥ 75 y of age, or pts 18–74 y of age with comorbidities that prevent use of IC or HSCT ( part 2). Key eligibility criteria include ECOG performance status of 0–2 (ECOG 3 is allowed for pts 18–74 y of age with comorbidities) and unfavorable-risk cytogenetics for pts with ND AML. The Oral-AZA starting dose is 300 mg QD × 14 d/28-d cycle, which can be de-escalated to 200 mg QD × 14 d depending on dose-limiting toxicities; oral VEN 400 mg QD is taken continuously (or 21 d/cycle for dose level −2). A modified toxicity probability interval-2 design is used to evaluate dose levels. Sample size depends on the dose levels utilized (≤ 18 pts/part). Enrollment began in 2021. The trial is ongoing at clinical sites in the United States and Australia. Clinical trial information: NCT04887857.

Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.

2577 Background: CC-90003 is an irreversible inhibitor of ERK 1/2 with potent anti-proliferative activity in KRAS and BRAF mutant tumor models. We conducted a first-in-human study of CC-90003 in patients with RAS or BRAF mutant tumors. Methods: Patients received escalating doses of oral CC-90003 on a 21/28 day cycle. Standard safety (adverse events, chemistry/hematology, physical findings, ECGs and cardiac ECHO/MUGA scans) and PK parameters were assessed. Response was assessed per RECIST 1.1. A proprietary ELISA-based assay measured ERK levels unbound to CC-90003 in peripheral blood mononuclear cells. Results: Nineteen patients (median age: 60 yrs) harboring KRAS (n = 15), NRAS (n = 1), or BRAF (n = 3) mutant tumors received CC-90003 doses from 20 to 160 mg /day. The MTD was 120 mg based on the occurrence of Grade 3 transaminase elevations (n = 2) and hypertension (n = 1) observed at 160 mg (the NTD). Patients completed a median of 2 cycles (range: 1 to 5). AEs (mostly Grade 1 or 2) reported in ≥ 3 patients included constitutional (asthenia, fatigue), gastrointestinal (anorexia, nausea/vomiting, diarrhea), hepatic (transaminase elevations) and neurologic (dizziness, gait disturbance, paresthesias) toxicities. Grade 1-3 neurotoxicity was observed primarily at doses from 80 to 160 mg/day and resolved with dose reduction/interruption. PK parameters were highly variable, with AUC and Cmax increasing overall, with increasing dose. CC-90003 accumulation was observed after multiple doses. There were no objective responses. Levels of free ERK were reduced by ≥80% compared to baseline by C1D8 at doses ≥ 80 mg/day. Conclusions: ERK inhibition may be an attractive target for the management of mutant RAS or BRAF-driven tumors, however proof-of-concept demonstration for CC-90003 was limited by a lack of objective responses, an unfavorable PK profile and unanticipated neurotoxicity. Clinical trial information: NCT02313012.

7087 Background: 5-azacitidine (AZA), through its effects on DNA metabolism, gene expression, and cell differentiation, has proven beneficial in treatment of MDS and AML and AZA therapy significantly increases survival in higher-risk MDS and AML compared to conventional care. Few studies have evaluated the pharmacokinetics (PK) of AZA and the renal elimination of AZA has not been previously published to our knowledge. Plasma PK of AZA are herein reported in patients receiving SC doses of 75 mg/m2. This study was designed to also assess the contribution of renal elimination to the overall clearance of AZA. Methods: Adult patients with MDS or AML and ECOG status 0–2 were treated with 7 consecutive daily SC doses of 75 mg/m2 AZA during their first treatment cycle. PK parameters of AZA were derived from drug concentrations in plasma and urine collected after the first and last dose (day 7) of AZA. Safety was evaluated by adverse event reporting (NCI-CTC). Results: Currently, 18 patients have been treated with SC AZA. AZA was rapidly absorbed and reached peak plasma concentrations (concs) within 0.5 hr post dosing. The AUCinf after SC doses was 1170 hr*ng/mL. The AZA concs declined in a pseudo bi-phasic manner with an elimination half-life of 1.25 hours. The plasma PK profiles after the first and last dose were superimposable. The apparent total clearance (CL/F) and volume of distribution (Vd/F) were 143 L/hr and 318 L, respectively. AZA recovery in urine was very small relative to dose (inf after SC doses is similar to the published AUC value (1044 hr*ng/mL) after 75 mg/m2 IV doses indicating approximating 100% systemic bioavailability. After SC dosing, CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism. Vd/F was 4–5 fold greater than total body water suggesting extensive AZA tissue distribution. Renal elimination appears to play a minor role in the overall clearance of AZA. [Table: see text]

4625 Background: MGCD0103 is an oral isotype-selective HDAC inhibitor that in pre-clinical studies demonstrated antitumor synergy with gem. The goals of this Phase I/II study (Trial 006) were to determine the maximum tolerated dose (MTD) of MGCD0103 in combination with gem in pts with solid tumors and to evaluate the efficacy of this combination in pts with pancreatic cancer (ca). Methods: Phase I part of this multicenter, open-label, dose-escalation trial studied adults (≥18 yrs) with refractory solid tumors. Phase II part of the trial was limited to gem naive pts with locally advanced or metastatic pancreatic ca. Pts (3–6 per cohort) received MGCD0103 (3x/week) in 28-day cycles at sequential ascending doses using a 3+3 design targeting a dose-limiting toxicity (DLT) rate of

8528 Background: MGCD0103 is an orally available selective inhibitor of histone deacetylases (HDACs) with significant biological activity in preclinical models of both solid tumors and hematopoietic cancers. Methods: Open-label, Phase II trial in adults (Trial 008) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Eligibility included: ≥1 site of measurable disease (≥2.0 cm), ECOG 0 or 1. MGCD0103 was given 3x/week starting at 110 mg; after 32 patients (pts) the starting dose was reduced to 85 mg. Tumor responses were determined every 2 cycles. PK was evaluated on Day 1, Cycle 1. Results: 50 pts received treatment; 33 DLBCL and 17 FL (median age [range], 61.5 years [32−80]; male, n=27; prior rituximab therapy: 96%; prior stem cell transplant: 33%). The response rate in pts with DLBCL met the protocol defined criteria for expansion beyond 21 pts, and enrollment of this cohort is now complete. Of 17 DLBCL pts with tumor reassessed by CT, most had tumor reduction,...