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Correlation analysis between pharmacodynamic and pharmacokinetic findings in part 1

Mean paclitaxel plasma concentrations following nab-paclitaxel administration alone or with CC-486 in part 1 arm B

Table S1. CC-486 Plus Carboplatin Dose Levels in Part 1 Arm A Table S2. CC-486 Plus nab-Paclitaxel Dose Levels in Part 1 Arm B Table S3. CC-486 Dose Levels in Part 1 Arm C Table S4. Number of Patients With Treatment Emergent Adverse Events for Part 1 Table S5. Number of Patients With Treatment-Emergent Adverse Events in Any Treatment Arm in Part 2 Table S6. Mean CC-486 Plasma Pharmacokinetic Parameters Table S7. Efficacy of CC-486 Alone or in Combination With Carboplatin or nab-Paclitaxel in Part 2 Table S8. Prior Treatment History of NPV Patients

Mean total carboplatin plasma concentration following carboplatin administration alone or with CC-486 in part 1 arm A

Pharmacodynamic Assessments

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors.Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486.Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug–drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1–14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days.Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072–80. ©2018 AACR.

Enasidenib; Conventional care Enasidenib; Atenció convencional Enasidenib; Atención convencional This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P

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.