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https://www.mdpi.com/2072-6694/15/4/1315

Abstract:

The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.

View Presentation: ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

Abstract:

Introduction: The safety and clinical activity of low-dose hypomethylating agents (HMAs; parenteral decitabine or azacitdine) for patients with LR-MDS has been reported (Jabbour et al, 2017). Oral decitabine/cedazuridine (ASTX727; fixed-dose combination of 35 mg decitabine/100 mg cedazuridine) is an oral DNMTi that provides equivalent exposure to intravenous decitabine at a standard dosing (SD) regimen (20 mg/m2 days 1-5 every 28 days; Garcia-Manero et al, 2020). An effective oral HMA therapy for patients with LR-MDS that reduces the number of transfusions while avoiding the toxicity associated with both myelosuppression and parenteral administration could ease the burden of HMA administration on patients and caregivers with potential improvement of quality of life. The Phase 1 part of this study explores the optimal dosing schedule of LD oral decitabine/cedazuridine in patients with LR-MDS.

Methods: A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted at US and EU medical centers in subjects with LR-MDS (IPSS low risk and Int-1). Dose selection for the ASTX727-03 Phase 1 study was divided into two phases (Stage A and Stage B). Phase 1 Stage A was designed to approximate the total dose of intravenous (IV) DEC (20 mg/m2 for 5 days) over a longer dosing period and randomized subjects to 3 Cohort regimens of 5 (Cohort A1), 10 (Cohort A2), or 15 mg (Cohort A3) DEC /100 mg CED daily for 10 days in 28-day cycles. In Phase 1 Stage B, subjects were treated with the following 3 LD oral decitabine/cedazuridine regimens of shorter duration; Cohort B1: 10 mg DEC / 100 mg CED daily for 5 days, Cohort B2: 10 mg DEC / 100 mg CED daily for 7 days, Cohort B3: 20 mg DEC / 100 mg CED daily for 5 days. Primary endpoints include determination of dose-limiting toxicity (DLT), frequency and severity of treatment-emergent adverse events (TEAEs), and the recommended Phase 2 dose (RP2D). Secondary endpoints include: pharmacodynamic (PD) activity, pharmacokinetics (PK), and clinical activity based on International Working Group (IWG) 2006 MDS response criteria and transfusion independence, Leukemia Free survival (LFS), and overall survival (OS).

Results: At the data cut-off date of June 17, 2022, 48 LR-MDS subjects were enrolled, and 47 received study treatment. Characteristics were: median age: 76 years (range 51 – 88), male: 31 (65%), and IPSS LR: 15 (31%) and Int-1: 33 (69%), respectively. The median duration of exposure is 9 cycles (range 1-34).

In Stage A, cohort A2 (10 mg, 10-day) was closed due to hematologic DLT (see Table 1) in all four treated subjects, hence cohort A3 (15 mg, 10-day) was closed prior to any subjects being randomized to that regimen. The final number of subjects treated in cohorts A1 (5 mg, 10-day), A2, and A3 were 10, 4, and 0, respectively. In Stage B, 33 subjects were randomly assigned to cohorts B1 (10 mg, 5-day), B2 (10 mg, 7-day), or B3 (20 mg, 5-day), with 11 subjects each treated with the respective dosing schedules. DLT was observed in 3 (30%), 4 (100%), 3 (27%), 7 (70%), and 7 (64%) subjects in Cohorts A1, A2, B1, B2, and B3, respectively. The DLT incidences were proportional to the dose intensity (total DEC dose per cycle) and number of days of study drug administration. All DLTs were related to neutropenia and in general regimens with higher total doses of DEC per cycle (Cohorts A2 and B3) had deeper neutrophil nadirs while regimens with longer dosing periods (7-10 days; Cohorts A1, A2, and B2) required longer to recover neutrophil counts to baseline and dose reductions and dose delays were observed more frequently than in Cohort B1. Adverse events were similar to those reported for standard dose oral decitabine/cedazuridine, with the most common grade ≥ 3 TEAEs being neutropenia (36%), anemia (28%), and febrile neutropenia (19%).

Clinical activity by dosing schedule is shown in Table 1, and bioavailability was confirmed by PK analysis. Of the 47 treated subjects, 22 subjects (47%) had reached the event of death as of the data cutoff date and median OS time was 929 days (95% CI: 526, NE). Median LFS was 690 days (95% CI: 428, 934).

Conclusions: Based on the results of the Phase 1 study, the dosing schedule of 10 mg DEC / 100 mg CED daily for 5 days, that balanced clinical efficacy

with an acceptable and manageable safety profile was selected as the RP2D. This regimen will be compared to 35 mg DEC / 100 mg CED for 3 days in a 28-day

cycle in the ongoing Phase 2 study.

View Poster: A Population Pharmacokinetic Model of Tolinapant in Subjects with Advanced Solid Tumors and Lymphomas

Abstract:

 Methods: Data from dose-escalation stage (Phase 1) and dose-expansion stage (Phase 2) from clinical study ASTX660-01 were included. Subjects recruited into Phase 1 received tolinapant in either powder (15, 30, 60, 120 and 180 mg; n=16) or capsule formulation (180, 210 and 270 mg; n=27). Subjects in Phase 2 only received capsule formulation (90, 120, 150 or 180 mg). A population PK model was developed with NONMEM v. 7.3 using first-order conditional estimation with eta-epsilon interaction (FOCE-I). Model selection was based on goodness-of-fit plots, objective function values, prediction and variance corrected visual predictive check (pvcVPC), and model plausibility. Confidence intervals (CIs) around the parameters were computed using the sampling importance resampling (SIR) method.^[1]

Results: The data comprised 3427 tolinapant concentration measurements from 163 subjects (Phase 1; n=43, Phase 2; n=120) aged 23 to 84 years. tolinapant PK was best described using a two-compartment nonlinear elimination model with absorption described by a transit compartment model. The rate of absorption was dependent on formulation and was described by separate transit rate constants (KTR) for powder and capsules. Population estimates of Michaelis-Menten constant (Km), maximum elimination rate (Vmax), and apparent central volume of distribution (Vc/F) were 918.3 ng/mL, 72.2 ng/L and 488.6 L, respectively. Between subject variability included on Vmax and Vc/F were 21.3% and 40%, respectively. An additive error model on log transformed data was used to account for the unexplained residual variability. All parameters were estimated with acceptable precision. The predictive performance of the model assessed by the pvcVPC indicated that the data were adequately described by the model.

Conclusion: A population PK model was developed for tolinapant in subjects with advanced solid tumors and lymphomas. This work is the first description of the tolinapant PK, and the next steps are to explore the exposure and efficacy relationships and investigate the anti-tumor activity of tolinapant in one or more selected tumor types.

Reference:

1. Dosne AG, Berstrand M, Harling K, Karlsson MO. Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling. J Pharmacokinet Pharmacodyn, 43(6):583–596, 2016.

View Presentation:

Trials-In-Progress, A Phase 1-2, Open-Label Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Activity of Tolinapant in Combination with Oral Decitabine/Cedazuridine and Oral Decitabine/Cedazuridine Alone in Subjects with Relapsed/Refractory Peripheral T-cell Lymphoma

Rationale

There are limited treatment options for patients with PTCL after front line therapy has failed. Tolinapant (ASTX660) is a novel oral non-peptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which also induces necroptosis in T-cell lymphoma models (Ferrari et al., Blood Advances, 2021). An ongoing Phase 1/2 study demonstrates an overall response rate (ORR) of >20% in relapsed/refractory PTCL with single agent tolinapant (Michot et al., EHA 2022). While there are limited studies using hypomethylating agents (HMAs) in PTCL, a recent prospective study showed 40% ORR (Wong et al., Leukemia, 2022). Preclinical data demonstrate decitabine treatment leads to re-expression of gene expression critical for necroptosis and synergy between decitabine and tolinapant in T-cell tumor models (Ward et al. ASH 2021; Manavalan et al; EHA abstract 2022). These data suggest that this combination may have synergistic activity in PTCL. There are minimal overlapping toxicities between the study drugs and no expected drug-drug interactions. Oral decitabine and cedazuridine (an inhibitor that enhances the oral bioavailability of decitabine) is an oral fixed dose combination of the two drugs with pharmacokinetic equivalence to IV decitabine. This combination was recently approved in the US, Canada, and Australia for the treatment of intermediate and high-risk MDS and CMML.

Study Design

ASTX660-03 is a Phase 1-2, open-label study investigating the safety and efficacy of combination tolinapant and oral decitabine/cedazuridine treatment in relapsed/refractory PTCL. To be eligible, subjects with ECOG PS ≤2 must have received at least two prior systemic therapies with evidence of documented progressive disease with at least one measurable lesion by CT. Subjects with CD30-positive disease must have received, be ineligible for, or intolerant to brentuximab vedotin. Key exclusion criteria include ejection fraction <50%, QTc >470 msec, and the use of concomitant medications that are either strong or moderate CYP3A4 inhibitors/inducers.

There is a lead-in phase to confirm tolerability of the MDS-approved regimen of oral decitabine/cedazuridine is tolerated in a PTCL population. Phase 1 is randomized to oral decitabine/cedazuridine alone or in combination with tolinapant. The combination arm will have escalation of tolinapant in dose ranges that have shown efficacy in PTCL. The oral decitabine/cedazuridine only arm will enroll 20-24 subjects. Once the combination arm reaches recommended Phase 2 dose/maximum tolerated dose there will be a dose expansion of 20 subjects in the combination arm prior to the initiation of the combination dosing in Phase 2, with an enrollment goal of 102 subjects. There will be no formal analysis in Phase 1. In Phase 2, there will be efficacy analysis for every 34 subjects, without a pause in enrollment. Anticipated study opening is May 2022.

View poster: 

PHARMACOKINETIC EXPOSURE EQUIVALENCE AND PRELIMINARY EFFICACY AND SAFETY FROM A RANDOMIZED CROSSOVER PHASE 3 STUDY OF AN ORAL HYPOMETHYLATING AGENT, ASTX727 (DEC-C), COMPARED TO IV DECITABINE IN AML PATIENTS

Abstract:

Background: Parenterally administered hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are approved in Europe for adult patients with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy as single agent or in combination with venetoclax. ASTX727 (DEC-C) is a fixed dose combination (FDC) tablet of 35 mg DEC and 100 mg cedazuridine, a novel cytidine deaminase inhibitor (CDAi). In clinical trials with myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) patients, DEC-C provides DEC exposures that are equivalent to IV DEC at the approved dose of 20 mg/m2 daily×5 and is approved as INQOVI® in the US, Canada, and Australia.

Aims: To demonstrate DEC exposure bioequivalence of oral DEC-C and IV-DEC and generate clinical data using DEC-C in AML patients.

Methods: The ASCERTAIN study was a randomized cross over design. Patients were randomized 1:1 to either Sequence A: DEC-C (35 mg DEC/100 mg cedazuridine) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B: receiving IV-DEC in Cycle 1 followed by DEC-C on Cycle 2 to compare PK [primary endpoint Area Under the Curve (AUC) equivalence over 5 days of dosing]. All patients received DEC-C from Cycle 3 onwards until treatment discontinuation to assess safety and clinical efficacy. Patients were eligible as per the EMA-approved decitabine label (newly diagnosed AML who are not candidates for standard induction chemotherapy). Clinical responses were assessed according to modified International Working Group (IWG) 2003 response criteria.

Results: 89 patients were randomized, of whom 87 were treated. The median age of patients was 78.0 years (range, 61 to 92) with 31 (35.6%) males and 56 (64.4%) females. Cytogenetic risk classification was poor-risk in 33 (37.9%) and intermediate-risk in 45 (51.7%) patients. For the primary endpoint, preliminary PK data was available from 69 patients who successfully completed PK assessments for both IV DEC and DEC-C cycles, and the DEC AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 904 for DEC-C and 907 for IV-DEC resulting in an oral/IV geometric LSM AUC ratio of 99.64% (90% CI of 91.23-108.8%). Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 10% were thrombocytopenia, anemia, febrile neutropenia, neutropenia, and pneumonia). As of the data cutoff date (10 SEP 2021), median follow up was 7.95 months (IQR 6.11-11.86). Of the 77 patients who had ≥6 months of follow up or discontinued treatment, the best response was complete response (CR) in 17 (22.1%, 95% CI: 13.4, 33.0%). In addition, 4 patients (5.2%) had CR with incomplete blood cell count recovery (CRi), with 1 patient (1.3%) who had CR with incomplete platelet recovery (CRp), resulting in composite response rate [CR + CRp] of 23.4% [18/77 patients, 95% CI: 14.5, 34.4%]. These results obtained with DEC-C are consistent with those observed for IV DEC. Based on preliminary and limited study follow-up with ~46% censored observations, the median survival was approximately 7.9 months (95% CI: 5.9, 13.0).

Summary/Conclusion: This randomized phase 3 study in AML patients not candidates for standard induction chemotherapy demonstrates that the oral FDC of DEC-C (35mg/100 mg) resulted in an equivalent DEC AUC exposure to IV-DEC at 20 mg/m2 over 5 days. In addition, safety findings and preliminary clinical activity is also consistent with published data from IV-DEC, suggesting that DEC-C has the potential to be an oral alternative to the standard IV decitabine Daily×5 regimen.