2022 ASH: Prolonged Survival in Bi-Allelic TP53-Mutated (TP53mut) MDS Subjects Treated with Oral Decitabine/Cedazuridine in the Ascertain Trial (ASTX727-02)

View Presentation: Prolonged Survival in Bi-Allelic TP53-Mutated (TP53mut) MDS Subjects Treated with Oral Decitabine/Cedazuridine in the Ascertain Trial (ASTX727-02)

Abstract:

Introduction: TP53 mutations (TP53mut) in myelodysplastic syndrome (MDS) patients have been characterized as an independent prognostic factor for poor outcome. These patients may have similar response rates to hypomethylating agents (HMAs) but markedly diminished overall survival (05) compared to those with wild-type (WT) TP53 status (9.4 vs. 20.7 months [mo.]; Takahashi, K, et al. Oncotarget. 2016). Further analyses have defined monoallelic (MA) and bi allelic (BA)/multi-hit TP53mut populations with very different survival outcomes (8.4 vs. 30 mo.; Bernard, et al. Nat Med. 2020). Oral decitabine/cedazuridine (ASTX727) is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) with pharmacokinetic (PK) exposure equivalent to the standard intravenous (IV) decitabine regimen of 20 mg/m2 daily X 5 days on a 28-day cycle. The ASCERTAIN study enrolled MDS and chronic myelomonocytic leukemia (CMML) subjects and the primary endpoint demonstrating PK (AUC) equivalence of oral decitabine/cedazuridine compared with IV decitabine was met (Garcia-Manero, ASH 2019); median overall survival (mOS) was 31.7 mo. (Savona, et al. MDS symposium 2021). Here we present preliminary analysis of the mutation profile of subjects enrolled on ASCERTAIN and evaluate the impact on overall and leukemia-free survival based on the NCCN MDS panel with a focus on the TP53 mutant population.

Methods: 133 subjects with MDS/CMML were enrolled to ASCERTAIN and were randomly assigned either IV decitabine for cycle 1 and oral decitabine/cedazuridine for cycle 2 or the opposite treatment sequence. All subjects continuing beyond cycle 2 received oral decitabine/cedazuridine for all subsequent cycles until treatment discontinuation for disease progression, toxicity, patient’s decision, or hematopoietic stem cell transplantation. Whole blood collected prior to treatment was used for DNA isolation and molecular abnormalities identified using next generation sequencing (NGS) hematologic malignancy panel of 179 genes including 30 genes from the NCCN MDS panel.

Results: Of the 133 treated subjects, NGS analysis was available for 125 subjects. The percentage of subjects with mutations in the following genes were: TET2 (36.8%), TP53 (35.2%), ASXL1 (28%), DNMT3A (25.6%), SRSF2_MFSD11 (17.6%), SF381 (15.2%), STAG2 (12.8%), EZH2 (11.2%), RUNX1 (11.2%), U2AF1 (10.4%), BCOR (10.4%), CBL (8.8%). TP53, EZH2, RUNX1, CBL, DNMT3A, SF381, and ASXL1 were selected for further analysis
based on their reported negative impact on OS and leukemia-free survival (LFS). TP53 and CBL mutations were closely associated with a worse OS (Hazard Ratio[HR] and 95% Cl: 1.70 (1.00, 2.87) and 2.54 (1.19, 5.43), respectively) and LFS (HR and 95% Cl: 1.63 (0.98, 2.72) and 2.01 (0.95, 4.26), respectively) compared with WT gene status, while subjects with DNMT3A mutation showed a trending advantageous relationship with OS and LFS over WT gene status. The TP53mut population (N=44) was characterized by median age 70.5 years, 63.6% M: 36.4% F, 91% MDS: 9% CMML, IPSS categories: 20% HR, 30% lnt-2, 39% lnt-1, 2% LR, 9% N/A, Cytogenetics: 27% Better-risk, 18% Intermediate risk, 48%
Poor risk, 5% N/A, ECOG 0: 39%, 1: 61%, MA 68%, BA/multi-hit 32%. The median OS and LFS of the TP53mut population were 25.5 and 22.1 mo., respectively, compared to the TP53 WT group with mOS and LFS estimates 33.7 and 31.7 months, respectively (Figure 1). The TP53mut population was further characterized by allelic status and found to have 14 subjects with BA mutations and 30 subjects with MA TP53 mutations without other chromosomal deletions. The respective estimated mOS and 95% Cl in the BA vs MA were 13.0 (5.3, 29.1) months vs. 29.2 (19.8, NE) mo. (Figure 2).

Conclusion: The NGS mutational profile of MDS and CMML subjects in the ASCERTAIN trial included 35% with TP53mut and this group had a worse survival than those with WT TP53 apparently driven by the poor outcome of those with BA TP53mut. Further LOH studies will help refine this analysis, but in this conservative estimate, treatment with oral decitabine/cedazuridine in the ASCERTAIN study resulted in an estimated survival of 13 months for BA TP53mut which compares favorably with historical results.

2022 ASH: ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

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.

2022 ASH: Phase 2 Study of Oral Decitabine/Cedazuridine in Combination with Magrolimab for Previously Untreated Subjects with Intermediate to Very High-Risk Myelodysplastic Syndromes (MDS)

View Poster: Phase 2 Study of Oral Decitabine/Cedazuridine in Combination with Magrolimab for Previously Untreated Subjects with Intermediate to Very High-Risk Myelodysplastic Syndromes (MDS)

Abstract:
Rationale
Hypomethylating agents (HMAs) are approved for higher risk MDS (azacitidine, decitabine, oral decitabine/cedazuridine US package insert). Parenteral therapy (subcutaneous or intravenous) is required 5-7 days each month, often resulting in hospital or clinic visits on a chronic basis and represents a substantial burden for this primarily elderly population and their caregivers. Not surprisingly, patients with higher risk MDS are often not started and/or have low compliance with parenteral HMAs, with patients preferring oral medications (Zeidan et al., CLML 2022). Magrolimab has demonstrated encouraging preliminary data in the higher-risk MDS population in combination with azacitidine and is currently being evaluated in a randomized Phase 3 study (ENHANCE, NCT04313881), comparing the efficacy and safety of magrolimab plus azacitidine with that of azacitidine plus placebo in previously untreated patients with higher-risk MDS. This phase 2 study examines the possibility of using an oral HMA (oral decitabine/cedazuridine) in combination with magrolimab which may provide the benefits without the burden of significant parenteral therapy (4-6 additional clinic days each month).

Study Design
ASTX727-10 is a phase 2, international, single-arm, open-label study investigating the safety and efficacy of combination oral decitabine/cedazuridine and magrolimab treatment in intermediate to very high-risk MDS, based on the MDS International Prognostic Scoring System – Revised (IPSS-R). Secondary objectives include evaluating the pharmacokinetic profiles of oral decitabine/cedazuridine and magrolimab, other clinical efficacy of the combination, and safety and efficacy in prespecified subgroups (e.g. IPSS-Molecular, p53 mutant status). To be eligible, subjects with ECOG Performance Status ≤2 must have previously untreated MDS per WHO 2016 classification with < 20% bone marrow blasts and be willing to undergo red blood cell transfusions to achieve a hemoglobin >9 gm/dl at the start of study treatment. Subjects must also be willing to undergo blood transfusions as per the parameters of the protocol and as clinically necessary. Key exclusion criteria include significant medical issues (including uncontrolled diabetes and New York Heart Association Class III-IV heart failure), creatinine clearance < 50 ml/min, immediate eligibility for hematopoietic stem cell transplant, secondary MDS, or MDS / (myeloproliferative neoplasm) overlap syndromes.
As part of the study, tolerability of the combination regimen will be confirmed in the first 6-18 subjects. Dose and/or dosing decreases identified during this dose limiting toxicity assessment will be applied to the entire study.

Approximately 100 subjects will be enrolled.

Anticipated study opening is November 2022.

2022 ACoP: A Population Pharmacokinetic Model of Tolinapant in Subjects with Advanced Solid Tumors and Lymphomas

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.

2022 TCLF – Encore Presentation: Preliminary Analysis of the Phase II Study Suing Tolinapant (ASTX6660) Monotherapy in 98 Peripheral T-Cell Lymphoma and 51 Cutaneous T-Cell Lymphoma Subjects with Relapsed Refractory Disease

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Preliminary Analysis of the Phase II Study Suing Tolinapant (ASTX6660) Monotherapy in 98 Peripheral T-Cell Lymphoma and 51 Cutaneous T-Cell Lymphoma Subjects with Relapsed Refractory Disease
 

Abstract:

Background:

There are limited treatment options for patients with PTCL and CTCL, especially when 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. Tolinapant is being evaluated in a first-in-human ongoing Phase I/II study in subjects with advanced solid tumors and lymphoma (NCT02503423). Phase I and the initial Phase II results were previously reported (Mita et al. Clin Cancer Res, 2020; Mehta et al., EHA 2019).

 

Aim:

Here we report the preliminary efficacy and safety analysis for the Phase II PTCL and CTCL cohorts.

Methods:

This is a single-arm open-label Phase II study. To be eligible, subjects must have documented progressive disease and received at least two prior systemic therapies. Subjects received tolinapant at the recommended Phase II dose of 180 mg/day on Days 1 to 7, and 15 to 22 in a 28-day cycle. The primary endpoint is investigator assessed best overall response rate (ORR) to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE V4.03. The efficacy data set is based on subjects who had tumor evaluation at baseline and at least 1 post-treatment evaluation, unless they died or stopped treatment due to progression or toxicity. The safety data set is based on all subjects that received at least one dose of tolinapant.

Results:

There were 98 PTCL subjects and CTCL 51 subjects that received drug with 98 and 50 evaluable, respectively. Enrollment is closed with a minimum of 6 months follow-up on all subjects at the time of the data cut (05JAN2022). Subject characteristics: median (range) age PTCL 62.5 (27, 82) and CTCL 62 (24,87), median number of previous therapies PTCL 3 (0-8) and CTCL 6 (1-10). Among all subjects, the most common related AEs of any grade (≥ 15%) were: lipase elevation (35%), amylase elevation (25%), rash (combined listings) (24%), ALT elevation (15%), and AST elevation (15%). Related AEs ≥ Grade 3 (≥ 5%) were: lipase elevation (15%), rash (9%), and amylase elevation (7%). Pancreatitis was identified in 2 subjects (1%) (both Grade 4). There were no related ≥ Grade 3 AEs for diarrhea, nausea or vomiting; for related Grade 2 AEs there was a 5% incidence of diarrhea and 1% incidence of nausea/vomiting.

The ORR for PTCL is 22%, including 9 complete responses (CRs) and 12 partial responses (PRs). The ORR in CTCL is 26% including 2 CRs and 11 PRs. The median durability of response for PTCL is 133 (Q1-Q3; 69 – 280) days and for CTCL is 148 (Q1-Q3; 103 – 294) days.

Conclusions:

In this Phase II study, the novel oral agent tolinapant has shown meaningful single-agent clinical activity against PTCL and CTCL with a manageable safety profile. A new PTCL study combining tolinapant with oral decitabine/cedazuridine in relapsed/refractory PTCL is currently enrolling subjects.

This abstract has been presented at EHA 2022.

2022 TCLF: 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

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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.

 

2022 EHA: Preliminary Analysis of the Phase II Study Suing Tolinapant (ASTX6660) Monotherapy in 98 Peripheral T-Cell Lymphoma and 51 Cutaneous T-Cell Lymphoma Subjects with Relapsed Refractory Disease

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Preliminary Analysis of the Phase II Study Suing Tolinapant (ASTX6660) Monotherapy in 98 Peripheral T-Cell Lymphoma and 51 Cutaneous T-Cell Lymphoma Subjects with Relapsed Refractory Disease

Abstract:

Background: There are limited treatment options for patients with Peripheral T-cell lymphoma (PTCL) and Cutaneous T-cell lymphoma (CTCL), especially when front line therapy has failed. Tolinapant (ASTX660) is a novel oral nonpeptidomimetic, 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). Tolinapant is being evaluated in a first-in-human ongoing Phase I/II study in subjects with advanced solid tumors and lymphoma (ClinicalTrials.gov NCT02503423). Phase I results were previously reported (Mita et al. Clin Cancer Res, 2020) and the recommended phase 2 dosing (RP2D) was established. Initial results for Phase II were previously reported at EHA 2019 (Mehta et al., EHA 2019, # PS1073).

Aims: Here we report the preliminary efficacy and safety analysis for the Phase 2 PTCL and CTCL cohorts.

Methods: Methods: This is a single-arm open-label Phase II study. To be eligible, subjects must have evidence of documented progressive disease and received at least two prior systemic therapies. Subjects received treatment with tolinapant at the RP2D 180 mg/day on Days 1 to 7, and 15 to 22 in a 28-day cycle. The primary endpoint is best overall response rate (ORR) as assessed by the investigator according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE v4.03. The efficacy data set is based on subjects who had tumor evaluation at baseline and at least 1 post-treatment tumor evaluation visit, unless they died or stopped treatment earlier due to clinical progression or toxicity. The safety data set is based on all subjects that received at least one dose of tolinapant.

Results: Results: As of the data cut of January 5, 2022, there were 98 subjects with PTCL and 51 subjects with CTCL that received drug and 98 and 50 subjects that were evaluable respectively. The study is currently closed to enrollment with a minimum of 6 months follow-up on all subjects at the time of the data cut. Subject characteristics: median (range) age PTCL 62.5 (27, 82) and CTCL 62 (24,87), median number of previous therapies PTCL 3 (0-8) and CTCL 6 (1-10). Among all subjects, the most common related AEs of any grade (≥ 15%) were: lipase elevation (35%), amylase elevation (25%), rash (combined listings) (24%), ALT elevation (15%), and AST elevation (15%). Related AEs ≥ Grade 3 (≥ 5%) were: lipase elevation (15%), rash (combined listings) (9%), and amylase elevation (7%). Pancreatitis was identified in 2 subjects (1%) (both Grade 4). There were no related ≥ Grade 3 AEs for diarrhea, nausea or vomiting; for related Grade 2 AEs there was a 5% incidence of diarrhea and 1% incidence of nausea/vomiting.

The ORR for PTCL is 22%, including 9 complete responses (CRs) and 12 partial responses (PRs). The ORR in CTCL is 26% including 2 CRs and 11 PRs. The median durability of response for PTCL is 133 (Q1-Q3; 69 – 280) days and for CTCL is 148 (Q1-Q3; 103 – 294) days. Pharmacodynamic and correlative analysis is ongoing with preliminary analysis suggesting an immunomodulatory antitumoral effect of tolinapant (Ferrari et al., Blood Advances, 2021).

Summary/Conclusion: In this Phase II study, the novel oral agent tolinapant has shown meaningful clinical activity against PTCL and CTCL with a manageable safety profile. These results support the continued development of tolinapant for the treatment of R/R PTCL and CTCL. A drug combination study using tolinapant in R/R PTCL is being developed.

2022 EHA: 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

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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.

2022 EHA: GUADECITABINE (SGI-110) VS. TREATMENT CHOICE (TC) IN RELAPSED/REFRACTORY(R/R) MYELODYSPLASTIC SYNDROME (MDS), RESULTS OF A GLOBAL, RANDOMIZED, PHASE 3 STUDY

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GUADECITABINE (SGI-110) VS. TREATMENT CHOICE (TC) IN RELAPSED/REFRACTORY(R/R) MYELODYSPLASTIC SYNDROME (MDS), RESULTS OF A GLOBAL, RANDOMIZED, PHASE 3 STUDY

Background: Guadecitabine (G) is a next-generation hypomethylating agent (HMA), administered as a small-volume subcutaneous (SC) injection, designed with the potential to overcome pharmacokinetic resistance to first-generation HMAs (decitabine and azacitidine). Preliminary guadecitabine phase 2 data in r/r MDS showed an overall survival of almost 12 months (Garcia-Manero,G, et al; Lancet Haematol http://dx.doi.org/10.1016/S2352-3026 [19]30029-8) leading to the ASTRAL-3 study.

Aims: Compare overall survival of guadecitabine to that of TC consisting of low-dose cytarabine (LDAC), intensive chemotherapy (IC), or best supportive care (BSC). Secondary objectives included multiple standard assessments of response and safety.

Methods: Subjects with r/r MDS or Chronic Myelomonocytic Leukemia (CMML) who had progressed or failed to respond after 6 full cycles of standard HMA therapy were randomized 2:1 between guadecitabine (60 mg/m2) SC Days 1-5 every 28 days vs. a pre-selected TC (BSC, IC, or LDAC). Stratification was by disease, disease burden
(>10% bone marrow blasts or not, geography, and pre-selected TC option). Primary endpoint was overall survival
(OS) and the study was designed with ~90% power to detect a hazard ratio of 0.68 (approximately 2.8 month
difference in median survival).

Results: 417 MDS/CMML subjects were randomized to G or TC (G:277, TC: 140). Demographics and disease status were reasonably balanced across the groups (see Table 1 below) as was percentage of commonly associated genetic
mutations (TET2, DNMT3A, SF3Baa, RUNX1, and TP53). Median guadecitabine exposure was 4 cycles and 3 cycles
for TC. Neither overall survival (G: median 9.1 months, TC: median 8.3 months, p=0.61, HR:0.94 with 95% CI:
[0.74-1.19]) nor leukemia-free survival (LFS) (G: median 5.7 months, TC: median 5.9 months; p=0.38) demonstrated
a significant difference between the two groups and subgroup analyses did not suggest a difference between
guadecitabine and any of the different TC options or different genetic mutations. Transfusion dependence for 8 weeks
was similar with 32.1% and 22.4% of the G group and 37.9% and 20.0% of the TC group being platelet transfusion
or red blood cell transfusion independent, respectively. Safety was consistent with known profiles of the respective
agents with the G group having a slightly higher overall incidence of adverse events (AE) (99.3% vs 92.6% for TC)
and grade 3 or higher AE (92.2% vs 70.5% for TC). The AEs with the highest incidence in subjects who received
guadecitabine were febrile neutropenia (38.5 vs 18.9% for TC), pneumonia (34.4% vs 18.9% for TC), neutropenia
(34.1% vs 15.6% for TC), and thrombocytopenia (32.2% vs 21.3% for TC).

Summary/Conclusion: This large, global, randomized phase 3 study did not demonstrate superiority of guadecitabine
over Standard TC in MDS/CMML patients who were refractory or relapsed following full course of prior HMA
treatment.

2022 EHA: COMBINING THE IAP ANTAGONIST, TOLINAPANT, WITH A DNA HYPOMETHYLATING AGENT ENHANCES ANTI-TUMOUR MECHANISMS IN PRECLINICAL MODELS OF T-CELL LYMPHOMA

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COMBINING THE IAP ANTAGONIST, TOLINAPANT, WITH A DNA HYPOMETHYLATING AGENT ENHANCES ANTI-TUMOUR MECHANISMS IN PRECLINICAL MODELS OF T-CELL LYMPHOMA

Abstract:
Background: Tolinapant is a potent, non-peptidomimetic antagonist of cIAP1, cIAP2 and XIAP. In a Phase 2 trial (NCT02503423), tolinapant has shown activity against highly pre-treated peripheral and cutaneous T-cell lymphoma (Samaniego et al., Hematological Oncology, 2019). Hypomethylating agents (HMAs) have also shown clinical responses in some subsets of PTCL (Lemonnier et al., Blood, 2019). Both HMAs and IAP antagonists show immunomodulatory anti-cancer potential in preclinical studies.

Aims: Here we have undertaken a biomarker-driven approach to understand the potential for induction of immunogenic forms of cell death, such as necroptosis, by rational combination of our clinical compounds in
preclinical models of TCL.

Methods: On-target effects of decitabine and tolinapant were measured by analysing levels of DNMT1 and cIAP1,respectively, by Western blotting in mouse and human cell lines. Levels of key necroptosis biomarkers (RIPK3, MLKL) were also monitored by Western blotting to provide evidence of lytic cell death contributing to a potential immune response. Karpas-299 cells genetically-manipulated to express RIPK3 were used to demonstrate involvement of necroptosis in drug-induced cell death (Cytotox NIR) in vitro. Cell death was monitored by viability (CellTiterGlo)or real-time microscopy (IncuCyte) assays. Levels of key immunomodulatory mediators or DAMPS were measured in tissue culture supernatants and mouse plasma. Levels of methylation in RIPK3 promoter regions were measured by pyrosequencing after bisulfite conversion. Comparative changes in gene expression were measured by RT-qPCR.

Results:
TCL cell lines treated with tolinapant, decitabine or both led to depletion of cIAP1 and DNMT1 in TCL cell lines,
demonstrating target engagement of both agents. The combination of tolinapant and decitabine synergistically
reduced viability of some human T-cell lymphoma cell lines.
Some cell lines, including Karpas-299, were resistant to tolinapant treatment and showed low expression of RIPK3,
which was found to be due to promoter methylation. Increased expression of RIPK3 in Karpas-299 by genetic
manipulation or by decitabine treatment resulted in enhanced lytic cell death upon tolinapant treatment.
Decitabine and tolinapant treatments resulted in expression of cytokines, chemokines and DAMPs, suggesting
potential for immune activation and the effects were enhanced when combined. Furthermore, normally silenced
cancer/testis antigen expression was increased by decitabine, potentially increasing the immunogenicity of the cells.
Evaluation of the combination of agents in mouse models suggested that increased necroptosis signal and immune-potentiating biomarker modulation can be achieved in vivo.

Summary/Conclusion: These data demonstrate that hypomethylating agents enhance immunogenic cell death induced by tolinapant through the re-expression of genes in the necroptotic pathway. In addition, modulation of cytokine response and cancer/testis antigen expression could enhance anti-tumour response. These findings provide a strong rationale to explore this combination clinically.