2023 Intl. Congress on MDS: PHASE 1 STUDY EVALUATING LOW-DOSE (LD) ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS

/in , ,

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

Abstract:

Introduction and Aims: Cedazuridine (CED), a cytidine deaminase inhibitor allows oral availability of decitabine (DEC); 5 daily doses of the fixed-dose combination of 35mg DEC/100mg CED provides equivalent exposure to an IV DEC regimen of 20mg/m2 D1-5 every 28 days(Garcia-Manero et al, 2020). This study explores the optimal dosing schedule of LD oral DEC/CED in LR-MDS patients.

Methods: A two-part Phase 1/2 study is being conducted in LR-MDS (IPSS low risk and lnt-1). Phase 1A, subjects were assigned to three regimens of DEC/CED (5mg/100mg, 10mg/100mg, and 15mg/100mg) for 10 days in a 28-day cycle. Phase 1B, subjects were assigned to three LD regimens with shorter durations of DEC/CED (10mg/100mg for 5 days, 10mg/100mg for 7 days, and 20mg/100mg for 5 days). The primary endpoints were dose-limiting toxicities (DLTs), safety, and the determination of the recommended phase 2 dose (RP2D). Secondary endpoints were pharmacokinetics, pharmacodynamic, and efficacy. Sub-analysis was performed based on genomic mutation profiles.

Results: 47 subjects received study treatment in various LD DEC/CED regimens. DLT associated with prolonged neutropenia were associated with higher dose and number of treatment days per cycle. The safety profile was generally consistent with decitabine treatment (myelosuppression). Neutropenia was less common with the low-dose/short-dose regimens. Clinical activity was observed in all dosing cohorts.

Conclusion: Based on the clinical efficacy and safety profile, 10mg DEC/100mg CED for 5 days was selected as the RP2D for further study. The RP2D regimen is being currently compared to 35mg DEC/100mg CED for 3 days in an ongoing Phase 2 study.

2023 Intl MDS Congress: Phase 2 Study of Oral Decitabine/Cedazuridine in Combination with Magrolimab for Previously Untreated Subjects with Intermediate to Very High-Risk Myelodysplastic Syndromes (MDS)

/in , ,

View Presentation: 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:
Background & Aims:
Parenteral therapy using hypomethylating agents (HMAs) requires 5-7 days each month, resulting in hospital or clinic visits on a chronic basis and represents a substantial burden for this primarily elderly population and their caregivers. Magrolimab has demonstrated encouraging preliminary data 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 of combination therapy without the burden of significant parenteral therapy.

Methods:
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 MDS International Prognostic Scoring System-Revised (IPSS-R). Secondary objectives include analysis for safety and efficacy assessments based on the IPSS- Molecular (IPSS-M) and p53 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. Key exclusion criteria include significant medical issues, creatinine clearance < 50 ml/min, immediate eligibility for hematopoietic stem cell transplant, or secondary MDS.

Results:
Approximately 100 subjects will be enrolled.

Conclusion:
The study is anticipated to open soon.

Shibuya, et al. “SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling”; Cancers 2023

/in , ,

Click link to view article:

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.

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

/in , ,

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

/in , ,

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)

/in , ,

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

/in , ,

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

/in , ,

View 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
 

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

/in , ,

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.

 

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

/in , ,

View 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

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.