ASTX727 for Peripheral Nerve Sheath Tumor
Recruiting in Palo Alto (17 mi)
+7 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Must not be taking: Antivirals, Anticancer
Disqualifiers: Uncontrolled diabetes, Active infections, Cardiovascular disease, others
No Placebo Group
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?
The purpose of this study is to see whether the study drug ASTX727 is an effective treatment for people who have MPNST with a PCR2 mutation. ASTX727 is a combination of two drugs (cedazuridine and decitabine) that have been designed to target cancer cells with a PCR2 mutation and to disrupt the cells' ability to survive and grow. The study researchers think that the study drug allows decitabine to work better than decitabine given alone.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, you must not have had any anti-cancer therapy within 14 days before starting the study drug, and for certain biological therapies, the interval must be at least 28 days.
Is ASTX727 (Decitabine/Cedazuridine) safe for humans?
ASTX727, a combination of decitabine and cedazuridine, has been studied for safety in humans, primarily for blood-related cancers like myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Common side effects include low blood cell counts, which can lead to infections or bleeding. Overall, it has been well-tolerated in clinical trials, with side effects similar to those seen with intravenous decitabine.12345
How is the drug ASTX727 different from other treatments for malignant peripheral nerve sheath tumors?
ASTX727 is unique because it combines decitabine, a drug that affects DNA methylation (a process that can turn genes on or off), with cedazuridine, which helps maintain decitabine levels in the body, potentially offering a new approach for treating malignant peripheral nerve sheath tumors where standard treatments are limited.678910
Eligibility Criteria
This trial is for adults with malignant peripheral nerve sheath tumors (MPNST) that have a specific mutation called PCR2. Participants must have tried at least one standard treatment or be unsuitable for chemotherapy, and their cancer should be advanced and measurable. They need to be in fair health overall, able to take pills, not pregnant or breastfeeding, willing to use contraception, and without certain heart conditions or recent major surgeries.Inclusion Criteria
Female patients of childbearing potential must agree to use two reliable methods of contraception starting at signing the ICF, during and for 6 months following the last dose of study drug
I am 18 years old or older.
My cancer cannot be removed by surgery and has spread.
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Exclusion Criteria
My heart's pumping ability is below 50%.
Patients with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent
I had major surgery less than 3 weeks ago or am still recovering from it.
See 10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive oral ASTX727 (cedazuridine and decitabine) on days 1-5 of each 21-day cycle with Pegfilgrastim support on day 7
16 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
8 weeks
Treatment Details
Interventions
- ASTX727 (Anti-metabolites)
Trial OverviewASTX727 is being tested as a potential treatment for MPNST with PCR2 mutation. It's a combo of cedazuridine and decitabine designed to target cancer cells more effectively than decitabine alone by disrupting the tumor cells' survival mechanisms.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: ASTX727 (cedazuridine and decitabine)Experimental Treatment1 Intervention
Patients who meet the eligibility criteria will be treated with oral ASTX727 (INQOVI) on days 1-5 of each 21-day cycle with Pegfilgrastim support on day 7. A delay in the start of subsequent cycles due to holidays, weather, or other circumstances will be permitted up to 7 days and not considered a protocol deviation. Drug dosing will be interrupted for any Grade 4 adverse events or clinically significant laboratory abnormalities. For Grade 3 or 4 AE, if the AE returns to Grade 1 or baseline, the patient may be re-escalated.
ASTX727 is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Inqovi for:
- Myelodysplastic Syndromes (MDS)
🇪🇺 Approved in European Union as Inqovi for:
- Myelodysplastic Syndromes (MDS)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)Middletown, NJ
Memorial Sloan Kettering Bergen (Limited Protocol Activities)Montvale, NJ
Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)Basking Ridge, NJ
Memorial Sloan Kettering Commack (Limited Protocol Activities)Commack, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
Taiho Pharmaceuticals, Inc.Collaborator
Astex Pharmaceuticals, Inc.Industry Sponsor
References
Decitabine/Cedazuridine: First Approval. [2021]A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. [2023]On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.
Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.
Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. [2022]Decitabine (5-aza-2'-deoxycytidine) inhibits DNA methylation and has dual effects on neoplastic cells, including the reactivation of silenced genes and differentiation at low doses and cytotoxicity at high doses. We evaluated, in a phase 1 study, low-dose prolonged exposure schedules of decitabine in relapsed/refractory leukemias. Patient cohorts received decitabine at 5, 10, 15, or 20 mg/m2 intravenously over one hour daily, 5 days a week for 2 consecutive weeks, doses 5- to approximately 30-fold lower than the maximum tolerated dose (MTD). There were 2 groups that also received 15 mg/m2 daily for 15 or 20 days. A total of 50 patients were treated (44 with acute myelogenous leukemia [AML]/myelodysplasia [MDS], 5 with chronic myelogenous leukemia [CML], and 1 with acute lymphocytic leukemia [ALL]), and the drug was well tolerated at all dose levels, with myelosuppression being the major side effect. Responses were seen at all dose levels. However, the dose of 15 mg/m2 for 10 days appeared to induce the most responses (11 of 17 or 65%), with fewer responses seen when the dose was escalated or prolonged (2 of 19 or 11%). There was no correlation between P15 methylation at baseline or after therapy and response to decitabine. We conclude that decitabine is effective in myeloid malignancies, and low doses are as or more effective than higher doses.
[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. [2019]To investigate the therapeutic effectiveness and side effects of decitabine combined with or without cytarabine-based low dose regimen for acute myeloid leukemia in geratic patients.
Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors. [2019]Malignant peripheral nerve sheath tumors (MPNST) are rare, highly aggressive sarcomas that can occur spontaneously or from pre-existing plexiform neurofibromas in neurofibromatosis type1 (NF1) patients. MPNSTs have high local recurrence rates, metastasize easily, are generally resistant to therapeutic intervention and frequently fatal for the patient. Novel targeted therapeutic strategies are urgently needed. Standard treatment for patients presenting with advanced disease is doxorubicin based chemotherapy which inhibits the actions of the enzyme topoisomerase IIα (TOP2A). Recent molecular studies using murine models and cell lines identified the bromodomain containing protein 4 (BRD4) and enhancer of zeste homolog 2 (EZH2) as novel targets for MPNST treatment. We investigated the expression and potential use of BRD4, EZH2 and TOP2A as therapeutic targets in human NF1-derived MPNSTs. The transcript levels of BRD4, EZH2 and TOP2A were determined in paired formalin-fixed paraffin-embedded (FFPE) neurofibroma/MPNST samples derived from the same NF1 patient and in a set of plexiform neurofibromas, atypical neurofibromas and MPNST. We further examined the effect on cell viability of genetic or pharmacological inhibition of BRD4, EZH2 and TOP2A in an MPNST cell line panel. Our results indicated that in MPNST samples BRD4 mRNA levels were not upregulated and that MPNST cell lines were relatively insensitive to the bromodomain inhibitor JQ1. We corroborated that EZH2 mRNA expression is increased in MPNST but failed to confirm its reported pivotal role in MPNST pathogenesis as EZH2 knockdown by siRNA did not interfere with cellular proliferation and viability. Finally, the relation between TOP2A levels and sensitivity for doxorubicin was examined, confirming reports that TOP2A mRNA levels were overexpressed in MPNST and showing that MPNST cell lines exhibited relatively high TOP2A protein levels and sensitivity to doxorubicin. We tentatively conclude that the potential for effective therapeutic intervention in MPNST by targeting BRD4, EZH2 and TOP2A individually, may be limited. Clinical studies are necessary to ultimately prove the relevance of BRD4 and EZH2 inhibition as novel therapeutic strategies for MPNST.
A Clinicopathologic Study of Head and Neck Malignant Peripheral Nerve Sheath Tumors. [2018]Head and neck high grade malignant peripheral nerve sheath tumors (HN-MPNSTs) are rare highly aggressive soft tissue sarcomas that show overlapping morphologic and immunophenotypic features with melanoma and other high grade sarcomas, resulting in diagnostic challenges, particularly in sporadic settings. Recent discoveries have implicated loss of function mutations in the polycomb repressive complex 2 (PRC2) components, including EED or SUZ12 genes, as one of the leading pathogenetic mechanisms in high grade MPNST. MPNSTs with PRC2 loss are associated with complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3), which emerged as a reliable immunohistochemical marker in the diagnosis of sporadic and radiation induced MPNST. As the diagnosis of MPNST in the HN is particularly challenging to distinguish from melanoma and other sarcoma types, we carried out a clinicopathologic analysis on HN-MPNST patients managed at our institution over a 20-year period (1997-2016), using the latest diagnostic criteria including H3K27me3 staining and other molecular investigations. The overall survival of HN-MPNST was compared with other HN soft tissue sarcomas. The diagnosis of HN-MPNST was confirmed in 13 patients (seven males and six females), with a mean age of 31 years; with 3 (23%) patients being of pediatric age. The most common site was the neck soft tissue (77%). Two-thirds of patients (n = 9) had stigmata of NF1, three had prior radiotherapy and only one developed a de novo MPNST. All except one tumor (86%) tested showed loss of H3K27me3 expression, including all non-NF1 patients. The 2 and 5-year DSS rates were 50 and 30%. The 2-year DFS rate was 21%. Adverse predictors on DSS included adult age (p = 0.011), prior-history of RT (p = 0.003) and recurrence (p = 0.003). Compared to other molecularly confirmed subsets of HN sarcomas (Ewing and Ewing-like sarcoma, rhabdomyosarcoma and synovial sarcoma), HN-MPNST had the worst overall survival (p
Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities. [2023]Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers of MPNST that can serve as therapeutic targets. Unsupervised analyses of methylome and transcriptome profiles identify two distinct subgroups of MPNSTs with unique targetable oncogenic programs. We establish two subgroups of MPNSTs: SHH pathway activation in MPNST-G1 and WNT/ß-catenin/CCND1 pathway activation in MPNST-G2. Single nuclei RNA sequencing characterizes the complex cellular architecture and demonstrate that malignant cells from MPNST-G1 and MPNST-G2 have neural crest-like and Schwann cell precursor-like cell characteristics, respectively. Further, in pre-clinical models of MPNST we confirm that inhibiting SHH pathway in MPNST-G1 prevent growth and malignant progression, providing the rational for investigating these treatments in clinical trials.
Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis. [2023]Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas of the peripheral nervous system that develop either sporadically or in the context of neurofibromatosis type 1 (NF1). MPNST diagnosis can be challenging and treatment outcomes are poor. We present here a resource consisting of the genomic characterization of 9 widely used human MPNST cell lines for their use in translational research. NF1-related cell lines recapitulated primary MPNST copy number profiles, exhibited NF1, CDKN2A, and SUZ12/EED tumor suppressor gene (TSG) inactivation, and presented no gain-of-function mutations. In contrast, sporadic cell lines collectively displayed different TSG inactivation patterns and presented kinase-activating mutations, fusion genes, altered mutational frequencies and COSMIC signatures, and different methylome-based classifications. Cell lines re-classified as melanomas and other sarcomas exhibited a different drug-treatment response. Deep genomic analysis, methylome-based classification, and cell-identity marker expression, challenged the identity of common MPNST cell lines, opening an opportunity to revise MPNST differential diagnosis.
Establishment and genomic characterization of a sporadic malignant peripheral nerve sheath tumor cell line. [2022]Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived neoplasms that occur sporadically or in patients with neurofibromatosis type 1 (NF1). Preclinical research on sporadic MPNSTs has been limited as few cell lines exist. We generated and characterized a new sporadic MPNST cell line, 2XSB, which shares the molecular and genomic features of the parent tumor. These cells have a highly complex karyotype with extensive chromothripsis. 2XSB cells show robust invasive 3-dimensional and clonogenic culture capability and form solid tumors when xenografted into immunodeficient mice. High-density single nucleotide polymorphism array and whole exome sequencing analyses indicate that, unlike NF1-associated MPNSTs, 2XSB cells have intact, functional NF1 alleles with no evidence of mutations in genes encoding components of Polycomb Repressor Complex 2. However, mutations in other genes implicated in MPNST pathogenesis were identified in 2XSB cells including homozygous deletion of CDKN2A and mutations in TP53 and PTEN. We also identified mutations in genes not previously associated with MPNSTs but associated with the pathogenesis of other human cancers. These include DNMT1, NUMA1, NTRK1, PDE11A, CSMD3, LRP5 and ACTL9. This sporadic MPNST-derived cell line provides a useful tool for investigating the biology and potential treatment regimens for sporadic MPNSTs.