ASTX727 for Peripheral Nerve Sheath Tumor

Recruiting at 7 trial locations

Overseen By Ciara Kelly, MBBCh BAO

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Antivirals, Anticancer

Disqualifiers: Uncontrolled diabetes, Active infections, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

25 Participants Needed

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. ^{1 2 3 4 5}

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. ^{6 7 8 9 10}

Research Team

Ping Chi

Principal Investigator

Memorial Sloan Kettering Cancer Center

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

My cancer cannot be removed by surgery and has spread.

Patients of childbearing potential must have a negative serum pregnancy test at screening and at cycle 1 day 1 (-3 days) prior to the first dose of study therapy being administered

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.

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

Trial Overview ASTX727 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

Group I: ASTX727 (cedazuridine and decitabine) Experimental Treatment 1 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)

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Taiho Pharmaceuticals, Inc.

Collaborator

Trials

1

Recruited

30+

Astex Pharmaceuticals, Inc.

Industry Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Findings from Research

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

Inqovi, a combination of decitabine and cedazuridine, was approved by the FDA for treating myelodysplastic syndromes (MDS) based on a phase III study involving 133 adults, showing similar effectiveness to intravenous decitabine.

The treatment demonstrated a complete remission rate of 21% in one study and 18% in another, with a median duration of remission lasting around 7.5 to 8.7 months, while adverse reactions were consistent with those seen in IV decitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. Kim, N., Norsworthy, KJ., Subramaniam, S., et al.[2023]

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

In a phase 1 study involving 50 patients with relapsed/refractory leukemias, decitabine was well tolerated at low doses, with myelosuppression being the main side effect.

The most effective response was observed with a dose of 15 mg/m2 for 10 days, leading to a 65% response rate, suggesting that lower doses of decitabine may be more effective than higher doses in treating myeloid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Issa, JP., Garcia-Manero, G., Giles, FJ., et al.[2022]

In a study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

In a study of malignant peripheral nerve sheath tumors (MPNST) from NF1 patients, BRD4 and EZH2 were investigated as potential therapeutic targets, but results showed that targeting these proteins may have limited effectiveness, as BRD4 was not upregulated and EZH2 knockdown did not affect cell viability.

The study confirmed that TOP2A levels were elevated in MPNSTs, and the tumors showed sensitivity to doxorubicin, suggesting that while targeting BRD4 and EZH2 may not be promising, doxorubicin remains a viable treatment option due to its effectiveness against tumors with high TOP2A expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors. Amirnasr, A., Verdijk, RM., van Kuijk, PF., et al.[2019]

Head and neck high grade malignant peripheral nerve sheath tumors (HN-MPNSTs) are highly aggressive sarcomas with a poor prognosis, showing a 2-year disease-specific survival rate of only 50% and a 5-year rate of 30% based on a study of 13 patients over 20 years.

Loss of H3K27me3 expression was found in 86% of tumors tested, making it a reliable immunohistochemical marker for diagnosing HN-MPNSTs, especially in distinguishing them from other similar tumors like melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Clinicopathologic Study of Head and Neck Malignant Peripheral Nerve Sheath Tumors. Owosho, AA., Estilo, CL., Huryn, JM., et al.[2018]

A study of 108 malignant peripheral nerve sheath tumors (MPNSTs) identified two distinct subgroups with different oncogenic pathways: MPNST-G1 with SHH pathway activation and MPNST-G2 with WNT/ß-catenin/CCND1 pathway activation, suggesting targeted treatment strategies.

In pre-clinical models, inhibiting the SHH pathway in MPNST-G1 effectively prevented tumor growth and progression, indicating a promising direction for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities. Suppiah, S., Mansouri, S., Mamatjan, Y., et al.[2023]

The genomic analysis of 9 human MPNST cell lines revealed that NF1-related lines closely mimic the genetic profiles of primary MPNSTs, highlighting the importance of these cell lines for translational research.

Sporadic MPNST cell lines showed distinct genetic alterations, including kinase-activating mutations and different drug responses, suggesting that current MPNST cell lines may need re-evaluation for accurate diagnosis and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis. Magallón-Lorenz, M., Terribas, E., Ortega-Bertran, S., et al.[2023]

A new sporadic malignant peripheral nerve sheath tumor (MPNST) cell line, 2XSB, was developed, which retains the molecular and genomic characteristics of the original tumor, making it a valuable resource for research.

Unlike NF1-associated MPNSTs, the 2XSB cell line has intact NF1 alleles and shows mutations in other key genes like CDKN2A, TP53, and PTEN, highlighting different genetic pathways involved in sporadic MPNSTs and providing insights for potential treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishment and genomic characterization of a sporadic malignant peripheral nerve sheath tumor cell line. Longo, JF., Brosius, SN., Znoyko, I., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. [2022]

5. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

A Clinicopathologic Study of Head and Neck Malignant Peripheral Nerve Sheath Tumors. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Establishment and genomic characterization of a sporadic malignant peripheral nerve sheath tumor cell line. [2022]