Itacitinib + ASTX727 for MDS/MPN

(ABNL-MARRO Trial)

Overseen By Theradex Oncology EU Inquiry

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Michael Savona

Must not be taking: Antineoplastics, Chemotherapy

Disqualifiers: Leukemia, Cardiac disease, Transplant, others

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

Compensation: Varies

Number of Visits: Unknown

105 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, there is a washout period for certain prior therapies, and you cannot continue any prohibited medications for which no alternative is available. It's best to discuss your specific medications with the trial team.

What data supports the idea that Itacitinib + ASTX727 for MDS/MPN is an effective treatment?

The available research shows that ASTX727, a combination of decitabine and cedazuridine, is effective for treating MDS and CMML, which are related to MDS/MPN. In Canada, patients using ASTX727 had a median survival of 21.6 months, indicating it is a promising alternative to other treatments. While there is no specific data on Itacitinib + ASTX727 for MDS/MPN, ASTX727 alone has shown effectiveness in similar conditions. Compared to another treatment, ruxolitinib combined with azacytidine, which had a response rate of 57% in MDS/MPN patients, ASTX727 offers a convenient oral option and addresses an unmet need for effective therapies. ^{1 2 3 4 5}

What safety data is available for the treatment Itacitinib + ASTX727 for MDS/MPN?

The safety data for ASTX727, also known as Decitabine/Cedazuridine, indicates that it is approved for the treatment of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) in the USA and Canada. Clinical studies have shown it to be a promising alternative to parenteral hypomethylating agents, with a median overall survival of 21.6 months and progression-free survival of 10.7 months in a Canadian study. The combination of oral decitabine with cedazuridine has demonstrated pharmacological equivalence with intravenous decitabine. However, specific safety data for the combination of Itacitinib with ASTX727 is not detailed in the provided research. Itacitinib, also known as INCB-039110, is not specifically mentioned in the context of safety data for MDS/MPN in the provided abstracts. ^{1 4 6 7 8}

Is the drug ASTX727 a promising treatment for MDS/MPN?

Yes, ASTX727, which is a combination of decitabine and cedazuridine, is a promising drug for treating MDS/MPN. It has been approved in the USA and Canada for treating certain types of blood cancers, including MDS and CMML. The combination increases the effectiveness of decitabine when taken orally, making it more convenient for patients. Clinical studies have shown positive responses, making it a valuable option for patients with these conditions. ^{1 2 3 9 10}

What is the purpose of this trial?

ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international European-American cooperation providing the framework for collaborative studies to advance treatment of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and explore clinical-pathologic markers of disease severity, prognosis and treatment response. ABNL MARRO 001 (AM-001) is an Open label, phase 1/2 study within the framework of the ABNL-MARRO that will test novel treatment combinations in MDS/MPN. Each Arm of AM-001 will test an active myeloid target compound in combination with ASTX727, an oral drug combining fixed doses of the DNA methyltransferase inhibitor (DNMTi) decitabine and the cytidine deaminase inhibitor E7727, also known as cedazuridine in a single tablet.

Research Team

Michael Savona, MD

Principal Investigator

Vanderbilt-Ingram Cancer Center

Eligibility Criteria

This trial is for adults with MDS/MPN overlap syndromes who haven't had certain treatments, can undergo bone marrow procedures, and have a life expectancy of at least 3 months. They must be able to perform daily activities with minimal assistance (ECOG status 0-2) and have proper liver and kidney function. Pregnant or breastfeeding women, those unwilling to use contraception, or individuals with recent other cancer treatments are excluded.

Inclusion Criteria

My liver and kidney tests are within normal ranges.

I haven't had any previous treatments for my condition, except for medications like erythropoietin or hydroxyurea.

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

Any psychological, familial, geographical or sociological condition that in the investigator's opinion would jeopardize the patient's ability to comply with the protocol.

Subjects who expect to conceive or father children within the projected duration of the study and/or who are unwilling to use highly effective methods of contraception throughout the duration of the study, starting with the screening visit through the end of treatment visit. For women of child-bearing potential (WOCBP), a negative urine pregnancy test at screening and immediately prior to initiating treatment on any AM-001 treatment Arm (Cycle 1 Day 1) is required.

Any concurrent serious or unstable medical or psychiatric condition that in the investigator's opinion would jeopardize the patient's ability to provide informed consent or to comply with the protocol.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Characterize the dose-limiting toxicities (DLTs) of each novel oral targeted agent in combination with oral ASTX727 to determine the recommended phase 2 dose (RP2D) and schedule

4 weeks

Phase 2 Treatment

Test the overall response to each novel ASTX727 combination therapy in MDS/MPN patients

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ASTX727
• Itacitinib

Trial Overview The ABNL-MARRO study tests combinations of itacitinib (a drug targeting myeloid cells) and ASTX727 (an oral tablet combining decitabine and cedazuridine) in patients with MDS/MPN overlap syndromes. It's an open-label phase 1/2 trial where the effectiveness of these drugs together will be evaluated.

Participant Groups

Group I: ASTX727 + itacitinib Experimental Treatment 2 Interventions

ASTX727 and itacitinib will be taken by mouth

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?

Michael Savona

Lead Sponsor

Trials

1

Recruited

110+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Theradex

Industry Sponsor

Trials

34

Recruited

1,600+

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]

In a study of 35 patients with myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs), the combination of ruxolitinib and azacytidine resulted in a 57% response rate, demonstrating its efficacy in treating this condition.

The treatment was well-tolerated, with serious side effects like grade 3/4 anemia and thrombocytopenia occurring in over half of the patients, but only one patient needed to stop treatment, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. Assi, R., Kantarjian, HM., Garcia-Manero, G., et al.[2021]

The AVIDA registry, which included 421 patients with myelodysplastic syndromes (MDS) across 105 US sites, demonstrated that azacitidine is effective in achieving hematologic improvement and transfusion independence, regardless of the administration route or dosing schedule.

The safety and tolerability of azacitidine were consistent with previous studies, confirming its effectiveness and safety for both lower- and higher-risk MDS patients in community practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA registry. Grinblatt, DL., Sekeres, MA., Komrokji, RS., et al.[2019]

Decitabine/cedazuridine (DEC-C) is the first oral hypomethylating agent approved in Canada for treating myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), showing a median overall survival of 21.6 months in a real-world study of 769 patients.

The treatment demonstrated a median progression-free survival of 10.7 months, indicating its potential as an effective and convenient alternative to traditional parenteral therapies, especially for older patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine in the Management of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia in Canada. Yun, JP., Ding, PQ., Dolley, A., et al.[2023]

The combination of oral cedazuridine and decitabine (C-DEC) has been shown to have a similar pharmacokinetic and pharmacodynamic profile to parenteral decitabine, making it a promising alternative for treating higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

Phase 2 and phase 3 clinical trials confirmed the bioequivalence of C-DEC to parenteral decitabine, leading to FDA approval for its use in intermediate/high-risk MDS and CMML, highlighting its efficacy and safety as an oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. Patel, AA., Cahill, K., Saygin, C., et al.[2023]

In a phase 1b study involving 46 patients with relapsed/refractory or HMA-naïve myelodysplastic syndrome, atezolizumab alone or in combination with azacitidine showed a high early death rate, with 61.9% of patients in cohort C experiencing death, raising safety concerns.

The study found poor efficacy, with no responses in cohort A and only 14.3% response in cohort B, leading to the conclusion that the risk-benefit profile for atezolizumab in these patient populations is unfavorable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome. Gerds, AT., Scott, BL., Greenberg, P., et al.[2022]

Luspatercept has shown significant efficacy in treating low-risk myelodysplastic syndromes (MDS), with 63% of patients experiencing hematological improvement and 38% achieving transfusion independence in clinical trials.

Oral decitabine combined with oral cedazuridine has demonstrated pharmacological equivalence to intravenous decitabine, achieving overall response rates of 60% and 43% in phase 2 and 3 trials for high-risk MDS, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New treatment for myelodysplastic syndromes: luspatercept and oral hypomethylating agents]. Usuki, K.[2022]

In a study of 2025 patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (azacitidine or decitabine), there was no significant difference in survival between the two drugs, with a median survival of 15 months for all patients.

For patients with refractory anaemia with excess blasts (RAEB), the median survival was 12 months, and again, no significant survival advantage was observed between azacitidine and decitabine, highlighting the need for further research on treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes. Zeidan, AM., Davidoff, AJ., Long, JB., et al.[2018]

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]

Topotecan, a topoisomerase I inhibitor, has shown promise as a single-agent treatment for myelodysplastic syndromes (MDS) and is now being explored in combination with other agents like cytarabine.

New targeted therapies, including histone deacetylase inhibitors and antiangiogenesis agents, are being developed and tested in clinical trials, aiming to improve treatment outcomes for MDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutic agents for the treatment of myelodysplastic syndromes. Cheson, BD., Zwiebel, JA., Dancey, J., et al.[2005]

References

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

Decitabine/Cedazuridine: First Approval. [2021]

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

A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. [2021]

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

Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA registry. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine in the Management of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia in Canada. [2023]

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

Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. [2023]

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

Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

[New treatment for myelodysplastic syndromes: luspatercept and oral hypomethylating agents]. [2022]

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

Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes. [2018]

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

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

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

Novel therapeutic agents for the treatment of myelodysplastic syndromes. [2005]