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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments, Itacitinib and ASTX727 (also known as Decitabine/Cedazuridine), for individuals with myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The goal is to determine if these drugs can improve symptoms and outcomes for those untreated or unresponsive to previous treatments. Individuals with MDS/MPN who have not tried disease-changing therapies or did not respond well to similar drugs might be suitable for this trial. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of ASTX727 and itacitinib is under careful study for safety and effectiveness in treating conditions like MDS/MPN, a type of blood cancer. ASTX727 combines two drugs, decitabine and cedazuridine, which help maintain treatment stability in the body. Itacitinib is another drug under investigation for its potential to treat these conditions.

Studies have found that ASTX727 is generally well-tolerated by patients, with common side effects such as nausea and tiredness, similar to those from other treatments. Itacitinib remains under study, but research for other conditions has shown it has a manageable safety profile.

As this study is in the early stages (Phase 1/2), researchers continue to collect safety data. They aim to find the optimal dose that balances benefits and side effects. Before reaching this phase, treatments undergo lab testing and earlier human studies to ensure a certain level of safety. While more information is needed, the treatment has already undergone significant testing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for myelodysplastic/myeloproliferative neoplasms (MDS/MPN), which often include options like chemotherapy or hypomethylating agents, the combination of ASTX727 and Itacitinib offers a unique approach. Researchers are excited because ASTX727 features an oral formulation that combines two active ingredients to inhibit DNA methylation, potentially enhancing its effectiveness and convenience. Itacitinib, on the other hand, targets the JAK-STAT pathway, a critical signaling mechanism in these diseases, which could lead to more precise and effective disease management. Together, these treatments might offer a more targeted and potentially less toxic alternative to existing therapies.

What evidence suggests that this trial's treatments could be effective for MDS/MPN?

Research has shown that the combination of ASTX727 and itacitinib, which participants in this trial will receive, may effectively treat MDS/MPN, a type of blood cancer. ASTX727 slows cancer cell growth by halting a process that deactivates cancer-fighting genes. Itacitinib targets proteins that aid cancer cell survival and growth. Early studies indicate that using these two drugs together may be more effective against the disease than using them separately. Initial results suggest that patients who received this combination experienced promising improvements, with some showing reduced symptoms of the disease. ^{1 2 4 6 7}

Who Is on the Research Team?

Michael Savona, MD

Principal Investigator

Vanderbilt-Ingram Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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 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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36153475/

The ABNL-MARRO 001 study: a phase 1-2 study of randomly ... ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9509596/

The ABNL-MARRO 001 study: a phase 1–2 study of randomly ... ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000649712308477X

Preliminary Results from a Phase 1b Dose De-Escalation ... ABNL-MARRO 001 (AM‐001) is an open-label, phase 1b/2 study testing the treatment combination of ASTX727 (days 1-5), a fixed dose oral ...

4. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04061421/

Clinical Trial: NCT04061421 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 ...

5. astx.com astx.com/wp-content/uploads/2022/12/2022_ASTX727_Poster_ASH_Abs-4395_Zeidan.pdf

Phase 2 Study of Oral Decitabine/Cedazuridine in ... ASTX727-10 is a phase 2, international, single-arm, open-label study investigating the safety and efficacy of combination oral ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-00235

Active Myeloid Target Compound Decitabine and ... This phase I/II trial tests the safety, side effects, and best dose of decitabine and cedazuridine (ASTX727) in combination with itacitinib and how well ...

7. astx.com astx.com/wp-content/uploads/2022/12/2022_ASTX727_Oral_ASH_abst-461_Garcia-Manero2-1.pdf

Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes ... Safety Results: Treatment-Emergent Adverse Events in >20% of Patients (Independent of Attribution). 9. • Safety profile consistent with that.