AZD6738 for Myelodysplastic Syndrome

Not currently recruiting at 4 trial locations

Overseen By Andrew M Brunner, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Massachusetts General Hospital

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Ataxia telangiectasia, Acute myeloid leukemia, HIV, Hepatitis B, others

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

Compensation: Varies

Number of Visits: 4

Duration: 28 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, AZD6738 (Ceralasertib), to determine its effectiveness in treating Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML), blood disorders that affect bone marrow. The researchers aim to assess whether AZD6738 can serve as an effective treatment for individuals whose conditions have not improved with other therapies. Suitable candidates for this trial have MDS or CMML that has not responded well to previous treatments or cannot undergo or choose not to have a stem cell transplant. Participants will take AZD6738 orally in cycles, so they must be able to swallow pills. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of 5 half-lives for potent inhibitors or inducers of CYP3A4 before starting AZD6738, or three weeks for St. John's Wort. For other medications, the decision will be made on a case-by-case basis with the study doctor.

Is there any evidence suggesting that AZD6738 is likely to be safe for humans?

Research has shown that AZD6738, also known as ceralasertib, has been tested for safety in people with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). In these studies, most patients tolerated the drug well. They took it in cycles, and most side effects were mild to moderate, such as fatigue or nausea. Serious side effects were rare but possible. This drug remains under study, and more information will become available as research progresses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for myelodysplastic syndrome, which often include medications like azacitidine and lenalidomide, AZD6738 offers a novel approach by targeting specific enzymes involved in DNA repair. Researchers are excited about AZD6738 because it inhibits a protein called ATR, which plays a crucial role in helping cancer cells survive when their DNA is damaged. By blocking ATR, AZD6738 aims to make cancer cells more vulnerable to damage and thus, easier to destroy. This targeted mechanism could potentially offer a more effective treatment option with a different side effect profile compared to existing therapies.

What evidence suggests that AZD6738 might be an effective treatment for Myelodysplastic Syndrome?

Research has shown that AZD6738, also known as ceralasertib, may help treat Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML). In studies with patients who had already tried other treatments, AZD6738 positively affected the disease. Specifically, data indicated that patients taking AZD6738 lived for about 12 to 13 months, suggesting it could benefit people with these conditions. The treatment blocks ATR, a protein that helps cancer cells repair themselves, making it harder for the cancer to grow. Overall, AZD6738 has shown potential in managing MDS and CMML. ^{1 2 6 7 8}

Who Is on the Research Team?

Andrew M Brunner, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults diagnosed with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) who have not responded to, or cannot tolerate, certain chemotherapy treatments. They should be in a stable condition without acute leukemia and must not have other active cancers. Participants need functioning major organs and agree to use contraception.

Inclusion Criteria

My MDS or CMML has returned after a stem cell transplant.

My MDS or CMML has returned after a stem cell transplant.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

Involvement in the planning and/or conduct of the study

My leukemia has spread to my brain or spinal cord.

I had a transplant less than 100 days ago and am not on strong immune-suppressing drugs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD6738 orally on a 28-day cycle to evaluate safety, tolerability, and effect on tumor growth

28 days

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including overall response rate and survival rates

2 years

What Are the Treatments Tested in This Trial?

Interventions

• AZD6738

Trial Overview The trial is testing AZD6738, an investigational drug for treating MDS/CMML. It's designed for patients whose disease has progressed after standard therapies or those ineligible for stem cell transplantation. The study will assess the drug's effectiveness and safety.

How Is the Trial Designed?

Group I: AZD6738 Experimental Treatment 1 Intervention

Patients will receive AZD6738 orally on a 28-day cycle

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

Enasidenib is a targeted therapy approved by the FDA for patients with refractory or relapsed acute myeloid leukemia (AML) who have a specific mutation (IDH2).

The drug has shown the ability to induce remissions in some patients and may decrease the need for blood transfusions, although its approval was based on less supporting evidence than typically required.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enasidenib Approved for AML, but Best Uses Unclear. [2018]

In a multicenter phase II study involving 39 patients (23 with acute myeloid leukemia and 16 with high-risk myelodysplastic syndrome), the VEGF receptor inhibitor cediranib showed no confirmed responses in treating these conditions, leading to the early closure of the trial.

Despite the lack of efficacy, common adverse events reported included thrombocytopenia, neutropenia, and fatigue, indicating that while the drug was not effective, it did have a safety profile that needs consideration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of AZD2171 (cediranib) in the treatment of patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Mattison, R., Jumonville, A., Flynn, PJ., et al.[2021]

Luspatercept has recently been approved as a targeted therapy for treating anemia in myelodysplastic syndromes (MDS) patients who do not respond to erythropoiesis stimulating agents, marking a significant advancement in treatment options.

Ongoing research is focused on developing new targeted therapies that address myeloid lineage signaling pathways and the immune microenvironment, which could enhance treatment strategies for MDS as current options are limited after treatment failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Myeloid Lineages and the Immune Microenvironment in Myelodysplastic Syndromes: Novel and Evolving Therapeutic Strategies. Chung, C.[2022]

In a study of 155 patients with myelodysplastic syndromes (MDS), vatalanib showed a modest hematological improvement in 5% of patients, with a higher response rate of 15% among those who remained on the treatment for at least 3 months.

While vatalanib delayed progression to acute myeloid leukemia (AML) and improved survival in low-risk patients (median overall survival of 36 months), its clinical use is limited due to significant side effects, including fatigue and nausea, and potential serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance). Gupta, P., Mulkey, F., Hasserjian, RP., et al.[2021]

The investigational drug enasidenib, which targets IDH2 mutations, has shown a safety profile and potential to improve survival in patients with relapsed or refractory acute myeloid leukemia.

In a clinical trial, enasidenib induced responses in 40.3% of patients, leading to a median overall survival of 9.3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positive First Trial of Enasidenib for AML. [2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03770429?term=AREA%5BInterventionSearch%5D(AZD6738)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=2

AZD6738 for Patients With Progressive MDS or CMML This research study is studying a research drug called AZD6738 as a possible treatment for Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia .

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1833/529604/Clinical-Activity-and-Safety-of-the-Oral-ATR

Clinical Activity and Safety of the Oral ATR Inhibitor ... Conclusion: Ceralasertib is an oral ATR inhibitor with clinical activity in patients with post-HMA MDS and CMML. The schedule of 160mg BID 7on/ ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124045804

Clinical Activity and Safety of the Oral ATR Inhibitor ... Ceralasertib is an oral ATR inhibitor with clinical activity in patients with post-HMA MDS and CMML. The schedule of 160mg BID 7on/7off

4. bloodcancerstoday.com bloodcancerstoday.com/post/ceralasertib-shows-promise-in-mds-and-cmml-with-reduced-toxicity-on-an-adjusted-schedule

Ceralasertib Shows Promise in MDS and CMML With ... Survival outcomes were similar between schedules, with a median overall survival of 12 months for the 14 on/14 off schedule and 13 months for ...

5. journals.lww.com journals.lww.com/hemasphere/fulltext/2022/06003/p758__inhibition_of_atr_with_ceralasertib.653.aspx

p758: inhibition of atr with ceralasertib (azd6738) for the ... Results: At the data cut-off (12/15/21) 32 patients have been enrolled with 30 evaluable: 22 with HR-MDS or CMML, and 8 with LR-MDS. The median age was 73 ...

6. vjhemonc.com vjhemonc.com/video/56euzhuztug-safety-and-activity-of-ceralasertib-in-the-treatment-of-mds/

ASH 2021 | Safety and activity of ceralasertib in the treatment ... Patients with MDS often have a poor survival outcome and limited therapeutic options after they stop responding to azacitidine and decitabine, ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03770429

Study Details | NCT03770429 | AZD6738 for Patients With ... This research study is studying a research drug called AZD6738 as a possible treatment for Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia .

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9359726/

ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor ... Here we observed AZD6738 was able to inhibit both BIR repair (Fig. 1F) and HRR (Fig. 1G) at concentrations >0.333 μmol/L. These data indicate ATR regulates ...