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LeukemiaPhase 1NCT03770429

AZD6738 for Patients With Progressive MDS or CMML

A Phase 1 study testing AZD6738 in people with Leukemia and Myelodysplastic Syndrome, run by Massachusetts General Hospital at 4 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This research study is studying a research drug called AZD6738 as a possible treatment for Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia . Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Leukemia, Myelodysplastic Syndrome
What is being tested?
AZD6738
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
52 participants
Where
4 sitesUnited States
Study dates
5 Aug 2019to 31 Dec 2026
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have a diagnosis of recurrent, persistent, or progressive myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) according to WHO 2016 diagnostic criteria:
  • For patients with higher-risk MDS (Intermediate, High, or Very High by IPSS-R, score >3.5), they must have been unresponsive to 4 cycles of decitabine or 6 cycles of azacitidine, progressed on any prior HMA, or intolerant of prior treatment with either azacitidine or decitabine (HMA) chemotherapy.
  • For patients with CMML, they must have received prior HMA chemotherapy and have been unresponsive to, progressed on, or be intolerant of this therapy; or those who decline or are not felt to be candidates for HMA chemotherapy.
  • Patients with MDS or CMML that has recurred after prior allogeneic stem cell transplantation.
  • For patients with lower-risk MDS (Low or Intermediate by IPSS-R, score ≤ 3.5, or any score post-HMA), they must be transfusion-dependent according to IWG criteria and must either be unresponsive to/progressed after prior ESA therapy or have an erythropoietin level > 500 U/L, who are not felt to be candidates for or lack other treatment options.
  • Female and male patients aged ≥ 18 years.
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  • ECOG performance status ≤2.
  • All participants must have adequate organ and marrow function as defined below within 21 days prior to study enrollment:
  • Total bilirubin < 1.5 mg/dL unless due to Gilbert's (<3.0 mg/dL)
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal
  • INR < 1.5x ULN
  • Creatinine clearance (estimated GFR) ≥45 mL/min/1.73 m2 as measured by the Cockroft-Gault formulation
  • Patients enrolled on Part 1 (Dose Finding) of the study need not have splicing factor mutation status known at the time of enrollment but local testing must be initiated or a sample appropriately stored for future testing prior to receiving drug.
  • Patients enrolled during Part 2 (Dose Expansion) of the study must have the results of splicing factor mutation testing, per local testing practices, prior to enrollment. Assessment can be performed at any time at or after MDS/CMML diagnosis.
  • Part 2 patients enrolled on the splicing factor mutated arm must have at least one of the following mutations:
  • SF3B1: E622 Y623 R625 N626 H662 T663 K666 K700 V701 I704 G740 K741 G742 A774 D781 U2AF1: S34 R156 Q157 SRSF2: P95 Deletion including amino acid P95 ZRSR2 Any frameshift or nonsense mutation
  • Part 2 patients enrolled on the splicing factor wildtype arm should lack the above mutations according to local testing. If patients have an alteration in a splicing factor that is not listed they would be included in the wildtype arm.
  • Eligible patient are not currently considered candidates for, or have declined, stem cell transplantation at the time of enrollment.
  • The effects of AZD6738 on the developing human fetus are unknown. For this reason and because agents that inhibit ATR may be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after the last dose of a study drug.
  • Females must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
  • Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
  • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  • Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution.
  • Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 1 week after the last study drug administration. Sexually active male patients must be willing to use barrier contraception i.e., condoms with all sexual partners. Where the sexual partner is a 'woman of child-bearing potential' who is not using effective contraception, men must use a condom (with spermicide) during the study and for 6 months after the last dose of a study drug.
  • Ability to swallow and retain oral medication.
  • Ability to understand and the willingness to sign a written informed consent document. Provision of informed consent should occur prior to any study-specific procedures.

Who cannot join

  • Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
  • Previous enrollment in the present study.
  • Participants with a diagnosis of ataxia telangiectasia.
  • Participants who have had systemic chemotherapy within 21 days or five half lives of the medications used, whichever is longer, prior to entering the study.
  • Hydroxyurea is allowed if necessary for count control.
  • Patients who have received treatment with a small molecule investigational medicinal product (IMP) within 21 days or five half-lives (or 42 days for biologics), whichever is longer, prior to first dose of study drug.
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  • Participants who have undergone major surgery within 28 days before first dose of study drug.
  • Participants who, with the exception of alopecia, have not recovered from any adverse events ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 2, unless those toxicities are deemed irreversible and unlikely to interfere with participation on the study per the treating investigator.
  • Participants who have had a prior allogeneic transplant must be at least 100 days out from transplant "day 0" and off systemic immunosuppressive therapy without active grade > 1 GVHD requiring more than 10mg prednisone/day or equivalent.
  • Patients receiving systemic corticosteroids may not be on a dose of > 10mg prednisone/day or equivalent up to 14 days prior to first dose of study drug.
  • Participants who are currently receiving any other investigational agents.
  • Participants with a diagnosis of/progression to acute myeloid leukemia, per WHO 2016 diagnostic criteria.
  • Active CNS involvement of leukemia; evaluation (e.g. lumbar puncture) is not necessary in absence of clinical suspicion.
  • Participants with a known hypersensitivity to AZD6738 or any excipient of the product.
  • Hematuria +++ on microscopy or dipstick.
  • Participants with prior exposure to an ATR or other DDR inhibitor.
  • Participants may not be receiving any medications or substances that are potent inhibitors or inducers of CYP3A4.
  • There is a required wash-out period of 5 half-lives from such agents prior to starting AZD6738, or three weeks for St. John's Wort.
  • For non-potent inhibitors or inducers of CYP3A4, the decision to allow a patient to enroll on the study will be made on a case-by-case basis with the Investigator and the Overall PI. Note these include common azole antifungals, macrolide antibiotics, and other medications listed in the concomitant medications section. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
  • Exposure of other drugs metabolised by CYP3A4 and/or CYP2B6 may be reduced and additional monitoring may be required (see Appendix G).
  • The use of herbal supplements or 'folk remedies' (and medications and foods that significantly modulate CYP3A activity) should be discouraged. If deemed necessary, such products may be administered with caution and the reason for use documented in the CRF (see Appendix G).
  • Uncontrolled intercurrent illness including, but not limited to, serious and active uncontrolled infection, symptomatic congestive heart failure, active inflammatory bowel disease, unstable respiratory or cardiac conditions, unstable angina pectoris, unstable cardiac arrhythmia, active bleeding diathesis (e.g. haemophilia or von Willebrand disease), uncontrolled seizures, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Any of the following cardiac diseases currently or within the last 6 months:
  • Unstable angina pectoris or acute myocardial infarction.
  • Congestive heart failure (NYHA ≥ Class 2) or known reduced LVEF < 50%.
  • Unstable conduction abnormality not controlled with pacemaker or medication e.g. third-degree heart block.
  • Unstable ventricular or supraventricular arrhythmias (patients with chronic controlled atrial arrhythmias in the absence of other cardiac abnormalities are eligible).
  • Symptomatic carotid stenosis, TIA, haemorrhagic or thrombotic stroke.
  • Cardiac procedures such as CABG, angioplasty or vascular stenting within 6 months of dosing.
  • Patients with relative hypotension (<90/60 mmHg) or clinically relevant orthostatic hypotension, including fall in blood pressure of > 20 mm Hg.
  • Resting corrected QT interval (QTc) >470 msec for females and >450 for males (Fredericia formula). Patients with known factors that increase the risk of QTc prolongation such as a personal/immediate family history of long QT syndrome are ineligible.
  • Active untreated or concurrent malignancy that is distinct in primary site or histology, excluding: non-melanoma skin cancer, noninvasive colonic polyps, superficial bladder tumors, cervical cancer in-situ, ductal carcinoma in situ of the breast, monoclonal B-cell lymphocytosis, or monoclonal gammopathy of undetermined significance. Patients may be receiving maintenance hormonal therapy for prior breast or prostate cancer. Other malignancies that were treated with curative intent at least 3 years prior to study screening and without evidence of active disease will be allowed.
  • Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control. Pregnant women are excluded from this study because AZD6738 is chemotherapy agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD6738, breastfeeding should be discontinued if the mother is treated.
  • HIV-positive participants, including those on combination antiretroviral therapy, are ineligible, both because of the potential for pharmacokinetic interactions with AZD6738, as well as an increased risk of lethal infections when treated with marrow-suppressive therapy. Screening for patients without suspected disease is not required. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
  • Patients who are known to have active infection with hepatitis B or hepatitis C based on serologic status. Screening for patients without suspected disease is not required. Patients treated with viral suppression are eligible.
  • Patients who have been vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
  • Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of AZD6738

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • BIDMC

    Boston, Massachusetts, 02215

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Massachusetts General Hospital Cancer Center

    Boston, Massachusetts, 02215

  • Washington University

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: A Phase Ib Study of AZD6738 for Patients With Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia Progressing on Front-Line Therapy

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

Read the detailed description

This is a Phase Ib clinical trial. A Phase I clinical trial tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved AZD6738 as a treatment for any disease.

AZD6738 is a a drug being studied as a potential treatment for individuals with Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia. It targets a specific pathway in cells that repairs damage to DNA, specifically by blocking a protein called ATR. ATR notices when there is injury to DNA, which is the blueprint that allows cells to function and replicate, and works to repair that damage. Studies done in a laboratory setting and cell lines suggest that MDS and CMML cells rely specifically on the ATR pathway to fix DNA damage and survive; by inhibiting ATR with AZD6738, MDS or CMML cells appear to selectively accumulate DNA damage and die, but healthy cells appear to be less sensitive to this target. This suggests that inhibiting ATR may be a way to selectively target MDS or CMML cells.

In this research study, the investigators are looking to first investigate the safety and tolerability of AZD6738. The investigators will also evaluate whether AZD6738 has any effect on tumor growth, measure the activity of AZD6738 in the bone marrow, and study how AZD6738 is cleared by the body.

Being tested
AZD6738
Keywords
Leukemia, Myelodysplastic Syndrome
Medical subject headings
Leukemia, Myelodysplastic Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AZD6738Drug

    MDS and CMML cells rely specifically on the ATR pathway to fix DNA damage and survive; by inhibiting ATR with AZD6738, MDS or CMML cells appear to selectively accumulate DNA damage and die, but healthy cells appear to be less sensitive to this target

Study groups in NCT03770429
Study groupRoleWhat they receive
AZD6738ExperimentalPatients will receive AZD6738 orally on a 28-day cycle
Receives: Drug: AZD6738

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Safety of AZD6738 in MDS and CMML (Incidence of dose limiting toxicities)

    Incidence of dose limiting toxicities within the first 28 days of treatment, and enumeration of treatment emergent adverse events graded according to CTCAE

    Measured: 2 years

Secondary outcomes (5)

  1. Overall Response Rate - splicing factor MUT

    We will determine the ORR (CR, mCR, PR, HI) as well as stable disease and progressive disease among patients with splicing factor mutations.

    Measured: 2 years

  2. Overall Response Rate - splicing factor WT

    We will determine the ORR (CR, mCR, PR, HI) as well as stable disease and progressive disease among patients without splicing factor mutations.

    Measured: 2 years

  3. Classification of Toxicity

    We will describe the frequency and severity of adverse events during treatment.

    Measured: 2 years

  4. Overall Survival Rate

    Proportion of patients alive at 1 year

    Measured: 2 years

  5. Progression Free Survival Rate

    Proportion of patients alive without disease progression at 1 year

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Dec 2018
  2. Study start5 Aug 2019
  3. Primary completion9 Apr 2025
  4. Study completion31 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
52 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03770429
Sponsor's protocol ID
18-477
Status last verified
Sep 2026
First submitted
1 Dec 2018
Last updated
30 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor-Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Publications

  • Brunner AM, Liu Y, Garcia JS, Mendez LM, Gutierrez C, Nonavinkere Srivatsan S, Shao J, Aubrey BJ, Amrein PC, Narayan R, Vedula RS, Friedman E, Neuberg DS, Andrade Campos M, Smith SA, Stone RM, Fathi AT, Walter MJ, Graubert TA, Jacoby MA. A Phase Ib/II study of ceralasertib, a selective inhibitor of ATR, in patients with relapsed or refractory MDS and CMML. Blood Adv. 2026 Jun 30:bloodadvances.2026019848. doi: 10.1182/bloodadvances.2026019848. Online ahead of print.

    PubMed 42379235

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing AZD6738 in people with Leukemia and Myelodysplastic Syndrome, run by Massachusetts General Hospital at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 30 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety of AZD6738 in MDS and CMML (Incidence of dose limiting toxicities) (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03770429, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Sep 2026.

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