<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03770429</url>
  </required_header>
  <id_info>
    <org_study_id>18-477</org_study_id>
    <nct_id>NCT03770429</nct_id>
  </id_info>
  <brief_title>AZD6738 for Patients With Progressive MDS or CMML</brief_title>
  <official_title>A Phase Ib Study of AZD6738 for Patients With Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia Progressing on Front-Line Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is studying a research drug called AZD6738 as a possible treatment for&#xD;
      Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia .&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase Ib clinical trial. A Phase I clinical trial tests the safety of an&#xD;
      investigational drug and also tries to define the appropriate dose of the investigational&#xD;
      drug to use for further studies. &quot;Investigational&quot; means that the drug is being studied.&#xD;
&#xD;
      The FDA (the U.S. Food and Drug Administration) has not approved AZD6738 as a treatment for&#xD;
      any disease.&#xD;
&#xD;
      AZD6738 is a a drug being studied as a potential treatment for individuals with&#xD;
      Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia. It targets a specific pathway in&#xD;
      cells that repairs damage to DNA, specifically by blocking a protein called ATR. ATR notices&#xD;
      when there is injury to DNA, which is the blueprint that allows cells to function and&#xD;
      replicate, and works to repair that damage. Studies done in a laboratory setting and cell&#xD;
      lines suggest that MDS and CMML cells rely specifically on the ATR pathway to fix DNA damage&#xD;
      and survive; by inhibiting ATR with AZD6738, MDS or CMML cells appear to selectively&#xD;
      accumulate DNA damage and die, but healthy cells appear to be less sensitive to this target.&#xD;
      This suggests that inhibiting ATR may be a way to selectively target MDS or CMML cells.&#xD;
&#xD;
      In this research study, the investigators are looking to first investigate the safety and&#xD;
      tolerability of AZD6738. The investigators will also evaluate whether AZD6738 has any effect&#xD;
      on tumor growth, measure the activity of AZD6738 in the bone marrow, and study how AZD6738 is&#xD;
      cleared by the body.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 5, 2019</start_date>
  <completion_date type="Anticipated">May 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of AZD6738 in MDS and CMML (Incidence of dose limiting toxicities)</measure>
    <time_frame>2 years</time_frame>
    <description>Incidence of dose limiting toxicities within the first 28 days of treatment, and enumeration of treatment emergent adverse events graded according to CTCAE</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate - splicing factor MUT</measure>
    <time_frame>2 years</time_frame>
    <description>We will determine the ORR (CR, mCR, PR, HI) as well as stable disease and progressive disease among patients with splicing factor mutations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate - splicing factor WT</measure>
    <time_frame>2 years</time_frame>
    <description>We will determine the ORR (CR, mCR, PR, HI) as well as stable disease and progressive disease among patients without splicing factor mutations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Classification of Toxicity</measure>
    <time_frame>2 years</time_frame>
    <description>We will describe the frequency and severity of adverse events during treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival Rate</measure>
    <time_frame>2 years</time_frame>
    <description>Proportion of patients alive at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival Rate</measure>
    <time_frame>2 years</time_frame>
    <description>Proportion of patients alive without disease progression at 1 year</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Factors associated with response/resistance</measure>
    <time_frame>2 years</time_frame>
    <description>We will perform sequencing for recurrent mutations in myeloid malignancies at baseline and at progression.</description>
  </other_outcome>
  <other_outcome>
    <measure>Biomarkers</measure>
    <time_frame>2 years</time_frame>
    <description>We will measure yH2AX by immunohistochemistry on bone marrow biopsies and assessed by staining intensity</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">52</enrollment>
  <condition>Leukemia</condition>
  <condition>Myelodysplastic Syndrome</condition>
  <arm_group>
    <arm_group_label>AZD6738</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive AZD6738 orally on a 28-day cycle</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD6738</intervention_name>
    <description>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</description>
    <arm_group_label>AZD6738</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
        Patients must have a diagnosis of recurrent, persistent, or progressive myelodysplastic&#xD;
        syndrome (MDS) or chronic myelomonocytic leukemia (CMML) according to WHO 2016 diagnostic&#xD;
        criteria:&#xD;
&#xD;
          -  For patients with higher-risk MDS (Intermediate, High, or Very High by IPSS-R, score&#xD;
             &gt;3.5), they must have been unresponsive to 4 cycles of decitabine or 6 cycles of&#xD;
             azacitidine, progressed on any prior HMA, or intolerant of prior treatment with either&#xD;
             azacitidine or decitabine (HMA) chemotherapy.&#xD;
&#xD;
          -  For patients with CMML, they must have received prior HMA chemotherapy and have been&#xD;
             unresponsive to, progressed on, or be intolerant of this therapy; or those who decline&#xD;
             or are not felt to be candidates for HMA chemotherapy.&#xD;
&#xD;
          -  Patients with MDS or CMML that has recurred after prior allogeneic stem cell&#xD;
             transplantation.&#xD;
&#xD;
          -  For patients with lower-risk MDS (Low or Intermediate by IPSS-R, score ≤ 3.5, or any&#xD;
             score post-HMA), they must be transfusion-dependent according to IWG criteria and must&#xD;
             either be unresponsive to/progressed after prior ESA therapy or have an erythropoietin&#xD;
             level &gt; 500 U/L, who are not felt to be candidates for or lack other treatment&#xD;
             options.&#xD;
&#xD;
          -  Female and male patients aged ≥ 18 years.&#xD;
&#xD;
          -  ECOG performance status ≤2.&#xD;
&#xD;
          -  All participants must have adequate organ and marrow function as defined below within&#xD;
             21 days prior to study enrollment:&#xD;
&#xD;
          -  Total bilirubin &lt; 1.5 mg/dL unless due to Gilbert's (&lt;3.0 mg/dL)&#xD;
&#xD;
          -  AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal&#xD;
&#xD;
          -  INR &lt; 1.5x ULN&#xD;
&#xD;
          -  Creatinine clearance (estimated GFR) ≥45 mL/min/1.73 m2 as measured by the&#xD;
             Cockroft-Gault formulation&#xD;
&#xD;
          -  Patients enrolled on Part 1 (Dose Finding) of the study need not have splicing factor&#xD;
             mutation status known at the time of enrollment but local testing must be initiated or&#xD;
             a sample appropriately stored for future testing prior to receiving drug.&#xD;
&#xD;
          -  Patients enrolled during Part 2 (Dose Expansion) of the study must have the results of&#xD;
             splicing factor mutation testing, per local testing practices, prior to enrollment.&#xD;
             Assessment can be performed at any time at or after MDS/CMML diagnosis.&#xD;
&#xD;
          -  Part 2 patients enrolled on the splicing factor mutated arm must have at least one of&#xD;
             the following mutations:&#xD;
&#xD;
        SF3B1: E622 Y623 R625 N626 H662 T663 K666 K700 V701 I704 G740 K741 G742 A774 D781 U2AF1:&#xD;
        S34 R156 Q157 SRSF2: P95 Deletion including amino acid P95 ZRSR2 Any frameshift or nonsense&#xD;
        mutation&#xD;
&#xD;
          -  Part 2 patients enrolled on the splicing factor wildtype arm should lack the above&#xD;
             mutations according to local testing. If patients have an alteration in a splicing&#xD;
             factor that is not listed they would be included in the wildtype arm.&#xD;
&#xD;
          -  Eligible patient are not currently considered candidates for, or have declined, stem&#xD;
             cell transplantation at the time of enrollment.&#xD;
&#xD;
          -  The effects of AZD6738 on the developing human fetus are unknown. For this reason and&#xD;
             because agents that inhibit ATR may be teratogenic, women of child-bearing potential&#xD;
             and men must agree to use adequate contraception (hormonal or barrier method of birth&#xD;
             control; abstinence) prior to study entry, for the duration of study participation,&#xD;
             and for 6 months after the last dose of a study drug.&#xD;
&#xD;
               -  Females must not be breast feeding and must have a negative pregnancy test prior&#xD;
                  to start of dosing if of child-bearing potential or must have evidence of&#xD;
                  non-child-bearing potential by fulfilling one of the following criteria at&#xD;
                  screening:&#xD;
&#xD;
                    -  Post-menopausal defined as aged more than 50 years and amenorrhoeic for at&#xD;
                       least 12 months following cessation of all exogenous hormonal treatments.&#xD;
&#xD;
                    -  Documentation of irreversible surgical sterilisation by hysterectomy,&#xD;
                       bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.&#xD;
&#xD;
                    -  Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH),&#xD;
                       luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal&#xD;
                       range for the institution.&#xD;
&#xD;
               -  Men treated or enrolled on this protocol must also agree to use adequate&#xD;
                  contraception prior to the study, for the duration of study participation, and&#xD;
                  for 1 week after the last study drug administration. Sexually active male&#xD;
                  patients must be willing to use barrier contraception i.e., condoms with all&#xD;
                  sexual partners. Where the sexual partner is a 'woman of child-bearing potential'&#xD;
                  who is not using effective contraception, men must use a condom (with spermicide)&#xD;
                  during the study and for 6 months after the last dose of a study drug.&#xD;
&#xD;
          -  Ability to swallow and retain oral medication.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
             Provision of informed consent should occur prior to any study-specific procedures.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Involvement in the planning and/or conduct of the study (applies to both Investigator&#xD;
             staff and/or staff at the study site).&#xD;
&#xD;
          -  Previous enrollment in the present study.&#xD;
&#xD;
          -  Participants with a diagnosis of ataxia telangiectasia.&#xD;
&#xD;
          -  Participants who have had systemic chemotherapy within 21 days or five half lives of&#xD;
             the medications used, whichever is longer, prior to entering the study.&#xD;
&#xD;
             • Hydroxyurea is allowed if necessary for count control.&#xD;
&#xD;
          -  Patients who have received treatment with a small molecule investigational medicinal&#xD;
             product (IMP) within 21 days or five half-lives (or 42 days for biologics), whichever&#xD;
             is longer, prior to first dose of study drug.&#xD;
&#xD;
          -  Participants who have undergone major surgery within 28 days before first dose of&#xD;
             study drug.&#xD;
&#xD;
          -  Participants who, with the exception of alopecia, have not recovered from any adverse&#xD;
             events ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 2, unless those&#xD;
             toxicities are deemed irreversible and unlikely to interfere with participation on the&#xD;
             study per the treating investigator.&#xD;
&#xD;
          -  Participants who have had a prior allogeneic transplant must be at least 100 days out&#xD;
             from transplant &quot;day 0&quot; and off systemic immunosuppressive therapy without active&#xD;
             grade &gt; 1 GVHD requiring more than 10mg prednisone/day or equivalent.&#xD;
&#xD;
          -  Patients receiving systemic corticosteroids may not be on a dose of &gt; 10mg&#xD;
             prednisone/day or equivalent up to 14 days prior to first dose of study drug.&#xD;
&#xD;
          -  Participants who are currently receiving any other investigational agents.&#xD;
&#xD;
          -  Participants with a diagnosis of/progression to acute myeloid leukemia, per WHO 2016&#xD;
             diagnostic criteria.&#xD;
&#xD;
          -  Active CNS involvement of leukemia; evaluation (e.g. lumbar puncture) is not necessary&#xD;
             in absence of clinical suspicion.&#xD;
&#xD;
          -  Participants with a known hypersensitivity to AZD6738 or any excipient of the product.&#xD;
&#xD;
          -  Hematuria +++ on microscopy or dipstick.&#xD;
&#xD;
          -  Participants with prior exposure to an ATR or other DDR inhibitor.&#xD;
&#xD;
          -  Participants may not be receiving any medications or substances that are potent&#xD;
             inhibitors or inducers of CYP3A4.&#xD;
&#xD;
               -  There is a required wash-out period of 5 half-lives from such agents prior to&#xD;
                  starting AZD6738, or three weeks for St. John's Wort.&#xD;
&#xD;
               -  For non-potent inhibitors or inducers of CYP3A4, the decision to allow a patient&#xD;
                  to enroll on the study will be made on a case-by-case basis with the Investigator&#xD;
                  and the Overall PI. Note these include common azole antifungals, macrolide&#xD;
                  antibiotics, and other medications listed in the concomitant medications section.&#xD;
                  As part of the enrollment/informed consent procedures, the patient will be&#xD;
                  counseled on the risk of interactions with other agents, and what to do if new&#xD;
                  medications need to be prescribed or if the patient is considering a new&#xD;
                  over-the-counter medicine or herbal product.&#xD;
&#xD;
               -  Exposure of other drugs metabolised by CYP3A4 and/or CYP2B6 may be reduced and&#xD;
                  additional monitoring may be required (see Appendix G).&#xD;
&#xD;
               -  The use of herbal supplements or 'folk remedies' (and medications and foods that&#xD;
                  significantly modulate CYP3A activity) should be discouraged. If deemed&#xD;
                  necessary, such products may be administered with caution and the reason for use&#xD;
                  documented in the CRF (see Appendix G).&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, serious and active&#xD;
             uncontrolled infection, symptomatic congestive heart failure, active inflammatory&#xD;
             bowel disease, unstable respiratory or cardiac conditions, unstable angina pectoris,&#xD;
             unstable cardiac arrhythmia, active bleeding diathesis (e.g. haemophilia or von&#xD;
             Willebrand disease), uncontrolled seizures, or psychiatric illness/social situations&#xD;
             that would limit compliance with study requirements.&#xD;
&#xD;
          -  Any of the following cardiac diseases currently or within the last 6 months:&#xD;
&#xD;
               -  Unstable angina pectoris or acute myocardial infarction.&#xD;
&#xD;
               -  Congestive heart failure (NYHA ≥ Class 2) or known reduced LVEF &lt; 50%.&#xD;
&#xD;
               -  Unstable conduction abnormality not controlled with pacemaker or medication e.g.&#xD;
                  third-degree heart block.&#xD;
&#xD;
               -  Unstable ventricular or supraventricular arrhythmias (patients with chronic&#xD;
                  controlled atrial arrhythmias in the absence of other cardiac abnormalities are&#xD;
                  eligible).&#xD;
&#xD;
               -  Symptomatic carotid stenosis, TIA, haemorrhagic or thrombotic stroke.&#xD;
&#xD;
               -  Cardiac procedures such as CABG, angioplasty or vascular stenting within 6 months&#xD;
                  of dosing.&#xD;
&#xD;
          -  Patients with relative hypotension (&lt;90/60 mmHg) or clinically relevant orthostatic&#xD;
             hypotension, including fall in blood pressure of &gt; 20 mm Hg.&#xD;
&#xD;
          -  Resting corrected QT interval (QTc) &gt;470 msec for females and &gt;450 for males&#xD;
             (Fredericia formula). Patients with known factors that increase the risk of QTc&#xD;
             prolongation such as a personal/immediate family history of long QT syndrome are&#xD;
             ineligible.&#xD;
&#xD;
          -  Active untreated or concurrent malignancy that is distinct in primary site or&#xD;
             histology, excluding: non-melanoma skin cancer, noninvasive colonic polyps,&#xD;
             superficial bladder tumors, cervical cancer in-situ, ductal carcinoma in situ of the&#xD;
             breast, monoclonal B-cell lymphocytosis, or monoclonal gammopathy of undetermined&#xD;
             significance. Patients may be receiving maintenance hormonal therapy for prior breast&#xD;
             or prostate cancer. Other malignancies that were treated with curative intent at least&#xD;
             3 years prior to study screening and without evidence of active disease will be&#xD;
             allowed.&#xD;
&#xD;
          -  Female patients who are pregnant, breast-feeding or male or female patients of&#xD;
             reproductive potential who are not employing an effective method of birth control.&#xD;
             Pregnant women are excluded from this study because AZD6738 is chemotherapy agent with&#xD;
             the potential for teratogenic or abortifacient effects. Because there is an unknown&#xD;
             but potential risk for adverse events in nursing infants secondary to treatment of the&#xD;
             mother with AZD6738, breastfeeding should be discontinued if the mother is treated.&#xD;
&#xD;
          -  HIV-positive participants, including those on combination antiretroviral therapy, are&#xD;
             ineligible, both because of the potential for pharmacokinetic interactions with&#xD;
             AZD6738, as well as an increased risk of lethal infections when treated with&#xD;
             marrow-suppressive therapy. Screening for patients without suspected disease is not&#xD;
             required. Appropriate studies will be undertaken in participants receiving combination&#xD;
             antiretroviral therapy when indicated.&#xD;
&#xD;
          -  Patients who are known to have active infection with hepatitis B or hepatitis C based&#xD;
             on serologic status. Screening for patients without suspected disease is not required.&#xD;
             Patients treated with viral suppression are eligible.&#xD;
&#xD;
          -  Patients who have been vaccinated with live, attenuated vaccines within 4 weeks of&#xD;
             first dose of study drug.&#xD;
&#xD;
          -  Refractory nausea and vomiting, chronic gastrointestinal diseases or previous&#xD;
             significant bowel resection, with clinically significant sequelae that would preclude&#xD;
             adequate absorption of AZD6738&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrew M Brunner, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Andrew M Brunner, MD</last_name>
    <phone>617-724-1124</phone>
    <email>abrunner@mgh.harvard.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>BIDMC</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lourdes Mendez, MD</last_name>
    </contact>
    <investigator>
      <last_name>Lourdes Mendez, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David P Steensma, MD</last_name>
    </contact>
    <investigator>
      <last_name>David P Steensma, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital Cancer Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andrew M Brunner, MD</last_name>
      <phone>617-724-1124</phone>
      <email>abrunner@mgh.harvard.edu</email>
    </contact>
    <investigator>
      <last_name>Andrew M Brunner, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Washington University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Meagan Jacoby, MD, PhD</last_name>
    </contact>
    <investigator>
      <last_name>Meagan Jacoby, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>December 1, 2018</study_first_submitted>
  <study_first_submitted_qc>December 7, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <last_update_submitted>January 13, 2021</last_update_submitted>
  <last_update_submitted_qc>January 13, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Andrew Mark Brunner, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Leukemia</keyword>
  <keyword>Myelodysplastic Syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>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.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>Data can be shared no earlier than 1 year following the date of publication.</ipd_time_frame>
    <ipd_access_criteria>Requests may be directed to: [contact information for Sponsor-Investigator or designee].</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03770429
org study id: 18-477
nct id: NCT03770429
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a research drug called AZD6738 as a possible treatment for
      Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia .
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety of AZD6738 in MDS and CMML (Incidence of dose limiting toxicities)
time frame: 2 years
description: Incidence of dose limiting toxicities within the first 28 days of treatment, and enumeration of treatment emergent adverse events graded according to CTCAE
measure: Overall Response Rate - splicing factor MUT
time frame: 2 years
description: We will determine the ORR (CR, mCR, PR, HI) as well as stable disease and progressive disease among patients with splicing factor mutations.
measure: Overall Response Rate - splicing factor WT
time frame: 2 years
description: We will determine the ORR (CR, mCR, PR, HI) as well as stable disease and progressive disease among patients without splicing factor mutations.
measure: Classification of Toxicity
time frame: 2 years
description: We will describe the frequency and severity of adverse events during treatment.
measure: Overall Survival Rate
time frame: 2 years
description: Proportion of patients alive at 1 year
measure: Progression Free Survival Rate
time frame: 2 years
description: Proportion of patients alive without disease progression at 1 year
measure: Factors associated with response/resistance
time frame: 2 years
description: We will perform sequencing for recurrent mutations in myeloid malignancies at baseline and at progression.
measure: Biomarkers
time frame: 2 years
description: We will measure yH2AX by immunohistochemistry on bone marrow biopsies and assessed by staining intensity
arm group label: AZD6738
arm group type: Experimental
description: Patients will receive AZD6738 orally on a 28-day cycle
intervention type: Drug
intervention name: AZD6738
description: 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
arm group label: AZD6738
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrew M Brunner, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Andrew M Brunner, MD
phone: 617-724-1124
email: abrunner@mgh.harvard.edu
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Andrew Mark Brunner, MD
investigator title: Principal Investigator
mesh term: Leukemia
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
mesh term: Syndrome
sharing ipd: Yes
ipd description: 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.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: Data can be shared no earlier than 1 year following the date of publication.
ipd access criteria: Requests may be directed to: [contact information for Sponsor-Investigator or designee].