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Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs

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ClinicalTrials.gov Identifier: NCT02907359
Recruitment Status : Recruiting
First Posted : September 20, 2016
Last Update Posted : December 21, 2018
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE September 8, 2016
First Posted Date  ICMJE September 20, 2016
Last Update Posted Date December 21, 2018
Actual Study Start Date  ICMJE October 2016
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 29, 2017)
Overall survival [ Time Frame: 18 Months ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 15, 2016)
Overall survival [ Time Frame: 27 Months ]
Change History Complete list of historical versions of study NCT02907359 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 29, 2017)
  • Transfusion independence [ Time Frame: 18 months ]
  • Marrow complete response [ Time Frame: 18 months ]
  • Survival rate [ Time Frame: 18 months ]
  • Leukemia-free survival [ Time Frame: 18 months ]
    As described in Time Frame.
  • Number of days alive and out of the hospital (NDAOH). [ Time Frame: 18 months ]
  • Disease response [ Time Frame: 18 months ]
  • Duration of response [ Time Frame: 18 months ]
  • Number of transfusions [ Time Frame: 18 months ]
  • Health-related quality of life [ Time Frame: 18 months ]
  • Incidence and severity of adverse events. [ Time Frame: 18 months ]
  • 30-day and 60-day all-cause mortality [ Time Frame: 18 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2016)
  • Transfusion independence [ Time Frame: 27 months ]
  • Marrow complete response [ Time Frame: 27 months ]
  • Survival rate [ Time Frame: 27 months ]
  • Leukemia-free survival [ Time Frame: 27 months ]
    As described in Time Frame.
  • Number of days alive and out of the hospital (NDAOH). [ Time Frame: 27 months ]
  • Disease response [ Time Frame: 27 months ]
  • Duration of response [ Time Frame: 27 months ]
  • Number of transfusions [ Time Frame: 27 months ]
  • Health-related quality of life [ Time Frame: 27 months ]
  • Incidence and severity of adverse events. [ Time Frame: 27 months ]
  • 30-day and 60-day all-cause mortality [ Time Frame: 27 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs
Official Title  ICMJE A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) Versus Treatment Choice in Adults With Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML) Previously Treated With Hypomethylating Agents
Brief Summary A Phase 3, randomized, open-label, parallel-group, multicenter study designed to evaluate the efficacy and safety of guadecitabine in subjects with MDS or CMML who failed or relapsed after adequate prior treatment with azacitidine, decitabine, or both. This global study will be conducted in approximately 15 countries. Approximately 408 subjects from approximately 100 study centers will be randomly assigned in a 2:1 ratio to either guadecitabine (approximately 272 subjects) or Treatment Choice (approximately 136 subjects). The study consists of a 14-day screening period, a treatment period, a safety follow-up visit, and a long-term follow-up period. The study is expected to last more than 2 years, and the duration of individual subject participation will vary. Subjects may continue to receive treatment for as long as they continue to benefit.
Detailed Description

Multicenter, randomized, open-label, parallel-group study of guadecitabine vs Treatment Choice (TC). Approximately 408 subjects will be randomly assigned 2:1 to either guadecitabine or TC.

  • Guadecitabine: approximately 272 subjects.
  • TC: approximately 136 subjects.

Before randomization, the investigator will assign each subject to one of the following TC options:

  • Low dose cytarabine (LDAC).
  • Standard Intensive Chemotherapy (IC) of a 7+3 regimen.
  • Best Supportive Care (BSC) only. BSC will be provided to all subjects as per standard and institutional practice. Subjects randomized to TC will not be allowed to cross over to guadecitabine. Data will be reviewed by an independent Data Monitoring Committee at regular intervals, primarily to evaluate safety during study conduct. Randomization will be stratified by disease category (MDS vs CMML), bone marrow (BM) blasts (BM blasts >10% vs BM blasts ≤10%), TC option (LDAC vs IC vs BSC), and study center region.

Guadecitabine: 60 mg/m2 given SC daily on Days 1-5 in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 6 total cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Beyond 6 cycles, treatment should continue as long as the subject continues to benefit. BSC should be given according to standard and institutional practice.

Treatment Choice (TC): Before randomization, the investigator will assign each subject to one of the following TC options:

  • Low dose cytarabine (LDAC) given as 20 mg/m2 SC or IV once daily for 14 days in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Standard Intensive Chemotherapy (IC) of a 7+3 regimen: given as cytarabine 100-200 mg/m2/day given as continuous infusion for 7 days and an anthracycline given as per institutional standard practice such as daunorubicin (45-60 mg/m2/day), or idarubicin (9-12 mg/m2/day), or mitoxantrone (8-12 mg/m2/day) by intravenous infusion for 3 days.
  • Best Supportive Care (BSC) only: given according to standard and institutional practice. BSC includes, but is not limited to blood transfusions (RBCs or platelets), growth factors including erythropoiesis stimulating agents (ESA), granulocyte stimulating factors (GSFs), iron chelating therapy, and broad spectrum antibiotics and/or antifungals.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndromes
  • Leukemia, Myelomonocytic, Chronic
Intervention  ICMJE
  • Drug: Guadecitabine
    Guadecitabine regimen is 60 mg/m2 given SC daily on Days 1-5 in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 6 total cycles in absence of unacceptable toxicity or disease progression requiring alternative therapy.
    Other Name: SGI-110
  • Other: Treatment Choice
    • BSC: according to standard/institutional practice; includes RBC or platelet transfusions; growth factors, ie, erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy; broad spectrum antibiotics and/or antifungals.
    • Low dose cytarabine: 20 mg/m2 SC or IV QD for 14 days in 28-day cycles. Other schedules allowed per institutional practice. Treatment for ≥4 cycles absent disease progression/toxicity. BSC per institutional/standard practice.
    • Standard Intensive Chemotherapy: recommended 7+3 given as cytarabine 100-200 mg/m2/day continuous infusion for 7 days and an anthracycline for 3 days. Anthracyclines per institutional practice include daunorubicin (45-60 mg/m2/day) or idarubicin (9-12 mg/m2/day) or mitoxantrone (8-12 mg/m2/day) by IV infusion. Subjects with complete or partial response after IC induction should receive ≥1 additional cycles with reduced cytotoxic doses then BSC per standard /institutional practice.
Study Arms  ICMJE
  • Experimental: Guadecitabine
    Guadecitabine 60 mg/m2 given subcutaneously daily on Days 1-5 in 28-day cycles. The total amount (in mg) of guadecitabine to be administered is determined by body surface area.
    Intervention: Drug: Guadecitabine
  • Active Comparator: Treatment Choice
    • Best Supportive Care.
    • Low dose cytarabine.
    • Standard Intensive Chemotherapy.
    Intervention: Other: Treatment Choice
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 15, 2016)
408
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adult subjects ≥18 years of age who are able to understand and comply with study procedures, and provide written informed consent before any study-specific procedure.
  • Cytologically or histologically confirmed diagnosis of MDS or CMML according to the 2008 World Health Organization (WHO) classification.
  • Performance status (ECOG) of 0-2.
  • Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows:

    1. Subject received HMA for at least 6 cycles and was still transfusion dependent (as defined in 5b below).
    2. Subject had disease progression prior to Cycle 6 defined as ≥50% increase in bone marrow blasts from pretreatment levels to >5%, or ≥2 g/dL reduction of Hgb from pretreatment levels with transfusion dependence after at least 2 cycles of HMA.

Other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed.

  • Subjects must have either:

    1. Bone marrow blasts >5% at randomization, OR
    2. Transfusion dependence, defined as having had transfusion (in the setting of active disease) of 2 or more units of RBC or platelets within 8 weeks prior to randomization.
  • Creatinine clearance or glomerular filtration rate ≥30 mL/min estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration).
  • Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential and men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to become pregnant or father a child while receiving treatment with guadecitabine, LDAC, or IC and for at least 3 months after completing treatment.

Exclusion criteria:

  • Subjects who have been diagnosed as having AML with peripheral blood or bone marrow blasts of ≥20%.
  • Subjects who may still be sensitive to repeated treatment with decitabine or azacitidine such as subjects who had response to prior decitabine or azacitidine treatment, but relapsed >6 months after stopping treatment with these agents.
  • Prior treatment with guadecitabine.
  • Hypersensitivity to decitabine, guadecitabine, or any of their excipients.
  • Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
  • Treated with any investigational drug within 2 weeks of the first dose of study treatment.
  • Total serum bilirubin >2.5 ULN (except for subjects with Gilbert's Syndrome for whom direct bilirubin is <2.5×ULN), or liver cirrhosis or chronic liver disease Child-Pugh Class B or C.
  • Known active HIV, HBV, or HCV infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed.
  • Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
  • Refractory congestive heart failure unresponsive to medical treatment, active infection resistant to all antibiotics, or advanced non-MDS associated pulmonary disease requiring >2 liters per minute oxygen.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Harold Keer, MD, PhD 925-719-0741 harold.keer@astx.com
Listed Location Countries  ICMJE Belgium,   Canada,   Czechia,   Denmark,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Poland,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02907359
Other Study ID Numbers  ICMJE SGI-110-07
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Astex Pharmaceuticals
Study Sponsor  ICMJE Astex Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Harold Keer, MD, PhD Astex Pharmaceuticals, Inc.
PRS Account Astex Pharmaceuticals
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP