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SL-401 in Combination With Azacitidine or Azacitidine/Venetoclax in Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

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ClinicalTrials.gov Identifier: NCT03113643
Recruitment Status : Recruiting
First Posted : April 13, 2017
Last Update Posted : September 18, 2019
Sponsor:
Collaborator:
Stemline Therapeutics, Inc.
Information provided by (Responsible Party):
Andrew Lane, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE April 10, 2017
First Posted Date  ICMJE April 13, 2017
Last Update Posted Date September 18, 2019
Actual Study Start Date  ICMJE June 26, 2017
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 13, 2019)
Maximum Tolerated Dose [ Time Frame: 2 years ]
To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of SL-401 in combination with azacitidine or in combination with azacitidine and venetoclax in this patient population and evaluate the safety of this regimen
Original Primary Outcome Measures  ICMJE
 (submitted: April 10, 2017)
Maximum Tolerated Dose [ Time Frame: 2 years ]
Change History Complete list of historical versions of study NCT03113643 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 16, 2019)
  • Complete Response Rate [ Time Frame: 2 years ]
    To estimate the complete remission (CR) / CR with incomplete count recovery (CRi) rate within 6 cycles of combination therapy consisting of SL-401 administered with azacitidine or in combination with azacitidine and venetoclax in subjects with AML and high-risk MDS
  • Time to response [ Time Frame: 2 years ]
    To estimate the time to response with SL-401 in combination with azacitidine or in combination with azacitidine and venetoclax
  • Duration of remission [ Time Frame: 2 years ]
    To estimate the duration of remission with SL-401 in combination with azacitidine or in combination with azacitidine and venetoclax
  • Progression Free Survival [ Time Frame: 1 and 2 years ]
    To estimate the 1 and 2-year progression free survival (PFS) with SL-401 in combination with azacitidine or in combination with azacitidine and venetoclax
  • Overall Survival [ Time Frame: 2 years ]
    To estimate the overall survival (OS) with SL-401 in combination with azacitidine or in combination with azacitidine and venetoclax
Original Secondary Outcome Measures  ICMJE
 (submitted: April 10, 2017)
  • Complete Response Rate [ Time Frame: 2 years ]
  • Time to response and duration of response [ Time Frame: 2 years ]
  • Progression Free Survival [ Time Frame: 2 years ]
  • Overall Survival [ Time Frame: 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE SL-401 in Combination With Azacitidine or Azacitidine/Venetoclax in Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)
Official Title  ICMJE Phase 1 Study of SL-401 in Combination With Azacitidine or Azacitidine/Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia (AML) or in Treatment-Naive Subjects With AML Not Eligible for Standard Induction Therapy or in Subjects With High-Risk Myelodysplastic Syndrome (MDS)
Brief Summary

This research study is studying a drug as a possible treatment for diagnosis of AML and high-risk MDS.

The interventions involved in this study are:

  • SL-401
  • Azacitidine
  • Venetoclax
Detailed Description

This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has approved azacitidine and venetoclax as a treatment option for AML. This regimen has not been approved for MDS. SL-401 has not been FDA approved for your specific disease, but it has been approved for other uses.

In this research study, the study drug SL-401 will be combined with the standard dose of azacitidine (for MDS patients) or azacitidine/venetoclax (for AML patients). The goal of this research study is to try and determine the safest, highest dose of study drug, SL-401, in combination with azacitidine or azacitidine/venetoclax that can be given to patients with AML or high-risk MDS. SL-401 works by stopping or slowing the growth of cancer stem cells, which are the undeveloped cells which can develop into cancer cells. The goals of this research study are to look at if this combination works to help treat your cancer and if there is any lasting effect of this combination. This study will also look at how the SL-401, in combination with azacitidine or azacitidine/venetoclax, affects certain proteins in your blood and bone marrow. SL-401 has been given to patients with AML and MDS in the past, but this is the first time it will be given in combination with another drug.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
Intervention  ICMJE
  • Drug: Azacitidine
    Chemotherapy
    Other Name: Vidaza
  • Drug: SL-401
    SL-401 works by targeting leukemia cells (blasts), and also possibly by stopping or slowing the growth of cancer stem cells, which are the undeveloped cells which can develop into cancer cells.
  • Drug: Venetoclax
    Venetoclax is a BH3-mimetic. Venetoclax blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of CLL cells. Overexpression of Bcl-2 in some lymphoid malignancies has sometimes shown to be linked with increased resistance to chemotherapy.
    Other Name: Venclyxto, Venclexta
Study Arms  ICMJE
  • Experimental: SL-401+ Azacitidine
    SL-401 will be administered every 4 weeks, on a 28 day cycle; SL-401 will be given intravenously; Azacitidine will be administered every 4 weeks, on a 28 day cycle; Azacitidine will be given intravenously or subcutaneously
    Interventions:
    • Drug: Azacitidine
    • Drug: SL-401
  • Experimental: SL-401+ Azacitidine + Venetoclax
    SL-401 will be administered every 4 weeks, on a 28 day cycle; SL-401 will be given intravenously; Azacitidine will be administered every 4 weeks, on a 28 day cycle; Azacitidine will be given intravenously or subcutaneously; Venetoclax will be administered for 21 days on a 28 day cycle; Venetoclax will be taken orally
    Interventions:
    • Drug: Azacitidine
    • Drug: SL-401
    • Drug: Venetoclax
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 13, 2019)
56
Original Estimated Enrollment  ICMJE
 (submitted: April 10, 2017)
36
Estimated Study Completion Date  ICMJE May 31, 2023
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed diagnosis of acute myeloid leukemia (AML) [Cohort B] or myelodysplastic syndrome (MDS) [Cohort A] per 2016 WHO criteria
  • CD123 / IL3RA expression on the subject's AML, determined locally within 3 months of first protocol treatment
  • Age >= 18 years with relapsed or refractory AML (hydroxyurea is not considered a prior treatment regimen) [Cohort B] OR Age >= 18 years with treatment-naïve AML who decline intensive induction chemotherapy or who are unfit due to co-morbidity or other factors (see APPENDIX A for unfitness definitions) (hydroxyurea is not considered a prior treatment regimen) [Cohort B] OR Age >= 18 years with MDS and >= 10% myeloblasts in the bone marrow [Cohort A]
  • ECOG performance status 0, 1, or 2
  • Adequate organ function as defined by:

    • Albumin > 3.2 g/dL (in the absence of receipt of intravenous albumin in the previous 72 hours)
    • Serum creatinine < 1.5x ULN
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5x ULN
    • Total bilirubin < 1.5x ULN (if thought to be > 1.5x ULN due to Gilbert's disease or the patient's AML, must discuss with the PI)
    • Creatine phosphokinase (CPK) < 2.5x ULN
    • Left ventricular ejection fraction > institutional lower limit of normal by MUGA scan or echocardiogram within 30 days of first protocol treatment
  • [Cohort B] WBC < 10,000 / uL on day of first therapy, cytoreduction may be achieved using hydroxyurea
  • Ability to understand and the willingness to sign a written informed consent document.
  • Able to adhere to study visit schedule and other protocol requirements including follow-up for survival assessment
  • Women of child-bearing potential must agree to use adequate contraception for the duration of study participation and for 2 months after completion of protocol treatment. Men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation and 2 months after completion of protocol treatment.

Exclusion Criteria:

  • Prior treatment with SL-401 [Cohort A or B] or venetoclax [Cohort B]
  • Diagnosis of acute promyelocytic leukemia
  • Received treatment with chemotherapy, radiation, or biologic cancer therapy within 14 days of first protocol treatment. Prior and concurrent hydroxyurea is permitted.
  • Hematopoietic stem cell transplantation (HSCT) within 60 days of screening, or receipt of immunosuppressive therapy for graft-versus-host disease treatment or prophylaxis within 30 days of screening, or active graft-versus-host-disease
  • Known CNS involvement by AML
  • Known positive status for HIV infection; known active hepatitis B or hepatitis C infection
  • Clinically significant cardiopulmonary disease including uncontrolled or NYHA class 3 or 4 congestive heart failure, uncontrolled angina, uncontrolled hypertension, uncontrolled arrhythmia, myocardial infarction or stroke within 6 months of first protocol treatment, or QTc > 480 ms
  • Patients with known active advanced malignant solid tumors are excluded (except for basal or squamous skin cancers, or carcinomas in situ). Patients with additional hematologic malignancies that require treatment are excluded.
  • Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in the developing fetus with SL-401 and azacitidine (negative urine or serum pregnancy test required within 14 days of Cycle 1, Day 1). Because nursing infants have unknown potential for adverse events secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with SL-401 and azacitidine.
  • Infection is a common feature of AML. Patients with active infection are permitted to enroll provided that the infection is controlled. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control
  • [Cohort B] Patients with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)
  • [Cohort B] Patients on strong CYP3A inducers within 7 days of first dose of study treatment.
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: Andrew Lane, MD, PhD 617-632-4589 andrew_lane@dfci.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03113643
Other Study ID Numbers  ICMJE 17-056
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Andrew Lane, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Dana-Farber Cancer Institute
Collaborators  ICMJE Stemline Therapeutics, Inc.
Investigators  ICMJE
Principal Investigator: Andrew Lane, MD, PhD Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date September 2019

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