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Pegcrisantaspase in Combination With Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)

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ClinicalTrials.gov Identifier: NCT04666649
Recruitment Status : Recruiting
First Posted : December 14, 2020
Last Update Posted : May 14, 2021
Sponsor:
Information provided by (Responsible Party):
Ashkan Emadi, MD, PhD, University of Maryland, Baltimore

Brief Summary:
Evaluate the safety and tolerability of pegcrisantaspase in combination with venetoclax (Ven-PegC) and estimate the maximum tolerated doses and/or biologically active doses of Ven-PegC in patients with relapsed or refractory acute myeloid leukemia (R/R AML)

Condition or disease Intervention/treatment Phase
Relapsed or Refractory Acute Myeloid Leukemia Drug: Venetoclax and pegcrisantaspase Phase 1

Detailed Description:

This research study is a non-randomized, open-label Phase Ib clinical trial evaluating venetoclax (Ven) administered orally daily in combination with pegcrisantaspase (PegC) administered IV biweekly, as part of a 28-day treatment cycle in adult subjects with relapsed or refractory acute myeloid leukemia (R/R AML).

The trial will consist of dose escalation to evaluate the safety and tolerability of Ven-PegC and estimate the maximum tolerated doses (MTDs) and/or biologically active doses (e.g. recommended phase 2 doses [RP2Ds]) of Ven-PegC in patients with R/R AML

Venetoclax is an FDA (the U.S. Food and Drug Administration) approved drug, but this combination ( Ven-PegC) has not been approved by the FDA.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
  1. Cohort1: The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 500 IU/m² of Pegcrisantaspase in an IV every 14 days ( per cycle)
  2. Cohort 2: The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 750 IU/m² of Pegcrisantaspase in an IV every 14 days ( per cycle)
  3. Cohort 3: The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 1000 IU/m ² of Pegcrisantaspase in an IV every 14 days ( per cycle)
  4. Cohort 4: The subject will take 600mg of Venetoclax every day as a pill by mouth and a dose of 1000 IU/m ² of Pegcrisantaspase in an IV every 14 days ( per cycle)
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pegcrisantaspase in Combination With Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia
Actual Study Start Date : March 10, 2021
Estimated Primary Completion Date : April 15, 2023
Estimated Study Completion Date : July 1, 2023


Arm Intervention/treatment
Experimental: Cohort 400mg of Venetoclax, 500 IU/m ² of Pegcrisantaspase
The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 500 IU/m ² of Pegcrisantaspase in an IV every 14 days ( per cycle)
Drug: Venetoclax and pegcrisantaspase
Therapeutic

Experimental: Cohort 400mg of Venetoclax, 750 IU/m ² of Pegcrisantaspase
The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 750 IU/m ² of Pegcrisantaspase in an IV every 14 days ( per cycle)
Drug: Venetoclax and pegcrisantaspase
Therapeutic

Experimental: Cohort 400mg of Venetoclax, 1000 IU/m² of Pegcrisantaspase
The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 1000 IU/m² of Pegcrisantaspase in an IV every 14 days ( per cycle)
Drug: Venetoclax and pegcrisantaspase
Therapeutic

Experimental: Cohort 600mg Venetoclax, 1000 IU/m ² of Pegcrisantaspase
The subject will take 600mg of Venetoclax every day as a pill by mouth and a dose of 1000 IU/m ² of Pegcrisantaspase in an IV every 14 days ( Per cycle)
Drug: Venetoclax and pegcrisantaspase
Therapeutic




Primary Outcome Measures :
  1. Incidence of regimen limiting toxicities (RLTs) [ Time Frame: One year (after 12 cycle's treatment) ]
    The period for determination of RLT will be from the first day of treatment until 30 days after receiving the first dose of Ven-PegC.

  2. Incidence of treatment-emergent adverse events (TEAE) [ Time Frame: One year (after 12 cycle's treatment) ]
    The period for determination of TEAE will be from the first day of treatment until 30 days after receiving the first dose of Ven-PegC.


Secondary Outcome Measures :
  1. The rate of CR [ Time Frame: One year (after 12 cycle's treatment) ]
    Complete Remission rate

  2. The rate of composite complete remission (CR+CRh+CRi+CRp) [ Time Frame: One year (after 12 cycle's treatment) ]
    The rate of Complete Remission rate, Complete Remission with Partial hematological recovery, Complete Remission with incomplete hematological recovery and Complete Remission with incomplete platelet recovery.

  3. Event-free Survival (EFS) [ Time Frame: One year (after 12 cycle's treatment) ]
    Event-free Survival (EFS)

  4. Overall Survival (OS) [ Time Frame: One year (after 12 cycle's treatment) ]
    Overall Survival (OS)

  5. The rate of conversion from transfusion dependence to transfusion independence [ Time Frame: One year (after 12 cycle's treatment) ]
    The rate of conversion from transfusion dependence to transfusion independence

  6. The rate of proceeding to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after administration of Ven-PegC [ Time Frame: One year (after 12 cycle's treatment) ]
    The rate of proceeding to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after administration of Ven-PegC

  7. Achievement of MRD <0.02% within 2 cycles of treatment with Ven-PegC [ Time Frame: Two months ]
    Achievement of Minimal Residual Disease <0.02% within 2 cycles of treatment with Ven-PegC

  8. Overall incidence and severity of AEs [ Time Frame: One year (after 12 cycle's treatment) ]
    Overall incidence and severity of Adverse Events



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A histologically or pathologically confirmed diagnosis of AML based on 2016 WHO classification. Patients with Complex Karyotype AML (CK-AML) and TP53-mutated AML are eligible for this study.
  • AML has relapsed after or is refractory to, first-line therapy, with a maximum of three prior lines of therapy. Patients whose AML has FLT3 or IDH1/IDH2 mutations should have received at least one available FLT3 or IDH1/IDH2 inhibitors
  • Age 18 years and older
  • ECOG performance status ≤ 2
  • Patients who have undergone allo-HSCT are eligible if they are ≥ 30 days post stem cell infusion, have no evidence of graft versus hose disease ( GVHD ) > Grade 1, and are ≥ 10 days off all immunosuppressive therapy
  • Previous cytotoxic chemotherapy must have been completed at least 10 days prior to day 1 of treatment on the study and all AEs (excluding alopecia, acne, rash) due to agents administered earlier should have recovered to < Grade 1. Patients with hematologic malignancies are expected to have hematologic abnormalities at study entry. These abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to < Grade 1
  • All biologic agents including hematopoietic growth factors must have been stopped at least 1 week prior to day 1 of treatment on the study
  • Patients must have adequate organ function as defined below:

    • Direct bilirubin ≤2X the institutional upper limit of normal (ULN) (except in patients with leukemic infiltration of the liver)
    • AST(SGOT)/ALT(SGPT) ≤3X ULN (except if attributable to leukemic infiltration of the liver)
    • Alkaline phosphatase ≤5X ULN
    • Creatinine Clearance (CrCl) ≥ 45 mL/min (except in patients with evidence of tumor lysis syndrome)
    • Patients with a history of CNS leukemia must be stable with clear CSF for > 2 months prior to day 1 of treatment (patient can receive intrathecal maintenance chemotherapy)
  • Female patients of childbearing potential must have a negative pregnancy test <1 week prior to enrollment. Female patients of childbearing potential who are sexually active and male patients who are sexually active and have female partners of childbearing potential must agree to use highly effective method of contraception with their partners during exposure to study drugs and for 30 days after the last dose of study drugs.
  • Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients receiving any other investigational agents, or concurrent chemotherapy or immunotherapy
  • Patients with acute promyelocytic leukemia (APL) confirmed with t(15;17) (i.e. FAB subtype M3 and M3 variant)
  • Prior treatment with any asparaginase product. Patients who received ≤12 weeks of a BCL-2 inhibitor including venetoclax are eligible.
  • Absolute peripheral blast > 100,000/μL. Hydroxyurea for blast count control is permitted before starting treatment and up to maximum of 10 days after starting treatment on the study. The decision to start hydroxyurea during this time is at the discretion of the treating physician.
  • Patients with the following clinical histories are excluded:

    • severe pancreatitis not related to cholelithiasis. Severe acute pancreatitis is defined by lipase elevation >5X ULN and with signs or symptoms
    • unprovoked deep venous thrombosis (DVT)
    • pulmonary emboli
    • hemorrhagic or thromboembolic stroke
    • other malignancies requiring systemic chemotherapy, immunotherapy or targeted therapy in the last three months
  • Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that per site Principal Investigator's judgment would limit compliance with study requirements
  • Pregnant women and female patients who are lactating and do not agree to stop breast- feeding.
  • Uncontrolled active seizure
  • Any other clinical conditions that in the opinion of the investigator would make the subject unsuitable for the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04666649


Contacts
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Contact: Ashkan Emadi, M.D.,Ph.D. 410-328-6841 aemadi@umm.edu
Contact: Sunita Sunita 410-328-8199 sphilip1@umm.edu

Locations
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United States, Maryland
Greenebaum Cancer Center at University of Maryland Medical Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Clinical Trials Office - Greenebaum Cancer Center at Universit    800-888-8823      
Sponsors and Collaborators
University of Maryland, Baltimore
Investigators
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Principal Investigator: Ashkan Emadi, M.D.,Ph.D. University of Maryland, Baltimore
Publications:
American Cancer Society. Key Statistics for AML. 2020.
FDA. Vyxeos (daunorubicin and cytarabine) liposome Label. US Food and Drug Administration 2017:https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf.
FDA. Venetoclax (Venclexta). Food and Drug Administration 2018:https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208573s013lbl.pdf
FDA. Erwinaze (asparaginase Erwinia chrysanthemi) Label. Food and Drug Administration 2019:https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125359s098lbl.pdf
Emadi A, Gartenhaus RB, Bhandary B, et al. Pegcrisantaspase and venetoclax combination is highly effective against acute myeloid leukemia (AML), mechanistically driven synergism between glutamine depletion and bcl-2 inhibition. European Hematology Association (EHA) 2019;Oral Presentation:S834.
FDA. Mylotarg (gemtuzumab ozogamicin) Label. US Food and Drug Administration 2017:https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf.
FDA. Oncaspar (pegaspargase) Food and Drug Administration 2019:https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/193411s5196lbl.pdf
FDA. Gilteritinib (Xospata). Food and Drug Administration 2019:https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211349s001lbl.pdf
FDA. Enasidenib (Idhifa). Food and Drug Administration 2019:https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209606s002lbl.pdf

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Responsible Party: Ashkan Emadi, MD, PhD, Professor of Medicine and Pharmacology University of Maryland, School of Medicine Associate Director for Clinical Research, University of Maryland, Baltimore
ClinicalTrials.gov Identifier: NCT04666649    
Other Study ID Numbers: 2087GCCC
First Posted: December 14, 2020    Key Record Dates
Last Update Posted: May 14, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ashkan Emadi, MD, PhD, University of Maryland, Baltimore:
Pegcrisantaspase
Venetoclax
Relapsed or refractory acute myeloid leukemia (R/R AML)
Ven-PegC
Maximum tolerated doses
Recommended phase 2 doses
Incidence of regimen limiting toxicities
Incidence of treatment-emergent adverse events
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Venetoclax
Antineoplastic Agents