Details

Details

Title A Phase 1 Dose-Escalation Study of AEB1102 (Co-ArgI-PEG) in Patients with Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Refractory to Hypomethylating Agents

IRB AGLA1916

CC 16-1113

Hospital Main Campus

Phase Phase 1

Disease Leukemia - Acute Myeloid (AML), Myelodisplastic Syndrome (MDS)

Drug AEB1102

Description

Description

Primary Objective
  • To determine the maximally tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of AEB1102 in patients with relapsed or refractory adult acute myeloid leukemia (R/R AML); with myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs); or with AML who are not candidates for aggressive remission induction therapy or who have refused aggressive remission induction therapy.
Secondary Objective(s)
  • To evaluate the safety profile of AEB1102 in the study patient population
  • To evaluate the anti-leukemic and anti-MDS effects of AEB1102 in the study patient population
  • To evaluate the pharmacokinetic (PK) profile of AEB1102 in the study population
  • To evaluate the pharmacodynamic (PD) profile of AEB1102 by the measurement of pre- and post-treatment blood arginine levels in the study population
  • To evaluate the immunogenicity of AEB1102 in the study population
Exploratory Objective(s)
  • To evaluate the activity of key enzymes in the Arginine (Arg) synthetic pathway including ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) in the blast cells of patients with relapsed/refractory AML or MDS refractory to HMAs.
  • To explore the relationship between the activity of key enzymes in the Arg synthetic pathway as outlined above and various genetic mutations in the blast cells of patients with R/R AMS of MDS refractory to HMAs.
Inclusion Criteria

Inclusion Criteria

  1. Patient or legal guardian is able and willing to provide written informed consent and to comply with all requirements of study participation (including all study procedures) prior to any screening procedures
  2. Age > 18 years
  3. Diagnosis of AML or MDS according to the WHO criteria (Appendices 2 and 3) (Blood 21:453, 2010)
  4. Subjects with prior therapy as follows:
    • Subjects with AML that is refractory to at least one attempt at induction or subjects with AML that has relapsed following at least one induction regimen or subjects who are not candidates for aggressive induction regimens or who have refused treatment with aggressive induction regimens (an induction regimen may include any number of regimens containing cytosine arabinoside plus an anthracycline including (but not limited to) any of the following: 7 days of cytosine arabinoside with 3 days of daunorubicin ("7+3"); followed, if necessary, by 5 days of cytosine arabinoside with 2 days of daunorubicin ("5+2"); followed by allogeneic stem cell transplantation and/or consolidation chemotherapy; and including intrathecal chemotherapy as indicated).
    • Subjects with AML who are not candidates for aggressive remission induction therapy must be > 75 years of age AND have one of the following: secondary AML following MDS; high-risk cytogenetics (see Appendix 7); or unfitness for intensive chemotherapy (see Appendix 8). Subjects may have received prior HMA therapy for the treatment of AML.
    • Subjects with Revised International Prognostic Scoring System (IPSS-R) high or very high risk MDS that is refractory to treatment with HMA therapy defined as MDS with progression to AML; failure to respond to HMA therapy after 4 treatment cycles; recurrence or progression of MDS following a response to an HMA or intolerance to HMAs. See Appendix 6 for the International Prognostic Scoring System for MDS.
  5. Adequate hepatic function defined as AST and ALT < 3X the ULN for the reference lab AND serum bilirubin < 2X the ULN for the reference lab
  6. Adequate renal function defined as a serum creatinine of < 2 mg/dL, or a calculated creatinine clearance of > 50 mL/minute based on the Cockroft-Gault equation
  7. ECOG Performance Score of 0-2
  8. Subjects must have recovered from the effects of any prior systemic therapy, radiotherapy or surgery
  9. If female and of child-bearing potential, has a negative serum pregnancy test within 7 days before enrollment
  10. If a sexually active (male or female), must be surgically sterile, post-menopausal (female), or must agree to use a physician-approved method of birth control during the study and for a minimum of 30 days after the last study drug administration
Exclusion Criteria

Exclusion Criteria

  1. Current CNS leukemia; subjects who have had CNS leukemia in the past, who have had negative CSF cytology and who receive periodic prophylactic intrathecal chemotherapy may be enrolled
  2. Acute promyelocytic leukemia or AML with a t(15;17) (q22;q12) cytogenetic abnormality
  3. Bcr/Abl positive leukemia
  4. Subject is < 60 days from ASCT; has chronic graft-versus host disease (GVHD) or requires continued treatment with systemic immunosuppressive agents
  5. Investigational therapy within 5 half-lives of the agent. If the agent has an exceedingly long half-life (eg, a monoclonal antibody), within 1 half-life of the agent. If the half-life is unknown, a washout period of 2 weeks is required.
  6. Uncontrolled infection
  7. Known HIV, hepatitis B or hepatitis C.
  8. Other active malignancy that requires therapy
  9. If female, is lactating or breast feeding
  10. Currently has any co-morbid condition that in the opinion of the investigator might compromise the patient's safety, might interfere with participation in the trial, or might interfere with the interpretation of trial results
  11. Is currently participating in another therapeutic clinical trial
  12. Has a history of hypersensitivity to PEG or any other component of the AEB1102 (Co-Arg-PEG) formulation