Clinical Trials /

Study of APVO436 in Patients With AML or MDS

NCT03647800

Description:

APVO436 is being studied in this Phase 1/1b, open-label, multi-center, dose-escalation study to evaluate the safety, pharmacokinetic/pharmacodynamic and clinical activity of APVO436 monotherapy in: 1) patients with AML that have relapsed on prior therapy or are refractory to therapy and are not candidates for intensive chemotherapy or transplant, and 2) patients with MDS that have > 5% blasts in the bone marrow or blasts in the peripheral blood who have also failed prior therapy with an hypomethylating agent (HMA). The primary objective of the Phase 1 part of the study is to determine the recommended dose of APVO436 administered intravenously to patients with AML or MDS. The primary objective of the Phase 1b part of the study is to evaluate the clinical activity of APVO436 in patients with AML or MDS.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of APVO436 in Patients With AML or MDS
  • Official Title: Phase 1/1B Open-Label, Dose-Escalation Study of APVO436 in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: Protocol 5001
  • NCT ID: NCT03647800

Conditions

  • AML
  • MDS

Interventions

DrugSynonymsArms
APVO436Dose Escalation

Purpose

APVO436 is being studied in this Phase 1/1b, open-label, multi-center, dose-escalation study to evaluate the safety, pharmacokinetic/pharmacodynamic and clinical activity of APVO436 monotherapy in: 1) patients with AML that have relapsed on prior therapy or are refractory to therapy and are not candidates for intensive chemotherapy or transplant, and 2) patients with MDS that have > 5% blasts in the bone marrow or blasts in the peripheral blood who have also failed prior therapy with an hypomethylating agent (HMA). The primary objective of the Phase 1 part of the study is to determine the recommended dose of APVO436 administered intravenously to patients with AML or MDS. The primary objective of the Phase 1b part of the study is to evaluate the clinical activity of APVO436 in patients with AML or MDS.

Detailed Description

      Phase 1 - Open-label, Dose Escalation: The dose escalation stage of the study will test
      step-dose and/or split-dose regimens infused weekly over 10 dose levels (cohorts). Cohorts 1
      to 10 will follow a 3 + 3 design. The next cohort is started after patients in the previous
      dose cohort have completed the first cycle of dosing and an evaluation for dose-limiting
      toxicities (DLTs) during the first cycle has been completed.

      Phase 1b - Expansion: The recommended-dose from Phase 1 will be further examined in 2
      expansion cohorts consisting 24 AML patients (Cohort 1) and 24 MDS patients (Cohort 2).
      Patients will receive APVO436 intravenously weekly for six 28-day cycles, unless disease
      progression, intolerable toxicity, or withdrawal of consent occurs earlier. Patients with
      evidence of clinical benefit at the end of Cycle 6 in the absence of unacceptable toxicity
      may also continue on study for up to 12 total cycles at the discretion of Investigator (6
      cycles in addition to the initial 6 cycles).
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalCD123 and CD3 epsilon bispecific antibody
  • APVO436
Expanded Cohort (Phase 1b)Experimental48 patients will receive the recommended dose of APVO436 determined from Phase 1.
  • APVO436

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent. Consent must be obtained prior to any study-related
             procedure.

          2. Age ≥ 18 years

          3. Histologically confirmed AML or MDS:

               1. AML - relapsed or refractory AML and refuses or is not a candidate for intensive
                  chemotherapy (due to prior failure or not eligible due to expected intolerance)
                  or allogeneic transplant

               2. MDS - relapsed or refractory MDS with > 5% blasts in the marrow or any blasts in
                  the peripheral blood. Patients must have failed prior treatment with an HMA
                  (azacitidine, decitabine, or other HMA agent); failure is defined as intolerance
                  to HMA, lack of response [no complete remission (CR) by at least 6 cycles], or
                  have IWG-defined progressive disease during or after treatment with an HMA.

          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          5. Life expectancy of > 2 months in the Investigator's opinion

          6. White blood cells (WBC) ≤ 25,000 cells/mm3 (may receive hydroxyurea to bring WBC count
             down prior to and during the first cycle of treatment with study drug if necessary)

          7. Creatinine ≤ 2 × upper limit of normal (ULN)

          8. Adequate liver test parameters: total bilirubin < 2.5 × ULN (if disease related or
             secondary to Gilbert's disease, then total bilirubin < 3.5 mg/dL), aspartate
             aminotransferase (AST), and alanine aminotransferase (ALT) < 3 × ULN

          9. Prothrombin time (PT) / international normalized ratio (INR) and partial
             thromboplastin time (PTT) < 1.5 × ULN

         10. Patients and partners of childbearing potential must be willing to use adequate
             contraception during the study and for 2 months after last study drug administration.
             Adequate contraception means less than 1% chance of pregnancy may occur with proper
             use of the method(s).

        Exclusion Criteria:

          1. Any central nervous system (CNS) (cerebral/meningeal) disease related to underlying
             malignancy

          2. History of seizures

          3. Acute promyelocytic leukemia

          4. Prior anti-CD123 therapy outside of this study

          5. Any clinically significant graft-versus-host disease (GVHD) secondary to prior
             allogenic transplant. Patients must be >90 days from transplant and have been on no
             immunosuppressive therapy for >30 days. Topical corticosteroids for minor skin rash
             (<5% body surface area) is acceptable. Prior solid organ transplant is acceptable
             provided the patient is on no immunosuppressive therapy.

          6. Any therapy or experimental treatment for MDS or AML within 7 days of the first dose
             of study drug. Must have recovered to Grade ≤ 1 from any Grade 2 to 4 toxicity from
             previous treatment. The use of hydroxyurea is acceptable and does not exclude the
             patient.

          7. Active, uncontrolled infection requiring systemic therapy. If the infection is
             controlled or has resolved, maintenance and/or prophylactic systemic antimicrobials
             are permitted.

          8. Major surgery within 3 weeks prior to first dose of study drug

          9. Known to be positive for HIV, hepatitis B virus surface antigen (HBsAg), hepatitis B
             core antibody (HBcAb), or hepatitis C virus (HCV)

         10. Pregnant or breast feeding

         11. Any other active systemic malignancies. Exceptions: noninvasive non-melanoma skin
             cancer, in situ carcinoma, cervical intraepithelial neoplasia, and breast or prostate
             cancer that is well controlled with anti-hormonal therapy

         12. Any current autoimmune disorder requiring immunosuppressive therapy

         13. Requires more than a replacement dose of corticosteroids (i.e., > 10 mg/day of
             prednisone or equivalent)

         14. Any uncontrolled medical condition, including but not limited to:

               1. Symptomatic congestive heart failure ≥ Class III (New York Heart Association
                  Functional Classification)

               2. Uncontrolled hypertension

               3. Unstable angina

               4. Myocardial infarction within previous 6 months

               5. Clinically significant arrhythmias not controlled by medication

               6. Uncontrolled metabolic disorders such as hypercalcemia

         15. Substance use disorder, psychiatric, cognitive, or any other condition that, in the
             opinion of the Investigator, would pose a risk to the patient's safety, may compromise
             the patient's ability to understand and comply with the protocol or provide informed
             consent, or interfere with the study evaluation

         16. Any difficulty complying with protocol requirements that may increase the risk
             associated with study participation or study drug administration, or may cause a
             safety concern for the patient
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:during first 28 to 35 days of treatment
Safety Issue:
Description:Identify the maximum tolerated dose in dose-escalation (Phase 1) by assessment of dose-limiting toxicities

Secondary Outcome Measures

Measure:Frequency and severity of adverse events as assessed by CTCAE v5.0
Time Frame:Patient will be followed for the duration of treatment, an expected average of 6 months, and for up to 7 days following last treatment
Safety Issue:
Description:The safety profile of APVO436 will be assessed by monitoring incidence and severity of adverse events
Measure:Maximum serum drug concentration
Time Frame:Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.
Safety Issue:
Description:Blood samples will be obtained from all patients for determination of the maximum serum concentration of APVO436
Measure:Area under the concentration-time curve (AUC)
Time Frame:Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.
Safety Issue:
Description:Blood samples will be obtained from all patients for determination of the AUC of APVO436
Measure:Elimination of half-life
Time Frame:Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.
Safety Issue:
Description:Blood samples will be obtained from all patients for determination of the T1/2 of APVO436
Measure:Changes in T-cell populations to measure pharmacodynamics of APVO436
Time Frame:Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.
Safety Issue:
Description:Blood samples will be collected from all patients and evaluated by flow cytometry for changes in T-cell populations
Measure:Changes in peripheral blasts to measure pharmacodynamics of APVO436
Time Frame:Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.
Safety Issue:
Description:Blood samples will be collected from all patients and evaluated by flow cytometry for changes in peripheral blasts
Measure:Immunogenicity of APVO436
Time Frame:Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.
Safety Issue:
Description:Blood samples will be collected from all patients and tested for antibody formation to APVO436

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Aptevo Research and Development LLC

Trial Keywords

  • APVO436

Last Updated

January 17, 2020