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Study of APVO436 in Patients With AML or MDS

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ClinicalTrials.gov Identifier: NCT03647800
Recruitment Status : Recruiting
First Posted : August 27, 2018
Last Update Posted : September 11, 2019
Sponsor:
Information provided by (Responsible Party):
Aptevo Therapeutics ( Aptevo Research and Development LLC )

Brief Summary:

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 APVO436administered 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.


Condition or disease Intervention/treatment Phase
AML MDS Biological: APVO436 Phase 1

Detailed Description:

Phase 1 - Open-label, Dose Escalation: The dose escalation stage of the study will test weekly doses from 0.3 mcg to 100 mcg over 10 dose levels (cohorts). Cohorts 1 to 3 consist of single patients and Cohorts 4 - 10 will consist of a minimum of 3 patients; an additional 3 patients may be added to the cohort if adverse events possibly related to APVO436 or dose-limiting toxicities (DLTs) occur. The next dose level 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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: The study is composed of two parts. The first part is a Phase 1 open-label, dose-escalation study to determine the recommended dose for Phase 1b. The second part is a Phase 1b open label expansion study to assess the clinical activity and safety of the dose established in the first part of the study in additional patients with AML or MDS. Patients will receive APVO436 intravenously (IV) weekly for up to six 28-day cycles, unless disease progression, intolerable toxicity, or withdrawal of consent occurs earlier.
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : December 13, 2018
Estimated Primary Completion Date : August 15, 2020
Estimated Study Completion Date : December 15, 2021


Arm Intervention/treatment
Experimental: Dose Escalation Cohort 1
0.3 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 2
1 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 3
3 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 4
9 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 5
12 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 6
20 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 7
30 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 8
50 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 9
75 mcg APVO436
Biological: APVO436
APVO436

Experimental: Dose Escalation Cohort 10
100 mcg APVO436
Biological: APVO436
APVO436

Experimental: Expanded Cohort (Phase 1b)
48 patients will receive the recommended dose of APVO436 determined from Phase 1.
Biological: APVO436
APVO436




Primary Outcome Measures :
  1. Maximum Tolerated Dose [ Time Frame: during first 28 days of treatment ]
    Identify the maximum tolerated dose in dose-escalation (Phase 1) by assessment of dose-limiting toxicities


Secondary Outcome Measures :
  1. 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 ]
    The safety profile of APVO436 will be assessed by monitoring incidence and severity of adverse events

  2. Maximum serum drug concentration [ Time Frame: Patient will have laboratory assessments prior to dosing on Day 1, Day 1, 2, 3, 8, 15, 22, and 1 to 7 days following last dose. ]
    Blood samples will be obtained from all patients for determination of the maximum serum concentration of APVO436

  3. Area under the concentration-time curve (AUC) [ Time Frame: Patient will have laboratory assessments prior to dosing on Day 1, Day 1, 2, 3, 8, 15, 22, and 1 to 7 days following last dose. ]
    Blood samples will be obtained from all patients for determination of the AUC of APVO436

  4. Elimination of half-life [ Time Frame: Patient will have laboratory assessments prior to dosing on Day 1, Day 1, 2, 3, 8, 15, 22, and 1 to 7 days following last dose. ]
    Blood samples will be obtained from all patients for determination of the T1/2 of APVO436

  5. Changes in T-cell populations to measure pharmacodynamics of APVO436 [ Time Frame: Patient will have laboratory assessments prior to dosing on Day 1, Day 1, 2, 3, 8, 15, 22, and 1 to 7 days following last dose. ]
    Blood samples will be collected from all patients and evaluated by flow cytometry for changes in T-cell populations

  6. Changes in peripheral blasts to measure pharmacodynamics of APVO436 [ Time Frame: Patient will have laboratory assessments prior to dosing on Day 1, Day 1, 2, 3, 8, 15, 22, and 1 to 7 days following last dose. ]
    Blood samples will be collected from all patients and evaluated by flow cytometry for changes in peripheral blasts

  7. Immunogenicity of APVO436 [ Time Frame: Patient will have laboratory assessments prior to dosing on Day 1, Day 1, 2, 3, 8, 15, 22, and 1 to 7 days following last dose. ]
    Blood samples will be collected from all patients and tested for antibody formation to APVO436



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:

  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. Prior allogeneic or solid organ transplant (with the exception of cornea or hair transplant)
  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

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): NCT03647800


Contacts
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Contact: Scott C Stromatt, MD 206-859-6675 sstromatt@apvo.com
Contact: Bret L Macpherson, MSc, MBA 206-859-6608 bmacpherson@apvo.com

Locations
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United States, Florida
Sylvester Comprehensive Cancer Center/UMHC Recruiting
Miami, Florida, United States, 33136
United States, Kansas
The University of Kansas Clinical Research Center Recruiting
Westwood, Kansas, United States, 66205
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
United States, Ohio
The Ohio State University Wexner Medical Center/James Cancer Hospital Recruiting
Columbus, Ohio, United States, 43210
United States, South Carolina
Greenville Health System, Institute for Translational Oncology Research Recruiting
Greenville, South Carolina, United States, 29605
United States, Utah
University of Utah, Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Aptevo Research and Development LLC
Investigators
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Study Director: Scott C Stromatt, MD Aptevo Therapeutics

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Responsible Party: Aptevo Research and Development LLC
ClinicalTrials.gov Identifier: NCT03647800     History of Changes
Other Study ID Numbers: Protocol 5001
First Posted: August 27, 2018    Key Record Dates
Last Update Posted: September 11, 2019
Last Verified: September 2019

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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 Aptevo Therapeutics ( Aptevo Research and Development LLC ):
APVO436