Study of APVO436 in Patients With AML or MDS

• ClinicalTrials.gov Identifier: NCT03647800
• Recruitment Status: Recruiting
• First Posted: August 27, 2018
• Last Update Posted: January 22, 2020
• Sponsor: Aptevo Research and Development LLC
• Information provided by (Responsible Party): Aptevo Therapeutics ( Aptevo Research and Development LLC )

Study Description

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 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.

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 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).

Study Design

• 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

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Escalation; CD123 and CD3 epsilon bispecific antibody	Biological: APVO436; APVO436
Experimental: Expanded Cohort (Phase 1b); 48 patients will receive the recommended dose of APVO436 determined from Phase 1.	Biological: APVO436; APVO436

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose [ Time Frame: during first 28 to 35 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, throughout the study, and up 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, throughout the study, and up 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, throughout the study, and up 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, throughout the study, and up 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, throughout the study, and up 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, throughout the study, and up to 7 days following last dose. ]
   Blood samples will be collected from all patients and tested for antibody formation to APVO436

Eligibility Criteria

• 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. 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

Contacts and Locations

Contacts

Contact: Scott C Stromatt, MD; 206-859-6675; sstromatt@apvo.com

Contact: Bret L Macpherson, MSc, MBA; 206-859-6608; macphersb@apvo.com

Locations

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, Texas

University of Texas Southwestern Medical Center; Recruiting

Dallas, Texas, United States, 75390

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

• Study Director: Scott C Stromatt, MD; Aptevo Therapeutics

More Information

• Responsible Party: Aptevo Research and Development LLC
• ClinicalTrials.gov Identifier: NCT03647800
• Other Study ID Numbers: Protocol 5001
• First Posted: August 27, 2018
• Last Update Posted: January 22, 2020
• Last Verified: January 2020

• 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