Study of APVO436 in Patients With AML or MDS
- Conditions
- MDSAML
- Interventions
- Biological: APVO436
- Registration Number
- NCT03647800
- Lead Sponsor
- Aptevo Research and Development LLC
- Brief Summary
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.
APVO436 is being studied in this Phase 1b, open-label, multi-center, two-part dose-escalation/dose expansion study to evaluate the safety, pharmacokinetic/pharmacodynamic (PK/PD), and clinical activity of APVO436 in patients with AML and MDS. The study will be conducted in 2 parts. The first part of this Phase 1B study is an open-label, multiple dose ascending dose escalation phase to determine the recommended dose (RP2D) level of APVO436 for future Phase 2 studies. The goal of the dose expansion phase of the study (Part 2) is to (i) evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care and (ii) obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities.
Study Objectives for Dose Escalation Phase
* Primary Objectives are to:
1. Determine the RP2D level of APVO436 administered intravenously (IV) in patients with AML or MDS, and
2. Evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care and obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities.
* Secondary Objectives are to:
1. Define the safety profile and immunogenicity of APVO436; to determine the PK/PD of APVO436; to evaluate the clinical activity of APVO436 in AML and MDS patients.
2. Further evaluate the safety profile and immunogenicity of APVO436 and the PK/PD of APVO436 and the relationship between PK/PD and clinical response.
Study Objectives for Dose Expansion Phase
* Primary Objective is to evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care.
* Secondary Objective is to obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities.
- Detailed Description
Part 1 - Dose Escalation:
Dosing will start at the minimum anticipated biologic effect level (MABEL) in single-patient cohorts for the first 3 dose cohorts up to and including 3 mcg. Patients enrolled will have either: 1) relapsed or refractory AML and refuse or are not eligible for intensive chemotherapy or an allogeneic stem cell transplant, or 2) relapsed or refractory MDS and have \> 5% blasts in the marrow or any circulating blasts in the peripheral blood and have failed a prior hypomethylating agent (HMA); failure is defined as intolerance to HMA, lack of response (no CR by at least 6 cycles), or have IWG defined progressive disease during or after treatment with an HMA.
In single-patient Cohorts 1 to 3, the next dose cohort will only enroll after the patient in the current dose cohort has completed the first cycle of dosing (4 weeks) and no Grade ≥ 2 adverse events (AEs) (hematologic or non-hematologic) have occurred. If any Grade ≥ 2 AE occurs in the single-patient cohorts, then that cohort and all subsequent single-patient cohorts will be expanded to a 3 + 3.
The next dose cohort in the 3 + 3 cohorts (all cohorts beyond Cohort 4) is started after patients in the previous dose cohort have completed the first cycle of dosing and an evaluation of AEs for DLTs during the DLT observation period has been completed. For the first 2 patients within each dose cohort, administration of the first dose must be separated by a minimum of 36 hours. At the conclusion of each cycle, patients with significant cytopenias without evidence of leukemia will have the dose delayed.
Beginning in Cohort 5, and for all cohorts going forward, stepped dosing will be introduced to mitigate against the development of infusion-related reactions and cytokine release syndrome.
Patients will receive APVO436 intravenously for six 28 day cycles, unless disease progression, intolerable toxicity, or withdrawal of consent occurs earlier. There is an option for longer treatment if the patient is responding. The RP2D level will be based on clinical activity, safety, incidence of DLTs, PK, and PD in each dose cohort.
Part 2 - Dose Expansion:
The MTD for APVO436 was not reached at a dose level of 240 µg/cycle (Cohort 10 in the dose escalation phase). The sub-MTD dose level of Cohort 6A was identified as the RP2D level of APVO436 for further evaluation during the expansion phase.
In the open-label, multi-center, dose expansion phase of the study (Part 2), a total of 90 primary AML patients will be enrolled into 5 cohorts of 18 patients each. The goal of this expansion phase of the study is to evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care and obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities.
In Cohorts 1-4, APVO436 will be administered at a fixed dosage of 18 mcg after a weekly ramp up during Cycle 1 (Cohorts 1, 3, 4) or Cycle 1-2 (Cohort 2). In Cohort 5, APVO436 will be administered at a fixed dose of 18 mcg twice weekly after a weekly ramp up during Cycle 1.
The specific patient populations and experimental treatments for the expansion phase are as follows:
Cohort 1. Induction with Chemotherapy (ChT) plus APVO436. 1st or 2nd Early Relapse. Patients may receive either Ara-C intermediate dose (IDAC) or MEC as the ChT backbone. Fit primary or secondary AML patients (Age: \>18 years) in 1st or 2nd relapse with last CR \<12 months or primary refractory disease will receive 4 x 28-day cycles of combined 2-drug immunochemotherapy: APA \[APVO436+Intermediate dose ARA-C (IDAC) or APMEC \[APVO436+MEC\].
Cohort 2. Induction with APVO436 + Venetoclax + Azacitidine - Frontline or 1st Relapse. Poor prognostic but fit primary or secondary AML patients (Age \>18 years) who are treatment-naïve or in 1st relapse will receive 4 x 28-day cycles of combined 3-drug immunochemotherapy: APVA \[APVO436+Venetoclax+Azacitidine\].
Cohort 3: Consolidation post 7+3 - Frontline + 1st Relapse. Fit primary AML patients (Age: \>18 years) with FLT3-negative intermediate or adverse risk AML (including but not limited to: TP53, RUNX1 and ASXL1 mutations and/or complex cytogenetics) who are treatment-naïve or in 1st relapse with a duration of CR1\<1 year will receive 4 x 28-day cycles of immunotherapy with APVO436 after hematologic recovery (ANC\>1,000/µL; Hgb ≥9 g/dL; Plt≥100,000/µL) post induction.
Cohort 4: MRD-positive (MRD+) 1st Remission, APVO436 + Azacitidine combination. \>18 years old MRD+ (at ≥0.1% level by multicolor-multiparameter flow cytometry \[MFC\] in Central Lab) high-risk 1st remission AML patients will be treated with 4 x 28-day cycles of APVO436 + oral azacitidine (Onureg, CC-486).
Cohort 5: MRD+ 2nd Remission, Single Agent APVO436. \>18 years old MRD+ (at ≥0.1% level by MFC in Central Lab) AML patients who are in 2nd remission post-induction with a standard of care regimen will be treated with 4 x 28-day cycles of APVO436 monotherapy.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 136
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description PART 2 Dose expansion - 5 cohorts APVO436 90 patients, 18/cohort in 5 dose expansion cohorts, will receive the recommended dose of APVO436 determined from Part 1 PART 1 Dose Escalation - 10 dose cohorts APVO436 CD123 and CD3 epsilon bispecific antibody
- Primary Outcome Measures
Name Time Method Part 1 - Dose Escalation: Maximum Tolerated Dose during first 28 to 35 days of treatment Identify the maximum tolerated dose in dose-escalation (Phase 1) by assessment of dose-limiting toxicities
Part 2 - Dose Expansion: Safety during first 28 to 35 days of treatment The cumulative incidence of Grade 3-4 AEs, and SAEs, and the incidence of AES of interest (≥Grade 2 CRS, ≥Grade 2 Infusion related reaction, ≥2 cardiac toxicity and ≥2 neurotoxicity as complications of CRS) for safety
- Secondary Outcome Measures
Name Time Method Part 1 - Dose Escalation: Changes in peripheral blasts to measure pharmacodynamics of APVO436 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
Part 1 - Dose Escalation: Immunogenicity of APVO436 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
Part 2 - Dose Expansion: Efficacy - Incidence of composite CR (CR + CRi + CRh) Patient will have assessment at the end of each Cycle (each Cycle is 28 days) up to 2 years Incidence of composite CR (CR + CRi + CRh) in relapsed patients as a measure of efficacy within the confines of a Phase 1B study.
Part 2 - Dose Expansion: Efficacy - MRD Status Patient will have assessment through study completion, an average of 1 year Incidence of patients who undergo HSCT post protocol therapy
Part 1 - Dose Escalation: Frequency and severity of adverse events as assessed by CTCAE v5.0 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
Part 1 - Dose Escalation: Maximum serum drug concentration 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
Part 1 - Dose Escalation: Area under the concentration-time curve (AUC) 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
Part 1 - Dose Escalation: Elimination of half-life 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
Part 1 - Dose Escalation: Changes in T-cell populations to measure pharmacodynamics of APVO436 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
Part 2 - Dose Expansion: Exploratory - 2-year LFS rate 2 years 2-year LFS rate;
Part 2 - Dose Expansion: Exploratory - MRD 1 month and 4 months Pre- and Post-protocol therapy (after 1 cycle and after 4 cycles) MRD burden in Cohort 3 Percent Reduction of MRD in Cohorts 4 and 5 after 1 cycle and 4 cycles of protocol therapy
Part 2 - Dose Expansion: Exploratory - LFS Up to 2 years Leukemia-free survival (LFS)
Part 2 - Dose Expansion: Exploratory - 1-year LFS rate 1 year 1-year LFS rate;
Trial Locations
- Locations (12)
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
The University of Kansas Clinical Research Center
🇺🇸Westwood, Kansas, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Greenville Health System, Institute for Translational Oncology Research
🇺🇸Greenville, South Carolina, United States
University of California, San Francisco Medical Center
🇺🇸San Francisco, California, United States
University of Florida College of Medicine
🇺🇸Gainesville, Florida, United States
The University of Texas M.D. Anderson Cancer Center
🇺🇸Houston, Texas, United States
Fred Hutchinson Cancer Research Center
🇺🇸Seattle, Washington, United States
University of Utah, Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
The Ohio State University Wexner Medical Center/James Cancer Hospital
🇺🇸Columbus, Ohio, United States
Sylvester Comprehensive Cancer Center/UMHC
🇺🇸Miami, Florida, United States