A Study of Vadastuximab Talirine Given Prior to or After Allogeneic Hematopoietic Stem Cell Transplant in AML Patients

Study Overview
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Brief Summary
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This study will examine the safety and anti-leukemic profile of SGN-CD33A (vadastuximab talirine) in patients with relapsed chemo-resistant AML, who are given vadastuximab talirine in sequence with standard treatments before a planned stem cell transplant, or as maintenance therapy after a stem cell transplant. The main purpose of the study is to find the best dose and determine the anti-leukemic activity of vadastuximab talirine, given either pre- or post-allogeneic stem cell transplant (alloSCT) for adults with relapsed or refractory AML. This will be determined by assessing the safety and tolerability of vadastuximab talirine. In addition, the pharmacokinetic profile and anti-leukemic activity of the study treatment will be assessed.

Official Title
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A Phase 1/2 Study of Vadastuximab Talirine Administered in Sequence With Allogeneic Hematopoietic Stem Cell Transplant in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Melphalan
* Drug: vadastuximab talirine
* Drug: vadastuximab talirine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed/refractory acute myeloid leukemia (AML) except for acute promyelocytic leukemia Eastern Cooperative Oncology Group status of 0 or 1 Adequate baseline renal and hepatic function For Pre-allo Part A (before stem cell transplant): Relapsed or refractory AML (greater than 5% blasts) For Pre-allo Part A (before stem cell transplant): Availability of an HLA matched related or unrelated donor For Pre-allo Part A (before stem cell transplant): Eligible for an allogeneic hematopoietic stem cell transplant For Post-allo Part B: Transplant must have been performed with active AML (greater than 5% blasts) using a conventional conditioning regimen and have achieved CR or CRi post-alloSCT (with ANC greater than or equal to 1,000 and platelet greater than or equal to 50,000) For Post-allo Part B: Treatment must begin at least 42 days, but no more than 100 days post-transplant. Exclusion Criteria: Inadequate heart function Inadequate lung function Previous central nervous system leukemia Any history of another metastatic malignancy Anti-leukemia treatment within14 days of study drug (other than hydroxyurea or 6-mercaptopurine), immunosuppressive therapy (except for GVHD treatment/prophylaxis in Part B), or investigational agents For Pre-allo Part A (before stem cell transplant): Partially matched donors (related or unrelated) and umbilical cord blood cells are excluded as the source of hematopoietic stem cells For Pre-allo Part A (before stem cell transplant): Prior alloSCT For Post-allo Part B: Active GVHD Grade 2 or higher For Post-allo Part B:History of veno-occlusive disease requiring defibrotide For Post-allo Part B: History of Grade 2 or higher hepatic GVHD For Post-allo Part B: Concurrent use of corticosteroids equivalent of prednisone at a dose of greater than 0.5 mg/kg

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pre-allo (before stem cell transplant)<br>Pre-allo reduced intensity chemotherapy vadastuximab talirine (melphalan and fludarabine) | Drug: Fludarabine<br>* 30 mg/m2/day intravenously, 5 to 2 days before the transplant (total dose of 120 mg/m2)<br>Drug: Melphalan<br>* Melphalan 140 mg/m2 intravenously, 2 days before the transplant<br>Drug: vadastuximab talirine<br>* Pre-allo (before stem cell transplant) given 14 days before the stem cell transplant<br>|
| Experimental: Post-allo (after stem cell transplant)<br>Post-allo vadastuximab talirine | Drug: vadastuximab talirine<br>* Post-allo (after stem cell transplant) given on Day 1 of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | AE: Adverse events; TEAE: Treatment-emergent adverse event. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Grade 1 = mild, no intervention needed; Grade 2 = moderate, minimal intervention needed; Grade 3 = severe or medically significant, hospitalization is required; Grade 4 = life-threatening, urgent intervention needed; Grade 5 = death related to adverse event. An AE is considered serious if it was fatal, life threatening, required hospitalization, was disabling/incapacitating, resulted in a birth defect or congenital anomally, or was otherwise considered to be medically significant. | Approximately 1 year | 
| Incidence of Laboratory Abnormalities | Number (count) of participants that experienced a Grade 3 or higher laboratory toxicity (hematology and chemistry). Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Grade 1 = mild, no intervention needed; Grade 2 = moderate, minimal intervention needed; Grade 3 = severe or medically significant, hospitalization is required; Grade 4 = life-threatening, urgent intervention needed; Grade 5 = death related to adverse event. | Approximately 1 year | 
| 1-year Survival Rate | 1-year survival rate estimated using Kaplan-Meier methods The start date for overall survival is the day of alloSCT. | 12 months | 
| Rate of MRD Negativity | Rate of MRD (minimal residual disease) negativity at Day -1 (1 day prior to transplant) and Day 30 post-transplant (Part A only) | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response of CR or CRi | Percentage of patients who achieved a best response of CRi (complete remission with incomplete blood count recovery) or CR (complete remission) | 9 weeks | 
| Duration of Response | Defined as the time from the start of the first documented complete response (CR) or complete remission with incomplete blood count recovery (CRi) to the documentation of relapse or death due to any cause. | 9 weeks | 
| Overall Survival | Defined as the time from the day of alloSCT to the date of death due to any cause. | Approximately 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia, AML, antibody-drug conjugate