Study of Iomab-B vs. Conventional Care in Older Subjects With Active, Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The primary objective of this study is to demonstrate the efficacy of Iomab-B, in conjunction with a Reduced Intensity Conditioning (RIC) regimen and protocol-specified allogeneic hematopoietic stem cell transplant (HCT), versus Conventional Care in patients with Active, Relapsed or Refractory Acute Myeloid Leukemia (AML).

Detailed Description
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SIERRA is a pivotal Phase 3 randomized controlled study of Iomab-B in Relapsed or Refractory AML patients. The SIERRA trial has a primary endpoint of durable Complete Remission (dCR) at six months and a secondary endpoint of overall survival following randomization to Iomab-B, as well as Event-Free Survival. Iomab-B is intended to prepare and condition patients for a bone marrow transplant, also referred to as a hematopoietic stem cell transplant, in a potentially safer and more efficacious manner than intensive chemotherapy conditioning that is the current standard of care in bone marrow transplant conditioning.

Official Title
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A Multicenter, Pivotal Phase 3 Study of Iomab-B Prior to Allogeneic Hematopoietic Cell Transplant Versus Conventional Care in Older Subjects With Active, Relapsed or Refractory Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia, Leukemia, Acute Myeloid, Myeloid Leukemia, Acute, Leukemia, Myeloid, Acute, Acute Myelogenous Leukemia, Leukemia, Acute Myelogenous, Myelogenous Leukemia, Acute, AML, Bone Marrow Transplant

Intervention / Treatment
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* Drug: Iomab-B
* Drug: Conventional Care
* Procedure: HCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have active, relapsed or refractory Acute Myeloid Leukemia (AML). Active, relapsed or refractory AML is defined as any one of the following (1) primary induction failure, or (PIF) after 2 or more cycles of therapy, or (2) first early relapse after a remission duration of fewer than 6 months, or (3) relapse refractory to salvage combination chemotherapy, or (4) second or subsequent relapse Have documented CD45 expression by leukemic cells via flow cytometry (a blast gate on CD45 vs. side scatter analysis consistent with AML) Be at least 55 years of age Have a circulating blast count of less than 10,000/mm3 (control with hydroxyurea is allowed) Have a calculated creatinine clearance (Cockcroft-Gault equation) > 50 mL/min Have adequate hepatic function (direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), defined as ≤ 2 times the upper limit of normal [ULN]) Have a Karnofsky score ≥ 70 Have an expected survival of > 60 days Have a central venous catheter line in place prior to study treatment administration Have 8/8 allele-level, related or unrelated, medically cleared HSC donor matching at human leukocyte antigen (HLA)-A, HLA-B, HLA-C, and DRB-1 with a donor who is medically cleared. Syngeneic donors that meet these criteria are allowed Women of childbearing potential, be surgically sterile or agree to practice abstinence or utilize acceptable contraception (intrauterine, injectable, transdermal, or combination oral contraceptive) through 1-year post transplant; Males who are sexually active with women of childbearing potential must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) from time of screening through 12 weeks after last dose of study drug Be able to understand the study procedures, agree to participate in the study program, and voluntarily provide written Informed Consent Exclusion Criteria: Have circulating HAMA noted on initial screening Have received prior radiation to maximally tolerated levels to any critical normal organ Have active leukemic central nervous system (CNS) involvement, as defined by any leukemic blasts detected in the cerebrospinal fluid (CSF) by morphology or flow cytometry and/or any chloromas detected by CNS imaging Have previously received HCT (including both allogeneic and autologous HCT) Have clinically significant cardiac disease (NYHA Class III or IV); clinically significant arrhythmia i.e. ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes. Myocardial infarction with uncontrolled angina within 6 months, congestive heart failure, or clinically significant cardiomyopathy Have abnormal QTcF (>450milliseconds) after electrolytes have been corrected (at least two different ECG readings and at least 15 minutes between readings). Subjects with paced rhythm or prolonged QTcF may be exempt from this exclusion if considered eligible for transplant per treating physician clinical judgement with optional cardiology consultation Have current or prior positive test results for human immunodeficiency virus (HIV) or hepatitis B (HBV) or C. Subjects who have positive HBV test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HBsAg), negative anti- hepatitis B core protein (HBc) and positive antibody to the HBsAg (anti-HBs) are not excluded. Subjects who have positive hepatitis test results with adequate organ function as defined in the protocol are not excluded Have active serious infection uncontrolled by antibiotics or antifungals Have acute promyelocytic leukemia and the associated cytogenic translocation t(15/17) Have active malignancy within 2 years of entry. Active malignancy is defined as those malignancies requiring treatment with anti-cancer therapy or in the event of indolent malignancies, having measurable disease. Exceptions to this exclusion include: myelodysplastic syndrome, treated non-melanoma skin cancer, completely resected Stage 0 or 1 melanoma no less than 1 year from resection, carcinoma in situ or cervical intraepithelial neoplasia, and successfully treated organ-confined prostate cancer with no evidence of progressive disease based on prostate specific antigen (PSA) levels and are not on active therapy Have a perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation Currently receiving any other active investigational agents

Ages Eligible for Study
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Minimum Age: 55 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Iomab-B<br>Iomab-B in conjunction with a Reduced Intensity Conditioning (RIC) regimen containing Fludarabine and low-dose Total Body Irradiation (TBI) prior to allogeneic HCT | Drug: Iomab-B<br> <br> Procedure: HCT<br> <br> |
| Active Comparator: Conventional Care<br>Defined as Investigator's choice of salvage chemotherapy with any combination of the following agents: Azacitidine (not allowed as a single agent), Carboplatin, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Daunorubicin, Decitabine (not allowed as a single agent with the exception of patients with documented TP53 mutations who have not previously received 10-day regimens of single agent decitabine), Doxorubicin, Enasidenib, Etoposide, Fludarabine, Gemtuzumab ozogamicin, Idarubicin, Ivosidenib (for subjects with IDH1 mutation), L-Asparaginase, Midostaurin (for FLT3 mutant or FLT3-ITD subjects only, not allowed as single agent), Mitoxantrone, Sorafenib (for FLT3 mutant or FLT3-ITD subjects only, not allowed as single agent), Thioguanine, Topotecan, Venetoclax (in combination with a hypomethylating agent). Chemotherapy agents not listed above may be administered after providing clinical justification and receiving medical monitor approval prior to initiation of treatment. | Drug: Conventional Care<br> <br> Procedure: HCT<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durable Complete Remission (dCR) | Defined as CR or CRp lasting 180 days or more from time of initial CR or CRp is documented with evidence of subsequent relapse | 6 months from time of initial CR or CRp | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) following randomization to Iomab-B versus Convetional Care | Patient overall survival | Over a 5 year period | 
| Event-Free Survival | Duration of time from randomization to the date of induction treatment failure (ITF), relapse or death | Over a 5 year period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCT, Acute Myeloid Leukemia, Leukemia, Acute Myeloid, Myeloid Leukemia, Acute, Bone Marrow Cell Transplant, Transplant, Bone Marrow, HSCT, Refractory AML, Relapsed AML, BC8, I-131, Iomab, Iomab-B, CD45, Iodine, Iodine-131, 131-I, AML, BMT, Radioimmunotherapy