Moxetumomab Pasudotox (CAT-8015, HA22) in Children With B-lineage Acute Lymphoblastic Leukemia and Minimal Residual Disease Prior to Allogeneic Hematopoietic Stem Cell Transplantation

This is a phase II, open-label, nonrandomized, prospective study to evaluate the activity, safety, and feasibility of administration of moxetumomab pasudotox in the pre-allogeneic hematopoietic cell transplantation (HCT) setting to patients with B-lineage Acute Lymphoblastic Leukemia (ALL) who are in a morphologic complete remission and have pre-transplant minimal residual disease (MRD) \> 0.01% (detected by flow cytometry). The primary objective of this study is to determine if treatment with moxetumomab pasudotox in the MRD positive setting is able to lead to MRD negativity (\< 0.01% by flow cytometry) or at least a 1-log10 reduction in MRD prior to allogeneic HCT.

This is a Phase 2 study designed to assess safety, feasibility and clinical activity of pre-HCT moxetumomab pasudotox for patients with ALL in morphologic CR but with MRD. It is hypothesized that subjects in a morphologic complete remission with proven minimal residual disease (MRD) after chemotherapy for ALL planned for allogeneic HCT who receive a course of moxetumomab pasudotox prior to the start of conditioning will show a marked reduction or elimination of detectable MRD after moxetumomab pasudotox treatment without adverse impact on the feasibility or safety of allogeneic HCT.

The primary objective of this study is to determine if treatment with moxetumomab pasudotox in the MRD positive setting is able to lead to MRD negativity (\< 0.01% by flow cytometry) or at least a 1-log10 reduction in MRD prior to allogeneic HCT.

Secondary objectives to be studied include: toxicity profile (including safety and feasibility of administration in the pre-HCT setting and ability to proceed to transplant, incidence of capillary leak syndrome, hemolytic uremic syndrome and other post-HCT toxicities), comparison of quantitative MRD assessments, progression-free survival, overall survival, pharmacokinetic profiles, immunogenicity to moxetumomab pasudotox, transplant-related mortality, acute and chronic graft-versus-host disease (GVHD), and relapse.

Eligibility Criteria:
Inclusion Criteria:

1. ≥ 6 months and \< 25 years of age
2. Histologically confirmed diagnosis of B-lineage ALL. Verification of CD22 expression is not required
3. Bone marrow in morphologic remission (any remission number) defined as \< 5% blasts (M1 classification) performed in local institution lab
4. CNS 1 (\< 5/μL WBCs in CSF and cytospin negative for blasts)
5. Evidence of bone marrow MRD defined as ≥ 0.01% by flow cytometry performed in the study central lab
6. Candidate committed to HCT independent of participation in this study, with the following requirements:

   * Meets local transplant center eligibility requirements for HCT
   * In the opinion of the HCT center will be ready to begin pre-transplant conditioning within 6 weeks of trial enrollment from a medical and psychosocial standpoint
   * Has an available HCT donor or identified cord blood unit. Related and unrelated donors, and bone marrow, peripheral blood, or cord blood stem cell sources allowed
7. Adequate organ function including the following:

   * Hepatic function: Total bilirubin \< 1.5 × upper limit of normal (ULN) (except in the case of subjects with known Gilbert's disease: \< 5 × ULN) and transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) \< 3 × ULN based on age- and institution specific laboratory-specific normal ranges
   * Renal function: Age-adjusted normal serum creatinine is required. A 24-hour creatinine clearance value \> 60 mL/min/1.73 m2 (updated Schwartz formula or nuclear GFR) must be obtained if serum creatinine is elevated.
   * Hematologic function: Absolute neutrophil count (ANC) \> 500/μL and platelet count \> 25,000/μL without transfusion
   * Oxygen saturation at rest or with exercise \> 88% as measured by pulse oximeter or PaO2 \> 55 mm Hg without need for supplemental oxygen at rest or with activity
   * Serum albumin \> 2 g/dL
8. Performance status:

   * Subjects ≥ 16 years of age: Karnofsky ≥ 60% (Appendix A)
   * Subjects \< 16 years of age: Lansky scale ≥ 60% (Appendix A)
   * Subjects who are unable to walk because of paralysis, but who are upright in a wheel chair will be considered ambulatory for the purpose of calculating the performance score
9. Patients \> 18 years of age must have the ability to give informed consent according to applicable regulatory and local institutional requirements. Legal guardian permission must be obtained for patients \< 18 years of age. Pediatric patients will be included in age appropriate discussion in order to obtain assent
10. Sexually active female subjects of childbearing potential and male subjects and their sexual partners who are of childbearing potential must agree to use contraception

Exclusion Criteria:

1. Active extramedullary disease at any site. (Note: Definitive therapy of known previous sites of extramedullary disease is allowed)
2. Females who are breast-feeding or pregnant
3. Subjects with known 11q23 MLL rearrangement are excluded.
4. Prior therapy:

   * Prior treatment with CAT-3888 (BL22), moxetumomab pasudotox (CAT-8015, HA22), any pseudomonas-exotoxin-containing compound, or any anti-CD22 directed therapy at any time in the past
   * Prior allogeneic or autologous HCT or adoptive cellular therapies, including T-cell chimeric antigen receptor (CAR) therapy
   * Chemotherapy \< 2 weeks prior to starting study drug with the following exception: There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such
   * Monoclonal antibody therapy \< 30 days from study enrollment
   * Other investigational agents currently or within 30 days prior to study enrollment
5. Subjects with an absolute contraindication to corticosteroid administration
6. HIV infection (due to increased risk of severe infection and unknown interaction of moxetumomab pasudotox with antiretroviral drugs)
7. Active hepatitis B or C infection as defined by seropositivity for hepatitis B (hepatitis B surface antigen \[HbsAg\]) or hepatitis C (hepatitis C antibody) and elevated liver transaminases (defined as above the ULN per the institution normal ranges)
8. Second malignancy other than non-basal cell carcinoma of the skin or in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and subject is in remission
9. Subject with clinical or laboratory evidence of active DIC
10. Subject with prior history of thrombotic microangiopathy or HUS within 3 months prior to enrollment
11. History of known congenital hypercoagulable condition
12. Previous life-threatening anaphylactic reactions to prior monoclonal antibody-based immunotherapy or any component of the moxetumomab pasudotox formulation
13. Subjects who will be or are currently being treated with high dose estrogen (high dose is defined as \>0.625mg daily as conjugated estrogens or equivalent) within 7 days prior to study enrollment