Asciminib and Inotuzumab Ozogamicin for Relapsed or Refractory Philadelphia Chromosome-positive B-cell Acute Lymphoblastic Leukemia (R/R Ph+ B-ALL)

Who can take part

• Documented and confirmed CD22+ R/R Ph+ B-ALL according to the World Health Organization (WHO) classification; Relapsed ALL is defined as the detection of ≥ 5% blasts in the bone marrow with or without non-central nervous system (CNS) extramedullary disease; Refractory ALL is defined as the failure to obtain a CRc after at least two courses of intensive induction or immunotherapy such as blinatumomab, or to CAR-T cells. Persistent MRD without ≥ 5% blasts in the bone marrow will not be sufficient for inclusion
• Disease must be positive for Ph (p190 or p210 transcript) by cytogenetics or PCR
• Disease must be positive for CD22, defined as any percentage of leukemic blasts expressing CD22
• Disease must be positive for t(9;22) by Cytogenetics and FISH. Subjects with complex translocations resulting in BCR::ABL1 fusion protein are eligible
• BCR-ABL mutational panel performed within 90 days prior to start of treatment, including the following 4 mutations: T315I and M244V, A337V, or F359C/I/V mutations. Specific panel may be determined per institution, however must include all aforementioned mutations. Note: T315I mutated patients are only eligible once Dose Level 3 is open to enrollment
• Subject must have recovered (no worse than Grade 1 severity) from effects of all previous treatments
• Able to provide informed consent
• Age ≥18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2 or Karnofsky ≥60%
• Adequate organ function defined by the following parameters:; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x the upper limit of normal (ULN); Total bilirubin ≤1.5x the ULN unless due to known Gilbert's disease or hemolysis due to blood transfusion; For patients with Gilbert's disease: total bilirubin ≤ 3x the ULN; Calculated glomerular filtration rate (GFR) of ≥ 15 mL/min/1.73 m2
• Female patients of childbearing potential must not be nursing or planning to become pregnant
• Female patients of childbearing potential require a negative urine or serum pregnancy test within 30 days of study therapy
• Female patients of childbearing potential must be willing to use at least 1 method of highly effective contraception during the study until 8 months after last dose of inotuzumab ozogamicin, or 1 week after the last dose of asciminib, whichever is later
• Male patients who are sexually active must be willing to use condoms and refrain from sperm donation during the study until 5 months after last dose of inotuzumab ozogamicin
• Willing to provide pretreatment bone marrow aspirate and biopsies samples as well as subsequent bone marrow aspirate and biopsies samples during the study

Who cannot take part

• Presence of severe and/or uncontrollable concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection)
• All prior Philadelphia chromosome-directed TKI therapy must be discontinued at least five days prior to study entry; corticosteroids and hydroxyurea are permitted during this period
• Treatment with chemotherapy, radiotherapy, or biologic therapy within 3 weeks prior to treatment Note: Hydroxyurea or corticosteroids is permitted; Previous treatment with ≥1 BCR-ABL-directed TKI
• Prior allogeneic stem cell transplant < 90 days prior to anticipated treatment start
• Patients with active GVHD (graft versus host disease) and/or receiving immunosuppressive drugs for GVHD
• Patients receiving calcineurin inhibitors < 4 weeks prior to anticipated treatment start
• Prior exposure to INO
• Prior exposure to asciminib
• Clinical suspicion for active CNS involvement by ALL; previously treated CNS involvement is allowed
• Second malignancy requiring treatment within 6 months of study enrollment, with the exception of non-melanoma skin cancers or cancers requiring hormonal therapy only
• Active, uncontrolled infection
• Human immunodeficiency virus (HIV) not controlled by standard therapy
• Active hepatitis B or C infection. Participants whose infections are controlled with antiviral therapy are allowed
• Patients with end stage renal disease requiring dialysis
• Ph-directed TKI within 5 days of treatment start
• The presence of mixed phenotype acute leukemia or CML in lymphoid blast phase
• Presence of BCR-ABL1 M244V, A337V, or F359C/I/V mutations other n-lobe known to confer clinical resistance to asciminib as detected by ABL1 kinase mutational panel
• Patients with T315I mutation as detected by ABL1 kinase mutational panel are excluded from asciminib dose levels lower than 200mg BID