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

Inclusion Criteria:

1. 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

2. Disease must be positive for Ph (p190 or p210 transcript) by cytogenetics or PCR

3. Disease must be positive for CD22, defined as any percentage of leukemic blasts expressing CD22

4. Disease must be positive for t(9;22) by Cytogenetics and FISH. Subjects with complex translocations resulting in BCR::ABL1 fusion protein are eligible.

5. 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

6. Subject must have recovered (no worse than Grade 1 severity) from effects of all previous treatments.

7. Able to provide informed consent

8. Age ≥18 years of age

9. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2 or Karnofsky ≥60%

10. 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

11. Female patients of childbearing potential must not be nursing or planning to become pregnant

12. Female patients of childbearing potential require a negative urine or serum pregnancy test within 30 days of study therapy.

13. 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.

14. 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

15. Willing to provide pretreatment bone marrow aspirate and biopsies samples as well as subsequent bone marrow aspirate and biopsies samples during the study.

Exclusion Criteria:

1. 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)
2. 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
3. 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
4. Prior allogeneic stem cell transplant < 90 days prior to anticipated treatment start
5. Patients with active GVHD (graft versus host disease) and/or receiving immunosuppressive drugs for GVHD
6. Patients receiving calcineurin inhibitors < 4 weeks prior to anticipated treatment start
7. Ph-directed TKI within 5 days of treatment start
8. Prior exposure to INO
9. Prior exposure to asciminib
10. The presence of mixed phenotype acute leukemia or CML in lymphoid blast phase
11. 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
12. Patients with T315I mutation as detected by ABL1 kinase mutational panel are excluded from asciminib dose levels lower than 200mg BID
13. Clinical suspicion for active CNS involvement by ALL; previously treated CNS involvement is allowed
14. Second malignancy requiring treatment within 6 months of study enrollment, with the exception of non-melanoma skin cancers or cancers requiring hormonal therapy only
15. Active, uncontrolled infection
16. Human immunodeficiency virus (HIV) not controlled by standard therapy
17. Active hepatitis B or C infection. Participants whose infections are controlled with antiviral therapy are allowed.
18. Patients with end stage renal disease requiring dialysis