Venetoclax Plus Inotuzumab for B-ALL

Inclusion Criteria:

• Participants must have histologically confirmed CD22+ B-ALL or B-LBL.

• Note: CD22 must be detected on ≥ 20% of lymphoblasts by flow cytometry ofperipheral blood, flow cytometry of bone marrow aspirate or tissue biopsy, orimmunohistochemistry of the bone marrow or tissue biopsy.

• Note: for R/R disease: ≥ 5% lymphoblasts must be documented in the diagnosticsample (blood, marrow, or tissue biopsy).

• Note: Participants with B-LBL (confirmed CD22-positive extramedullary disease,but none or minimal marrow involvement) are eligible if eligibility criteriaotherwise met.

• Note: Participants with Philadelphia-chromosome positive B-ALL are eligible butmust be refractory to 2 or more tyrosine kinase inhibitors (TKIs), refractoryto ponatinib, or ineligible to receive all available TKIs.

• Note: Participants with chronic myeloid leukemia (CML) in lymphoid blast crisisare eligible but must be refractory to 2 or more TKIs, refractory to ponatinib,or ineligible to receive all available TKIs.

• Participants must have disease that is relapsed or refractory (R/R) to 1 or morecycles of cytotoxic chemotherapy.

• Note: There is no limit to number or type of prior therapies (prior inotuzumabozogamicin is not permitted).

• Note: Philadelphia-chromosome positive B-ALL patients previously treated withTKI are eligible without receiving cytotoxic chemotherapy if they areunsuitable for standard cytotoxic chemotherapy.

• Participants be aged ≥ 18 years.

• ECOG performance status of 0-3.

• Adequate organ function.

• Serum total bilirubin ≤ 1.5x upper limit of normal (ULN), unless due toGilbert's syndrome or of non-hepatic origin (i.e. hemolysis).

• ALT and AST ≤ 2.5x ULN, unless clearly due to disease, in which case ≤ 5x ULNis permissible.

• Creatinine clearance of ≥ 30 mL/min calculated using Cockcroft-Gault formula ormeasured by 24-hour urine collection.

• Women of childbearing potential must have a negative serum or urine beta humanchorionic gonadotropin (β-hCG) pregnancy test result within 14 days prior to thefirst dose of study drugs. Women of non-childbearing potential are those who arepostmenopausal greater than 1 year or who have had a bilateral tubal ligation orhysterectomy. The effects of venetoclax and inotuzumab ozogamicin on the developinghuman fetus are unknown. For this reason, women of child-bearing potential and menmust agree to use adequate contraception (hormonal or barrier method of birthcontrol; abstinence) prior to study entry, during treatment, and for at least 8 and 5 months after the last dose, respectively. Should a woman become pregnant orsuspect she is pregnant while she or her partner is participating in this study, sheshould inform her treating physician immediately.

• Human immunodeficiency virus (HIV)-infected participants on effectiveanti-retroviral therapy with undetectable viral load within 6 months are eligiblefor this trial. Medication list must be carefully reviewed to ensure nocontra-indicated drug-drug interactions.

• For participants with known evidence of chronic hepatitis B virus (HBV) infection,the HBV viral load must be confirmed to be undetectable (and appropriate suppressivetherapy must be initiated in consultation with an infectious disease expert, ifindicated).

• Participants with a known history of hepatitis C virus (HCV) infection must have anundetectable HCV viral load confirmed.

• Participants with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen are eligible for this trial. The treatinginvestigator must review such cases with the overall PI prior to confirmingeligibility.

• Participants with prior HSCT or chimeric antigen receptor T-cell (CAR-T) therapy (autologous or allogeneic) are eligible if they are day +60 from cell infusion anddo not have active Glucksberg grade 2 or higher graft versus host disease (GVHD).Patient must be off calcineurin inhibitor for 2 weeks.

• Ability to understand and the willingness to sign and date written informed consentdocument.

Exclusion Criteria:

• Absolute blast count of ≥25 K/µL prior to initiation of study treatment. Steroids,hydroxyurea, and/or vincristine may be used to reduce blast count.

• Prior treatment with inotuzumab ozogamicin at any time.

• Prior treatment with venetoclax for relapsed disease; if venetoclax used duringfirst-line therapy, 60 or more days must have elapsed since last dose of venetoclax.Note: The number of patients with prior receipt of venetoclax will be capped at 50%of the participants enrolled in the dose expansion phase.

• Treatment for ALL with chemotherapy within 14 days of first dose of study drugsexcept for hydroxyurea, steroids, vincristine, and/or intra-thecal chemotherapy.

• Symptomatic central nervous systemic (CNS) disease and CNS-3 disease. AsymptomaticCNS-2 disease is permitted. Prior CNS disease is not an exclusion. See Appendix Bfor definition of CNS disease.

• Participants with history of decompensated hepatic cirrhosis, veno-occlusive disease (VOD)/sinusoidal obstructive syndrome (SOS), or severe liver disease.

• Patient with uncontrolled intercurrent illness, or severe acute or chronic medicalor psychiatric condition or laboratory abnormality that in the opinion of theinvestigator may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and/or would make the patient inappropriate for enrollment into thisstudy.

• Participants who have not recovered from adverse events due to prior anti-cancertherapy (i.e., have residual toxicities > grade 1) except for alopecia.

• Participants who are receiving any other investigational agents.

• Participants receiving any medications or substances within 7 days that are strongCYP3A4 inhibitors (such as fluconazole, voriconazole, posaconazole, isavuconazole,and clarithromycin) or inducers (such as rifampin, rifabutin, phenytoin,carbamazepine, and St. John's Wort) of CY3A4 are ineligible. Because the lists ofthese agents are constantly changing, it is important to regularly consult afrequently updated medical reference (Appendix C). Of note, anti-fungal azoletherapy may be re-introduced after venetoclax dose escalation as outlined in theprotocol.

• Participants who have consumed grapefruit, grapefruit products, Seville oranges (used in marmalade), or star fruit within 3 days prior to starting venetoclax.

• Malabsorption syndrome or other conditions (such as inability to swallow pills) thatpreclude enteral route of venetoclax administration.

• Participants with psychiatric illness/social situations that would limit adherenceto study requirements.

• Pregnant women are excluded from this study because the effects of venetoclax andinotuzumab ozogamicin on the developing human fetus are unknown with the potentialfor teratogenic or abortifacient effects. There is an unknown but potential risk foradverse events in nursing infants secondary to treatment of the mother withvenetoclax and inotuzumab ozogamicin and therefore breastfeeding should bediscontinued.