A Phase 1 Study of Venetoclax in combination with Inotuzumab Ozogamicin for B-cell Acute lymphoblastic leukemia (B-ALL)

Protocol # :
B-cell Acute Lymphoblastic Leukemia
B-Cell Lymphoma
Disease Sites
Lymphoid Leukemia
Principal Investigator
Luskin, Marlise, R.

Trial Description

This research study is evaluating the safety and efficacy of administering venetoclax and
inotuzumab ozogamicin in combination in patients with acute lymphoblastic leukemia (ALL)

The names of the study drugs involved in this study are:

- Venetoclax

- Inotuzumab ozogamicin

- Dexamethasone

Eligibility Requirements

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 of
peripheral blood, flow cytometry of bone marrow aspirate or tissue biopsy, or
immunohistochemistry of the bone marrow or tissue biopsy.

- Note: for R/R disease: ≥ 5% lymphoblasts must be documented in the diagnostic
sample (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 criteria
otherwise met.

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

- Note: Participants with chronic myeloid leukemia (CML) in lymphoid blast crisis
are 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 more
cycles of cytotoxic chemotherapy.

- Note: There is no limit to number or type of prior therapies (prior inotuzumab
ozogamicin is not permitted).

- Note: Philadelphia-chromosome positive B-ALL patients previously treated with TKI
are eligible without receiving cytotoxic chemotherapy if they are unsuitable 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 to Gilbert'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 ULN is

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

- Women of childbearing potential must have a negative serum or urine beta human
chorionic gonadotropin (β-hCG) pregnancy test result within 14 days prior to the first
dose of study drugs. Women of non-childbearing potential are those who are
postmenopausal greater than 1 year or who have had a bilateral tubal ligation or
hysterectomy. The effects of venetoclax and inotuzumab ozogamicin on the developing
human fetus are unknown. For this reason, women of child-bearing potential and men
must agree to use adequate contraception (hormonal or barrier method of birth control;
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 or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.

- Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial.
Medication list must be carefully reviewed to ensure no contra-indicated drug-drug

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

- Participants with a known history of hepatitis C virus (HCV) infection must have an
undetectable HCV viral load confirmed.

- Participants with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial. The treating investigator must
review such cases with the overall PI prior to confirming eligibility.

- 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 and do
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 consent

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 during
first-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 drugs except
for hydroxyurea, steroids, vincristine, and/or intra-thecal chemotherapy.

- Symptomatic central nervous systemic (CNS) disease and CNS-3 disease. Asymptomatic
CNS-2 disease is permitted. Prior CNS disease is not an exclusion. See Appendix B for
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 medical or
psychiatric condition or laboratory abnormality that in the opinion of the
investigator may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and/or would make the patient inappropriate for enrollment into this

- Participants who have not recovered from adverse events due to prior anti-cancer
therapy (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 strong
CYP3A4 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 of these agents are
constantly changing, it is important to regularly consult a frequently updated medical
reference (Appendix C). Of note, anti-fungal azole therapy may be re-introduced after
venetoclax dose escalation as outlined in the protocol.

- 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) that
preclude enteral route of venetoclax administration.

- Participants with psychiatric illness/social situations that would limit adherence to
study requirements.

- Pregnant women are excluded from this study because the effects of venetoclax and
inotuzumab ozogamicin on the developing human fetus are unknown with the potential for
teratogenic or abortifacient effects. There is an unknown but potential risk for
adverse events in nursing infants secondary to treatment of the mother with venetoclax
and inotuzumab ozogamicin and therefore breastfeeding should be discontinued.