This is a Phase Ib Study to determine the Maximum Tolerated Dose (MTD) of Venetoclax in
combination with Gemtuzumab Ozogamicin(GO) in subjects with relapsed/refractory acute myeloid
leukemia. Using a standard 3+3 design, subjects will receive once cycle of combination
therapy. After one cycle of combination therapy, subjects showing response will continue on
to one cycle of consolidation therapy with GO\Veneoclax. Subjects who respond to combination
therapy will continue on maintenance Venetoclax until progression or unacceptable toxicity.
Dose-limiting toxicity, defined as an adverse event related (possible, probably, or definite)
to Venetoclax and/or Gemtuzumab fulfilling one of the following criteria:
- Hematologic toxicity: treatment-related grade 3 or worse neutropenia and/or
thrombocytopenia due to bone marrow hypocellularity present at the end of cycle one (day
28) with an additional 28 days allowed for count recovery (i.e. present at day 56);
specifically grade 3 or worse neutropenia or thrombocytopenia with the bone marrow
documented to be free of leukemic infiltration. Note: patients who enter the study with
grade 3 or worse cytopenias will not be evaluable for hematologic dose-limiting
- Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity occurring
within the first cycle (excluding grade 3-4 infections during cycle one).
The study will also evaluate the Overall Response Rate, Anti-leukemic activity, Relapse-free
Survival (RFS), event-free survival (EFS) , and overall survival (OS). The study will
evaluate quality of life using the European Organization for the Research and Treatment of
Cancer 30 item questionnaire (EORTC QLQ-C30).
Subjects must meet all of the following applicable inclusion criteria to participate in
- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
- Ages 18 to 75 years at the time of consent.
- ECOG Performance Status of 0-2 within 7 days prior to registration; see Appendix I.
- Patients must have AML, as defined, that is relapsed or refractory. Prior therapy
including chemotherapy, immunotherapy, biological or targeted therapy (e.g. FMS-like
tyrosine kinase-3 (FLT3) inhibitors, other kinase inhibitors, azacitidine, ATRA) is
- CD33 expression (by flow or IHC) in at least 20% of the leukemia blasts per local
- Prior cancer treatment must be completed at least 21 days prior to registration and
the subject must have recovered from all reversible acute toxic effects of the regimen
(other than alopecia) to ≤Grade 1 or baseline.
- Demonstrate adequate organ function as defined in the table in the protocol; all
screening labs to be obtained within 28 days prior to registration.
- Females of childbearing potential must have a negative serum or urine pregnancy test
within 7 days prior to registration. NOTE: Females are considered of child bearing
potential unless they are surgically sterile (have undergone a hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at
least 12 consecutive months
- Females of childbearing potential and males must be willing to use effective
contraception during treatment and for at least 30 days after the last dose of
Venetoclax. Females will be advised to use effective contraception for at least 6
months after the last dose of Gemtuzumab and males for at least 3 months after the
last dose of Gemtuzumab.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study
Subjects meeting any of the criteria below may not participate in the study:
- Patients with history of prior use of GO or Venetoclax NOTE: Starting with dose cohort
3, prior therapy with venetoclax is allowed, provided patients do not have evidence of
p53 deletion or mutations. If the dose cohort is de-escalated to dose cohort 2 due to
toxicity in cohort 3, prior exposure to venetoclax will continue to be allowed,
provided patients do not have evidence of p53 deletion/mutations.
- History of myeloproliferative neoplasm [MPN] including myelofibrosis, essential
thrombocythemia, polycythemia vera, CML with or without BCR-ABL1 translocation, and
AML with BCR-ABL1 translocation.
- More than three lines of prior therapy. A line of therapy consists of ≥1 complete
cycle of a single agent, a regimen consisting of a combination of several drugs, or a
planned sequential therapy of various regimens (e.g., 3-6 cycles of initial therapy
with bortezomib-dexamethasone [VD] followed by stem cell transplantation [SCT],
consolidation, and lenalidomide maintenance is considered 1 line).
- WBC >25 × 109/L. Cytoreduction is required (hydroxyurea as per local standard of
- Acute promyelocytic leukemia.
- Unresolved ≥grade 2 clinically significant nonhematologic toxicities from prior
anticancer therapy or unresolved disseminated intravascular coagulation ≥ grade 2 per
CTCAE v5 criteria.
- History of other malignancies within 1 year prior to study entry, with the exception
of: adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the
skin; previous malignancy confined and surgically resected (or treated with other
modalities), with curative intent.
- Investigational drug within 4 weeks of study entry.
- History of CHF requiring treatment, left ventricular ejection fraction ≤ 50%, cardiac
insufficiency grade III or IV per New York Heart Association classification (NYHA; see
Appendix II), or chronic stable angina
- Patients who are HIV positive.
- Known CNS involvement with AML.
- Previous hematopoietic stem cell transplant within 2 months.
- Previous history of veno-occlusive disease/sinusoidal obstruction syndrome.
- Patients who are positive for hepatitis B or C infection with the exception of those
with an undetectable viral load within 3 months. Subjects with serologic evidence of
prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] may participate.
- Active uncontrolled infection or severe systemic infection. Enrollment is possible
after control of infection, at discretion of the treating physician.
- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).
- Patients who have received strong and/or moderate CYP3A inducers or inhibitors within
7 days prior to the initiation of study treatment unless deemed necessary by the
treating physician. (See protocol)
- Patients who have consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Starfruit within 3 days prior to the
initiation of study treatment.
- Malabsorption syndrome or other condition that precludes enteral route of
- Psychological, familial, sociological, or geographical condition that would preclude
study compliance and follow-up.
- Unable or unwilling to undergo a screening bone marrow study.
- Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the patient
inappropriate for enrollment in this study.