A phase 1 study of triplet therapy with navitoclax, venetoclax, and decitabine for high-risk myeloid malignancies

The purpose of this research study is to test the safety of a new three drug combination of
navitoclax, decitabine, and venetoclax to treat advanced myeloid malignancies.

The names of the drugs involved in this study are:

- Venetoclax

- Decitabine

- Navitoclax

Inclusion Criteria:

- 18 years or older

- Subjects must have a diagnosis of one of the following:

- Myelofibrosis in accelerated phase (AP-MF), defined by WHO as 10-19% blasts in
either bone marrow or blood. There is no requirement for prior therapy.

- Myelofibrosis in blast phase (BP-MF), defined as ≥ 20% blasts in either bone
marrow or blood. There is no requirement for prior therapy.

- Untreated secondary AML (s-AML), which includes subjects with therapy-related
disease or known antecedent MDS or MDS/MPN. All these subjects must be ineligible
or not recommended for any available approved therapy as determined by the
treating provider. For subjects with known antecedent MDS or MDS/MPN, they must
have received prior HMA therapy (minimum number of cycles are not required in
this setting).

- MDS/MPN overlap syndromes (e.g. CMML) with ≥ 5% blasts in either bone marrow or
blood. No requirements for prior therapy.

- MDS with excess blasts defined as ≥ 5% blasts in either bone marrow or blood must
be ineligible for any available approved therapy including intensive chemotherapy
and immediate allogeneic stem cell transplant per treating investigator and must
meet at least one of the following criteria: 1) persistent disease despite prior
exposure to venetoclax plus HMA for at least 3 cycles, 2) disease progression per
IWG 2006 criteria on venetoclax plus HMA or on M15-954 protocol, or 3) persistent
disease after at least four cycles of any HMA-based therapy.

- ECOG performance status ≤ 2 (see Appendix A)

- Baseline platelet count ≥ 25 x 109/L

- Subjects must have adequate organ function as defined below:

- Aspartate transaminase (AST) and alanine transaminase (ALT) < 3 x ULN

- Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
non-hepatic origin)

- Subject must have adequate renal function as demonstrated by a creatinine
clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula

- aPTT ≤ 1.5 x ULN

- INR ≤ 1.5 x ULN

- Prior treatment-related toxicities must be grade 1 or baseline except for alopecia.

- Moderate/strong inhibitors of CYP3A are allowed if they cannot be substituted;
however, patients must be on these agents for at least 2-3 days prior to treatment
start. (See section 5.5 for details on concomitant medications and dose adjustment.)

- If female, subject must be either :

- Postmenopausal (surgically sterile or age > 55 years with no menses for 12 or
more months without an alternative medical cause or age greater than or equal to
55 or less with no menses for 12 or more months without an alternative medical
cause and an FSH level > 40 IU/L); or

- Of children bearing potential. These subjects must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. 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. Subject must
agree to have a negative urine or serum beta-HCG test result during screening and
repeated within 7 days prior to study drug (local labs are allowed) to be
eligible.

- Subject must voluntarily sign and date an informed consent

- Subjects must be able to swallow pills

Exclusion Criteria:

- Subject cannot have had prior navitoclax or any BCL-XL therapy. Otherwise, there are
no restrictions on any other prior therapies. Prior venetoclax is allowed.

- Subject is eligible and willing to receive intensive chemotherapy for their specific
disease.

- Anti-leukemic therapy within 14 days of first day of study treatment except for
hydroxyurea. If on hydroxyurea, then subject needs to be off hydroxyurea at least 3
days prior to first dose of study treatment. If on venetoclax, then a wash-out period
of at least five times the half-life of the treatment.

- Subject with known and active concurrent malignancy requiring treatment. Subjects with
basal or squamous skin cancers or carcinomas in situ are allowed. Exception: hormonal
or topical therapies are allowed.

- Subject has known active/uncontrolled HIV and on contraindicated medication due to
drug-drug CYP inducer interaction. HIV testing is not required.

- Subject has known and active CNS involvement with AML.

- Evidence of other clinically significant uncontrolled condition(s) including, but not
limited to:

- Uncontrolled and/or active systemic infection (viral, bacterial or fungal).
Controlled infections are allowed.

- Chronic, active hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
Note: subjects with serologic evidence of prior vaccination to HBV (i.e.
hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and
anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from
intravenous immunoglobulins (IVIG) may participate. Subjects that have prior HCV
that has been definitively treated with negative HCV viral load prior to study
initiation and no evidence of cirrhosis are allowed to participate.

- Recent diagnosis of myocardial infarction or worse heart failure within the last six
months.

- Treatment with any moderate or strong CYP3A inducers (see Appendix D for examples)
within 7 days prior to the first dose of study drug.

- Administration or consumption of any of the following within 3 days prior to the first
dose of study drug:

- Grapefruit or grapefruit products

- Seville oranges (including marmalade containing Seville oranges)

- Star fruit

- White blood cell count (WBC) greater than or equal to 25 x 109/L. Exception: Subjects
with myelofibrosis or MDS/MPN overlap syndrome may enter study with WBC greater than
or equal 25 x 109/L on the first day of therapy only if the absolute blast count is <
5 x 109/L; hospitalization for subjects with this particular disease subset is
required during dose ramp-up of venetoclax for TLS monitoring. This criterion is
intended to exclude AML patients at high risk of TLS, but permit entry of patients
with MF or CMML who frequently have leukocytosis without AML transformation who are at
low risk for TLS.

- Ongoing requirement for anticoagulation with the exception of low-dose anticoagulation
medications used to maintain patency of a central venous catheter or for deep venous
thrombosis prophylaxis. Antiplatelet agents such as aspirin and clopidogrel are not
allowed if platelet count < 50 x 109/L.

- Known history of immune thrombocytopenia that previously required therapy.

- Known history of platelet refractoriness and HLA alloimmunization prior to study
start.

- History of serious or life-threatening bleeding in last 12 months that has not been
definitively treated.

- Uncontrolled, systemic infection (viral, bacterial, or fungal). Antibiotic use is
permitted. (See Section 5.5 for concomitant drugs)

- Active and known SARS-CoV-2 infection.

- If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, then the
subject must undergo molecular (e.g. PCR) testing to rule out SARS-CoV-2
infection.

- Subjects positive for active SARS-CoV-2 infection may re-screen after they meet
either criteria A or B indicating SARS-CoV-2 infection has resolved with viral
clearance: A) ≥14 days since first the PCR test result in an asymptomatic
subject; OR B) ≥14 days since recovery, defined as resolution of fever without
use of anti-pyretics and improvement in symptoms.

- Other 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 subject inappropriate
for enrollment into this study.

- Vaccination with live, attenuated vaccines ≤4 weeks prior to initiation of study
treatment or anticipation of need for such a vaccine during the study. All other
recommended vaccinations including COVID19 is permitted.