| Eligibility |
Inclusion Criteria:
1. Patients must be at least 18 years old
2. CMML according to WHO and:
Cohort 1: HMA-naïve CMML-2 or HMA-naïve CMML-1, with Int-1, Int-2 or high risk by the
Molecular CMML-Specific Prognostic Scoring system (CPSS-Mol) in whom HMA therapy is
indicated.
Cohorts 2 and 3: CMML-1 or CMML-2 and failure to HMA defined as no response after 4
cycles of azacitidine, decitabine, guadecitabine, oral decitabine/cedazuridine,
ASTX030, or relapse or progression after any number cycles.
3. ECOG Performance Status of =2.
4. Patients must have the following laboratory values:
total bilirubin =1.5 × the ULN (Patients with Gilbert's syndrome can be included with
total bilirubin >1.5 x ULN as long as direct bilirubin is < 35% of total bilirubin and
= 1.5 x ULN) ALT and AST =2.5 × ULN, and creatinine clearance =60 mL/min based on the
Cockcroft-Gault Glomerular Filtration Rate estimation.
5. Patients must have a serum or high-sensitivity urine pregnancy test (for females of
childbearing potential) that is negative at the Screening Visit and within 72 hrs
prior to initiation of treatment (first dose of study drug).
6. Patients must be willing and able to comply with the scheduled study visits, treatment
plans, laboratory tests, use of 2 methods of birth control (including a barrier
method) for patients who are women of childbearing potential (WOCBP) and for male
patients
7. White blood cell (WBC) count <50,000/L (<10,000/L prior to starting Cycle 1 Day 1 with
venetoclax on Cohorts 2 and 3). Hydroxyurea may be used to control leukocytosis prior
to and for the first 28 days of study treatment (i.e cycle 1). Use of hydroxyurea
beyond this point may be permitted as clinically indicated, on a case-by-case basis
and after discussion with the PI.
Exclusion Criteria:
1. Patients who are currently receiving treatment for a malignancy (not including basal
cell carcinoma, non melanoma skin cancer, cervical carcinoma in situ, or localized
prostate cancer treated with hormone therapy). Patients with history of other cancers
should be free of disease for at least 2 years prior to the Screening Visit.
2. Patients who have an active, life-threatening, or clinically-significant uncontrolled
systemic infection requiring hospitalization.
3. Patients who have a known malabsorption syndrome or other condition that may impair
absorption of study medication (e.g., gastrectomy).
4. Immunocompromised patients with increased risk of opportunistic infections, including
known HIV-positive patients with CD4 counts =350 cells/mm3 or history of opportunistic
infection in the last 12 months. Note: To ensure that effective ART, when used in
eligible HIV-positive patients, is tolerated and that toxicities are not confused with
investigational drug toxicities, patients should be on an established ART for at least
4 weeks and have an HIV viral load less than 400 copies/mL prior to the Screening
Visit.
5. Patients with a known active or chronic hepatitis B or active HCV infection. Patients
with a history of HCV infection who have completed curative therapy for HCV at least
12 weeks before the Screening Visit and have a documented undetectable viral load at
the Screening Visit are eligible for enrollment.
6. Patients who have other severe acute or chronic medical conditions (and/or psychiatric
conditions or laboratory abnormalities) that may increase the expected risk to the
patient (i.e., the risk associated with the study participation or study drug
administration) or that may interfere with the interpretation of study results or, in
the judgment of the investigator, would make the patient inappropriate for entry into
this study.
7. Patients who have not adequately recovered from a major surgery within 4 weeks prior
to starting study drug administration.
8. Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A
supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to
the first dose of the study drug.
9. Patients received strong inducers of CYP3A4 (see Appendix 4) within 2 weeks prior to
the first tamibarotene administration.
10. Patients who received any other investigational agents within 4 weeks prior to the
Screening Visit or <5 half-lives since completion of previous investigational therapy
have elapsed, whichever is shorter.
11. Patients require concurrent treatment with any investigational or approved oncology
agent.
12. Patients with Grade =2 hypertriglyceridemia, defined as >300 mg/dL (CTCAE, version 5).
13. Patients with QTc interval >480 msec based on average of triplicate ECG readings at
the Screening Visit using the Fridericia formula (QTcF), with the exception of
patients with right bundle branch block or left bundle branch block.
14. Pregnant females, breastfeeding females, and males or females of childbearing
potential not willing to comply with contraceptive requirements (as described in
Appendix 2)
15. Patients who have a hypersensitivity to tamibarotene, azacitidine or venetoclax, or to
any of their excipients, including sodium hydrosulfite.
16. Patients for whom treatment with tamibarotene is contraindicated.
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