Description:
This phase I/II trial studies the side effects and best dose of venetoclax in combination
with cedazuridine and decitabine (ASTX727) in treating patients with high risk
myelodysplastic syndrome or chronic myelomonocytic leukemia who have not received prior
treatment (treatment-naive). Chemotherapy drugs, such as venetoclax, cedazuridine, and
decitabine, work in different ways to stop the growth of cancer cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading.
Title
- Brief Title: Venetoclax in Combination With ASTX727 for the Treatment of Treatment-Naive High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
- Official Title: A Phase I/II Study of Venetoclax in Combination With ASTX727 (Cedazuridine/Decitabine) in Treatment-Naïve High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)
Clinical Trial IDs
- ORG STUDY ID:
2020-0129
- SECONDARY ID:
NCI-2020-09915
- SECONDARY ID:
2020-0129
- NCT ID:
NCT04655755
Conditions
- Chronic Myelomonocytic Leukemia
- Myelodysplastic Syndrome
Interventions
Drug | Synonyms | Arms |
---|
Decitabine and Cedazuridine | ASTX727, CDA Inhibitor E7727/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Tablet, Inqovi | Treatment (venetoclax, ASTX727) |
Venetoclax | ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto | Treatment (venetoclax, ASTX727) |
Purpose
This phase I/II trial studies the side effects and best dose of venetoclax in combination
with cedazuridine and decitabine (ASTX727) in treating patients with high risk
myelodysplastic syndrome or chronic myelomonocytic leukemia who have not received prior
treatment (treatment-naive). Chemotherapy drugs, such as venetoclax, cedazuridine, and
decitabine, work in different ways to stop the growth of cancer cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading.
Detailed Description
PRIMARY OBJECTIVE:
I. To determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase
2) of venetoclax in combination with ASTX727 in patients with treatment-naive high-risk
myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with bone marrow
excess blasts > 5%.
SECONDARY OBJECTIVES:
I. Rate of complete remission (CR). II. Rate of marrow/morphologic complete remission (mCR).
III. Rate of hematologic improvement (HI; erythroid/platelet/neutrophil responses).
IV. Rate of red blood cell (RBC) transfusion independence. V. Rate of platelet (PLT)
transfusion independence. VI. Rate of cytogenetic response. VII. Rate of bone marrow blast
response. VIII. Time to transformation to acute myeloid leukemia (AML). IX. Duration of
response (DOR). X. Overall survival (OS). XI. Progression-free survival (PFS). XII.
Disease-free survival (DFS). XIII. Time to next MDS treatment (TTNT). XIV. Event-free
survival (EFS).
EXPLORATORY OBJECTIVE:
I. To investigate the effects of therapy on MDS and to identify biological markers of
response to venetoclax and/or its combination with ASTX727.
OUTLINE: This is a phase I, dose-escalation study of venetoclax, followed by a phase II
study.
Patients receive venetoclax orally (PO) once daily (QD) on days 1-14. Patients also receive
ASTX727 PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression
or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3-6 months for up to 5
years.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (venetoclax, ASTX727) | Experimental | Patients receive venetoclax orally PO QD on days 1-14. Patients also receive ASTX727 PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | - Decitabine and Cedazuridine
- Venetoclax
|
Eligibility Criteria
Inclusion Criteria:
- Patients with treatment-naive high-risk (HR)-MDS or CMML (intermediate [Int]-2 or high
risk by the International Prognostic Scoring System [IPSS] with overall score >= 1.5)
with excess blasts > 5. Note: Patients with therapy-related MDS are eligible.
Hydroxyurea is allowed to lower the white cell count =< 10,000/ul prior to initiation
of venetoclax
- Total bilirubin < 3 x upper limit of normal (ULN) unless increase is due to Gilbert's
disease or leukemic involvement
- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3.0 x ULN unless
considered due to leukemic involvement
- Creatinine < 2 x ULN unless related to the disease
- Signed written informed consent
- Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
at least 12 months) or if of childbearing potential, must have a negative serum or
urine pregnancy test within 72 hours before the start of the treatment. Women of
childbearing potential must agree to use an adequate method of contraception during
the study and until 3 months after the last treatment
- Males must be surgically or biologically sterile or agree to use an adequate method of
contraception during the study until 3 months after the last treatment
- Age >= 18 years of age
Exclusion Criteria:
- Patients having received any prior BCL2 inhibitor therapy
- Patients with MDS with IPSS risk categories low or Int-1 (overall IPSS score < 1.5)
- Patient with known human immunodeficiency virus (HIV) infection (due to potential
drug-drug interactions between antiretroviral medications and venetoclax). HIV testing
will be performed at screening, only if required per local guidelines or institutional
standards
- Patient known to be positive for hepatitis B or C infection (hepatitis C virus
antibody [HCV Ab] indicative of a previous or current infection; and/or positive
hepatitis B surface antigen [HBs Ag] or detected sensitivity on hepatitis B
virus-deoxyribonucleic acid [HBV-DNA] polymerase chain reaction [PCR] test for hepatis
B core antibody [HBc Ab] and/or HBs Ab positivity) with the exception of those with an
undetectable viral load within 3 months of screening. (Hepatitis B or C testing is not
required). Subjects with serologic evidence of prior vaccination to HBV [i.e., HBs
Ag-, and anti-HBs+] may participate
- Patient has received strong and/or moderate CYP3A inducers within 7 days prior to the
initiation of study treatment
- Patient has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Starfruit within 3 days prior to the
initiation of study treatment
- Patient has a cardiovascular disability status of New York Heart Association class >
2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but
ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain
- Patient has chronic respiratory disease that requires continuous oxygen, or
significant history of renal, neurologic, psychiatric, endocrinologic, metabolic,
immunologic, hepatic, cardiovascular disease, any other medical condition or known
hypersensitivity to any of the study medications including excipients of azacitidine
that in the opinion of the investigator would adversely affect his/her participating
in this study
- Patient has a malabsorption syndrome or other condition that precludes enteral route
of administration
- Patient exhibits evidence of other clinically significant uncontrolled systemic
infection requiring therapy (viral, bacterial or fungal)
- Patient has received a live attenuated vaccine within 4 weeks prior to the first dose
of study drug
- Patient has a history of other malignancies within 2 years 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; requires discussion with TA MD
- Patient has a white blood cell count > 25 x 10^9/L. (Hydroxyurea or leukapheresis are
permitted to meet this criterion)
- Female subject has positive results for pregnancy test
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Incidence and severity of all reported adverse events (Phase I) |
Time Frame: | Up to 28 days |
Safety Issue: | |
Description: | The overall incidence and severity of all reported adverse events using Common Toxicity Criteria version 5.0. |
Secondary Outcome Measures
Measure: | Rate of complete remission |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | Will be estimated with the 95% credible interval. |
Measure: | Rate of marrow/morphologic complete remission |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | Will be estimated with the 95% credible interval. |
Measure: | Rate of hematologic improvement (HI; erythroid/platelet/neutrophil responses) |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | Will be estimated with the 95% credible interval. |
Measure: | Rate of red blood cell transfusion independence |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | Will be estimated with the 95% credible interval. |
Measure: | Rate of platelet transfusion independence |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | Will be estimated with the 95% credible interval. |
Measure: | Rate of cytogenetic response |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | Will be estimated with the 95% credible interval. |
Measure: | Rate of bone marrow blast response |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | Will be estimated with the 95% credible interval. |
Measure: | Duration of response |
Time Frame: | From the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first, assessed up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Time to transformation to acute myeloid leukemia |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | Time to transformation to acute myeloid leukemia is defined as the period from treatment till transformed to acute myeloid leukemia. |
Measure: | Overall survival |
Time Frame: | From treatment start till death, assessed up to 5 years |
Safety Issue: | |
Description: | Will be estimated using the method of Kaplan and Meier. |
Measure: | Progression-free survival |
Time Frame: | From treatment start till disease progression or death, assessed up to 5 years |
Safety Issue: | |
Description: | Will be estimated using the method of Kaplan and Meier. |
Measure: | Disease-free survival |
Time Frame: | Up to 5 years post treatment |
Safety Issue: | |
Description: | |
Measure: | Time to next myelodysplastic syndrome (MDS) treatment |
Time Frame: | From initial treatment start till the next MDS treatment, assessed up to 5 years |
Safety Issue: | |
Description: | Will be estimated using the method of Kaplan and Meier. |
Measure: | Event-free survival |
Time Frame: | From treatment initiation to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first, assessed up to 5 years |
Safety Issue: | |
Description: | Will be estimated using the method of Kaplan and Meier. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | M.D. Anderson Cancer Center |
Last Updated
December 7, 2020