Chronic Myelomonocytic LeukemiaPhase 1/2NCT04160052
Venetoclax and Azacitidine for the Treatment of High-Risk Recurrent or Refractory Myelodysplastic Syndrome
A Phase 1/2 study testing Azacitidine and Venetoclax in people with Chronic Myelomonocytic Leukemia and Myelodysplastic Syndrome, run by M.D. Anderson Cancer Center at 1 site in United States.
Trial summary
This phase I/II trial studies the side effects and best dose of venetoclax when given together with azacitidine in treating patients with high-risk myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Recurrent Myelodysplastic Syndrome
- What is being tested?
- Azacitidine and Venetoclax
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 51 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Oct 2019to 3 Feb 2026
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- For phase I, patients can be HMA-naive high-risk MDS (Int-2 or high risk by the International Prognostic Scoring System [IPSS] with overall score >= 1.5) with excess blasts > 5%, or relapsed/refractory MDS post-HMA failure (defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or progression of disease or relapse at any time after prior response to HMA therapy) with > 5% blasts
- For phase II, patients will be divided into 2 cohorts: Cohort A: patients with HMA-naive high-risk MDS (Int-2 or high risk by the IPSS with overall score >= 1.5) with excess blasts > 5%. Cohort B: patients with relapsed/refractory MDS post-HMA failure (defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or progression of disease or relapse at any time after prior response to HMA therapy) with > 5% blasts are eligible. Note: Patients with chronic myelomonocytic leukemia (CMML) and 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) < 4 x ULN unless considered due to leukemic involvement
- Creatinine < 2 x ULN unless related to the disease
- Signed written informed consent. Consent may be translated for Non-English Speaking Patients per institutional policy.
- 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
Who cannot join
- Patients having received any prior BCL2 inhibitor therapy
- Patients with MDS with IPSS risk categories low or Int-1 (overall IPSS score < 1.5)
- Pregnant or breastfeeding
- Cognitively impaired patients
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase I/II of Venetoclax in Combination With Azacitidine in Treatment Naïve and Relapse Refractory High Risk MDS Individuals"
This phase I/II trial studies the side effects and best dose of venetoclax when given together with azacitidine in treating patients with high-risk myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as venetoclax and azacitidine, 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.
Read the detailed description
PRIMARY OBJECTIVE:
- To determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase 2) of venetoclax in combination with azacitidine in patients with treatment-naive high-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with bone marrow excess blasts > 5% and patients that are relapsed/refractory to prior hypomethylating agent (HMA) therapy.
SECONDARY OBJECTIVES:
- 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. Time to next MDS treatment (TTNT). XIII. Event-free survival (EFS).
EXPLORATORY OBJECTIVE:
- To investigate the effects of therapy on MDS and to identify biological markers of response to venetoclax and/or its combination with azacitidine.
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 1-7 or 1-14 and azacitidine subcutaneously (SC) or intravenously (IV) over 15 minutes on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for up to 5 years.
- Conditions
- Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Recurrent Myelodysplastic Syndrome, Refractory Myelodysplastic Syndrome, Therapy-Related Myelodysplastic Syndrome
- Being tested
- Azacitidine, Venetoclax
- Medical subject headings
- Leukemia, Myelomonocytic, Chronic, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzacitidineDrug
Also called 5 AZC, 5-AC, 5-Azacytidine, 5-AZC
Given SC or IV
VenetoclaxDrug
Also called ABT-0199, ABT-199, ABT199, GDC-0199
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Treatment (venetoclax, azacitidine) | Experimental | Patients receive venetoclax orally PO QD on days 1-7 or 1-14 and azacitidine SC or IV over 15 minutes on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity. Receives: Drug: Azacitidine; Drug: Venetoclax |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum tolerated dose (MTD) of the combination regimen of venetoclax and azacitidine (Phase I)
The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity.
Measured: Up to 8 weeks
Incidence of adverse events (Phase I)
Safety data will be summarized by category, severity, and frequency.
Measured: Up to 5 years
Secondary outcomes (14)
Overall response rate (Phase 2)
Will be defined as the proportion of patients who had complete remission (CR), partial remission (PR), marrow complete remission, or hematologic improvement lasting at least 4 weeks. Will estimate the overall response rate for the combination treatment, along with the 95% confidence interval.
Measured: Up to 5 years
Rate of CR
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measured: Up to 5 years
Rate of marrow/morphologic CR
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measured: Up to 5 years
Rate of hematologic improvement
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measured: Up to 5 years
Rate of red blood cell transfusion independence
Measured: Up to 5 years
Rate of platelet transfusion independence
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measured: Up to 5 years
Rate of cytogenetic response
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measured: Up to 5 years
Rate of bone marrow blast response
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measured: Up to 5 years
Time to transformation to acute myeloid leukemia
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measured: Up to 5 years
Duration of response
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measured: 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
Overall survival
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measured: From treatment start till death or last follow-up, assessed up to 5 years
Progression-free survival
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measured: From treatment to progression or last follow-up, assessed up to 5 years
Time to next myelodysplastic syndrome treatment
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measured: Up to 5 years
Event-free survival
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measured: From the date of 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Nov 2019
- Study start1 Oct 2019
- Primary completion3 Feb 2026
- Study completion3 Feb 2026
Why it stopped: \<75% participation
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Myelomonocytic LeukemiaStudies of the same condition, open and under way.
- More trials run by M.D. Anderson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 51 participants (actual)
Sponsor and investigators
- Lead sponsor
- M.D. Anderson Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Guillermo Garcia-Manero, Principal investigator, M.D. Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04160052
- Sponsor's protocol ID
- 2019-0368
- Other IDs
- NCI-2019-06873, 2019-0368
- Status last verified
- Jan 2026
- First submitted
- 4 Nov 2019
- Last updated
- 12 Feb 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Bazinet A, Darbaniyan F, Jabbour E, Montalban-Bravo G, Ohanian M, Chien K, Kadia T, Takahashi K, Masarova L, Short N, Alvarado Y, Yilmaz M, Ravandi F, Andreeff M, Kanagal-Shamanna R, Ganan-Gomez I, Colla S, Qiao W, Huang X, McCue D, Mirabella B, Kantarjian H, Garcia-Manero G. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study. Lancet Haematol. 2022 Oct;9(10):e756-e765. doi: 10.1016/S2352-3026(22)00216-2. Epub 2022 Sep 2.
PubMed 36063832