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Venetoclax and Azacitidine for the Treatment of High-Risk Recurrent or Refractory Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT04160052
Recruitment Status : Recruiting
First Posted : November 12, 2019
Last Update Posted : November 12, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief 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). 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.

Condition or disease Intervention/treatment Phase
Blasts More Than 5 Percent of Bone Marrow Nucleated Cells Chronic Myelomonocytic Leukemia Recurrent High Risk Myelodysplastic Syndrome Recurrent Myelodysplastic Syndrome Refractory High Risk Myelodysplastic Syndrome Therapy-Related Myelodysplastic Syndrome Drug: Azacitidine Drug: Venetoclax Phase 1 Phase 2

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 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:

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. Time to next MDS treatment (TTNT). XIII. Event-free survival (EFS).

EXPLORATORY OBJECTIVES:

I. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 116 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II of Venetoclax in Combination With Azacitidine in Treatment Naïve and Relapse Refractory High Risk MDS Individuals
Actual Study Start Date : October 1, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: Treatment (venetoclax, azacitidine)
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.
Drug: Azacitidine
Given SC or IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of the combination regimen of venetoclax and azacitidine (Phase I) [ Time Frame: Up to 8 weeks ]
    The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity.

  2. Incidence of adverse events (Phase I) [ Time Frame: Up to 5 years ]
    Safety data will be summarized by category, severity, and frequency.


Secondary Outcome Measures :
  1. Overall response rate (Phase 2) [ Time Frame: Up to 5 years ]
    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.

  2. Rate of CR [ Time Frame: Up to 5 years ]
    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.

  3. Rate of marrow/morphologic CR [ Time Frame: Up to 5 years ]
    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.

  4. Rate of hematologic improvement [ Time Frame: Up to 5 years ]
    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.

  5. Rate of red blood cell transfusion independence [ Time Frame: Up to 5 years ]
  6. Rate of platelet transfusion independence [ Time Frame: Up to 5 years ]
    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.

  7. Rate of cytogenetic response [ Time Frame: Up to 5 years ]
    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.

  8. Rate of bone marrow blast response [ Time Frame: Up to 5 years ]
    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.

  9. Time to transformation to acute myeloid leukemia [ Time Frame: Up to 5 years ]
    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.

  10. 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 ]
    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.

  11. Overall survival [ Time Frame: From treatment start till death or last follow-up, assessed up to 5 years ]
    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.

  12. Progression-free survival [ Time Frame: From treatment to progression or last follow-up, assessed up to 5 years ]
    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.

  13. Time to next myelodysplastic syndrome treatment [ Time Frame: Up to 5 years ]
    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.

  14. Event-free survival [ Time Frame: 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 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • 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

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)
  • Pregnant or breastfeeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04160052


Contacts
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Contact: Kiran Naqvi 713-745-5073 knaqvi@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Kiran Naqvi    713-745-5073      
Principal Investigator: Kiran Naqvi         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kiran Naqvi M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04160052    
Other Study ID Numbers: 2019-0368
NCI-2019-06873 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2019-0368 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: November 12, 2019    Key Record Dates
Last Update Posted: November 12, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Myelodysplastic-Myeloproliferative Diseases
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors