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Clinical Study of Venetoclax Combined With Azacytiside in the Treatment of Myelodysplastic/Myeloproliferative Neoplasms in Adults

Primary Purpose

Myelodysplastic/Myeloproliferative Neoplasms, Adult

Status
Enrolling by invitation
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
venetoclax combined with azacitidine
Sponsored by
The First Affiliated Hospital of Soochow University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Myelodysplastic/Myeloproliferative Neoplasms

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male or female, Age (years) >= 18；

  2. Patients newly diagnosed or previously treated with MDS/MPNs (CMML, MDS/MPN-U, aCML) according to 2016 WHO diagnostic criteria:

    Initial diagnosis: CMML: CPSS-mol intermediate risk 2 and above; aCML; MDS/MPN-U.

    Previous treatment: HMA treatment failed.

  3. Eastern Cooperative Oncology Group (ECOG) Performance status of 0,1, 2 ;
  4. Liver function: Total bilirubin ≤3 upper limit of normal (ULN); aspartate aminotransferase (AST) ≤3 ULN; alanine aminotransferase (ALT)≤3 ULN；
  5. Renal function#Ccr ≥30 ml/min;
  6. Patients who sign the informed consent must have the ability to understand and be willing to participate in the study and sign the informed consent.

Exclusion Criteria:

  1. Acute myeloid leukemia
  2. Myelodysplastic syndrome
  3. Subjects who had previously been treated with Venetoclax
  4. Subjects who are known to be allergic to ingredients of the study drug or their analogues
  5. HIV infection
  6. HBV-DNA or HCV-RNA positive
  7. Subjects with grade 2 or above cardiac failure and those considered unsuitable for inclusion by the investigator
  8. Subjects who are pregnant or breastfeeding
  9. Subjects reject to participate in the study

Sites / Locations

  • The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment regime

Arm Description

On day 1 of each cycle, decitabine 75 mg/m2 will be given subcutaneously, and will continue for 5 days. Simultaneously the patient will start out with Venetoclax 100mg and progress to 400mg until the 14 day cycle is finished.

Outcomes

Primary Outcome Measures

Overall Response Rate (ORR)
ORR (equals the rates of complete remission [CR]+partial remission [PR]+complete cytogenetic remission [CCyR]+marrow response [MR[+clinical benefit [CB] )of venetoclax in combination with azacitidine. CR and CCyR are shown in the secondary outcome measures below. PR: Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and blast equivalents) reduced by 50%, but remaining>5% of cellularity except in cases of MDS/MPN with≤5% bone marrow blasts at baseline. MR: Optimal marrow response: Presence of all marrow criteria necessary for CR without normalization of peripheral blood indices. Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but remaining>5% of cellularity, or reduction in grading of reticulin fibrosis from baseline on at least 2 bone marrow evaluations spaced at least 2 months apart. CB: Hematology improvement, spleen response and symptom response.

Secondary Outcome Measures

Complete remission rate
Bone marrow: ≤5% myeloblasts (including monocytic blast equivalent in case of CMML) with normal maturation of all cell lines and return to normal cellularity Osteomyelofibrosis absent or equal to "mild reticulin fibrosis" (≤grade 1 fibrosis). Peripheral blood: Leukocyte≤10×10E9 cells/L; Hemoglobin≥11g/dL; Platelets≥100×10E9/L, ≤450×10E9/L; Neutrophils≥1.0×10E9/L; Blasts 0%; Neutrophil precursors reduced to≤2%; Monocytes ≤1.0× 10E9/L. Extramedullary disease: Complete resolution of extramedullary disease present before therapy (eg, cutaneous disease, disease-related serous effusions), including palpable hepatosplenomegaly.
Complete remission rate of bone marrow morphology
Presence of all marrow criteria necessary for CR without normalization of peripheral blood indices as presented above.
Hematology improvement (HI) rate
Percentages of participants with HI (erythroid/platelet/neutrophil responses) Erythroid response: Hemoglobin increase by≥2.0 g/dL; Transfusion independence (TI) for ≥8 week for patients requiring at least 4 packed red blood cell transfusions in the previous 8 week; Only red blood cell transfusions given based on physician's judgment for a pretreatment Hgb of ≤8.5 g/dL will count in the red blood cell TI response evaluation. Platelet response: TI when previously requiring platelet transfusions of at least a rate of 4 platelet transfusions in the previous 8 week; Pretreatment≤20×10E9/L: increase from<20×10E9/L to>20×10E9/L and by at least 100%; Pretreatment>20×10E9/L but≤100×10E9/L: absolute increase of ≥30×10E9/L. Neutrophil response: Pretreatment≤0.5×10E9/L at least 100% increase and an absolute increase≥0.5×10E9/L; Pretreatment>0.5×10E9/L and≤1.0×10E9/L, at least 50% increase and an absolute increase ≥0.5×10E9/L.
Complete cytogenetic remission rate
Resolution of previously present chromosomal abnormality (known to be associated with myelodysplastic, syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic karyotyping with minimal of 20 metaphases or FISH.
Incidence of severe infection (≥grade 3 )
Assessed using CTCAE 5
Spleen response rate
Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpable.
Symptom response rate
Improvement in symptoms as noted by decrease of ≥50% as per the MPN-SAF TSS scoring<20 were not considered eligible for measuring clinical benefit.

Full Information

First Posted
February 21, 2022
Last Updated
March 7, 2022
Sponsor
The First Affiliated Hospital of Soochow University
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1. Study Identification

Unique Protocol Identification Number
NCT05282719
Brief Title
Clinical Study of Venetoclax Combined With Azacytiside in the Treatment of Myelodysplastic/Myeloproliferative Neoplasms in Adults
Official Title
A Multi-center, Phase II, Single-arm Clinical Study of Venetoclax Combined With Azacytiside in the Treatment of Myelodysplastic/Myeloproliferative Neoplasms in Adults
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Enrolling by invitation
Study Start Date
April 2022 (Anticipated)
Primary Completion Date
August 2022 (Anticipated)
Study Completion Date
February 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The First Affiliated Hospital of Soochow University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No

5. Study Description

Brief Summary
To explore the efficacy of venetoclax combined with azacytidine in Myelodysplastic / myeloproliferative neoplasms（MDS/MPN）, so as to improve the overall survival and treatment status of MDS/MPN patients.
Detailed Description
At present, there is no standardized treatment strategy for MDS/MPN. The purpose of our study is to explore the efficacy of venetoclax combined with azacytidine in the treatment of MDS/MPN, so as to improve the overall survival and treatment status of patients with MDS/MPN. After the participants were treated with four cycles of venetoclax combined with azacytidine, the efficacy was evaluated according to the 2015 adult MDS/MPN response criteria to determine the disease status. Participants with disease progression and intolerance withdrew from the study during treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic/Myeloproliferative Neoplasms, Adult

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
33 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment regime
Arm Type
Experimental
Arm Description
On day 1 of each cycle, decitabine 75 mg/m2 will be given subcutaneously, and will continue for 5 days. Simultaneously the patient will start out with Venetoclax 100mg and progress to 400mg until the 14 day cycle is finished.
Intervention Type
Drug
Intervention Name(s)
venetoclax combined with azacitidine
Other Intervention Name(s)
combination of venetoclax plus azacitidine
Intervention Description
On day 1 of each cycle, decitabine 75 mg/m2 will be given subcutaneously, and will continue for 5 days. Simultaneously the patient will start out with Venetoclax 100mg and progress to 400mg until the 14 day cycle is finished.
Primary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
ORR (equals the rates of complete remission [CR]+partial remission [PR]+complete cytogenetic remission [CCyR]+marrow response [MR[+clinical benefit [CB] )of venetoclax in combination with azacitidine. CR and CCyR are shown in the secondary outcome measures below. PR: Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and blast equivalents) reduced by 50%, but remaining>5% of cellularity except in cases of MDS/MPN with≤5% bone marrow blasts at baseline. MR: Optimal marrow response: Presence of all marrow criteria necessary for CR without normalization of peripheral blood indices. Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but remaining>5% of cellularity, or reduction in grading of reticulin fibrosis from baseline on at least 2 bone marrow evaluations spaced at least 2 months apart. CB: Hematology improvement, spleen response and symptom response.
Time Frame
Study start date to study end date, or death, whichever comes first, up to 4 years
Secondary Outcome Measure Information:
Title
Complete remission rate
Description
Bone marrow: ≤5% myeloblasts (including monocytic blast equivalent in case of CMML) with normal maturation of all cell lines and return to normal cellularity Osteomyelofibrosis absent or equal to "mild reticulin fibrosis" (≤grade 1 fibrosis). Peripheral blood: Leukocyte≤10×10E9 cells/L; Hemoglobin≥11g/dL; Platelets≥100×10E9/L, ≤450×10E9/L; Neutrophils≥1.0×10E9/L; Blasts 0%; Neutrophil precursors reduced to≤2%; Monocytes ≤1.0× 10E9/L. Extramedullary disease: Complete resolution of extramedullary disease present before therapy (eg, cutaneous disease, disease-related serous effusions), including palpable hepatosplenomegaly.
Time Frame
Study start date to study end date, or death, whichever comes first, up to 4 years
Title
Complete remission rate of bone marrow morphology
Description
Presence of all marrow criteria necessary for CR without normalization of peripheral blood indices as presented above.
Time Frame
Study start date to study end date, or death, whichever comes first, up to 4 years
Title
Hematology improvement (HI) rate
Description
Percentages of participants with HI (erythroid/platelet/neutrophil responses) Erythroid response: Hemoglobin increase by≥2.0 g/dL; Transfusion independence (TI) for ≥8 week for patients requiring at least 4 packed red blood cell transfusions in the previous 8 week; Only red blood cell transfusions given based on physician's judgment for a pretreatment Hgb of ≤8.5 g/dL will count in the red blood cell TI response evaluation. Platelet response: TI when previously requiring platelet transfusions of at least a rate of 4 platelet transfusions in the previous 8 week; Pretreatment≤20×10E9/L: increase from<20×10E9/L to>20×10E9/L and by at least 100%; Pretreatment>20×10E9/L but≤100×10E9/L: absolute increase of ≥30×10E9/L. Neutrophil response: Pretreatment≤0.5×10E9/L at least 100% increase and an absolute increase≥0.5×10E9/L; Pretreatment>0.5×10E9/L and≤1.0×10E9/L, at least 50% increase and an absolute increase ≥0.5×10E9/L.
Time Frame
Study start date to study end date, or death, whichever comes first, up to 4 years
Title
Complete cytogenetic remission rate
Description
Resolution of previously present chromosomal abnormality (known to be associated with myelodysplastic, syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic karyotyping with minimal of 20 metaphases or FISH.
Time Frame
Study start date to study end date, or death, whichever comes first, up to 4 years
Title
Incidence of severe infection (≥grade 3 )
Description
Assessed using CTCAE 5
Time Frame
Study start date to study end date, or death, whichever comes first, up to 4 years
Title
Spleen response rate
Description
Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpable.
Time Frame
Study start date to study end date, or death, whichever comes first, up to 4 years
Title
Symptom response rate
Description
Improvement in symptoms as noted by decrease of ≥50% as per the MPN-SAF TSS scoring<20 were not considered eligible for measuring clinical benefit.
Time Frame
Study start date to study end date, or death, whichever comes first, up to 4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female, Age (years) >= 18； Patients newly diagnosed or previously treated with MDS/MPNs (CMML, MDS/MPN-U, aCML) according to 2016 WHO diagnostic criteria: Initial diagnosis: CMML: CPSS-mol intermediate risk 2 and above; aCML; MDS/MPN-U. Previous treatment: HMA treatment failed. Eastern Cooperative Oncology Group (ECOG) Performance status of 0,1, 2 ; Liver function: Total bilirubin ≤3 upper limit of normal (ULN); aspartate aminotransferase (AST) ≤3 ULN; alanine aminotransferase (ALT)≤3 ULN； Renal function#Ccr ≥30 ml/min; Patients who sign the informed consent must have the ability to understand and be willing to participate in the study and sign the informed consent. Exclusion Criteria: Acute myeloid leukemia Myelodysplastic syndrome Subjects who had previously been treated with Venetoclax Subjects who are known to be allergic to ingredients of the study drug or their analogues HIV infection HBV-DNA or HCV-RNA positive Subjects with grade 2 or above cardiac failure and those considered unsuitable for inclusion by the investigator Subjects who are pregnant or breastfeeding Subjects reject to participate in the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Suning Chen, Professor
Organizational Affiliation
The First Affiliated Hospital of Soochow University
Official's Role
Principal Investigator
Facility Information:
Facility Name
The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology
City
Suzhou
State/Province
Jiangsu
ZIP/Postal Code
215000
Country
China

12. IPD Sharing Statement

Learn more about this trial

Clinical Study of Venetoclax Combined With Azacytiside in the Treatment of Myelodysplastic/Myeloproliferative Neoplasms in Adults

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