Venetoclax Added to Fludarabine + Busulfan Prior to Transplant for AML, MDS, and MDS/MPN
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|ClinicalTrials.gov Identifier: NCT03613532|
Recruitment Status : Recruiting
First Posted : August 3, 2018
Last Update Posted : July 14, 2021
This clinical trial involves individuals who have been diagnosed with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), or MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-unclassifiable) and are planning to have an allogeneic hematopoietic stem cell transplant ("bone marrow transplant"). The goal of this research study is to (1) test the safety of adding the study drug, Venetoclax, to a standard of care conditioning regimen for bone marrow transplantation as a possible means of eliminating residual (left-over) disease prior to transplant and (2) to test the safety of combination Venetoclax and azacitidine as "maintenance therapy" after transplant to possibly prevent disease recurrence.
- The name of the study drug involved in this study is Venetoclax.
- It is expected that about 45 people will take part in this research study.
|Condition or disease||Intervention/treatment||Phase|
|Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS) Chronic Myelomonocytic Leukemia (CMML) MDS/Myeloproliferative Neoplasm-unclassifiable (MDS/MPN-unclassifiable) Hematopoietic Stem Cell Transplant||Drug: Venetoclax Drug: Fludarabine Drug: Busulfan Drug: Azacitidine||Phase 1|
- This research study is a Phase I clinical trial, which tests the safety of an investigational drug and tries to define the appropriate dose and schedule of the investigational drug to use for further studies. "Investigational" means that the drug is being studied.
There are two parts to this research study:
- Part 1 is to determine a safe dose of the study drug, Venetoclax, when given in combination with a standard chemotherapy and Part 2 is to determine the safety of post-transplant maintenance therapy with the combination of azacytidine and venetoclax. Participants enrolled in Part 1 of this study, will receive Venetoclax in combination with conditioning chemotherapy (prior to transplantation).
- Participants enrolled in Part 2 of the study, will also receive Venetoclax in combination with conditioning chemotherapy (prior to transplantation) and will have the opportunity to receive maintenance chemotherapy (after transplantation) for potentially a year.
Both Part 1 and Part 2 of this research study will have a Dose-Escalation phase. The Dose-Escalation phase is the part of the study where treatment dose and schedule are being tested.
- In Part 1, the Dose-Escalation phase is when venetoclax will be given at different doses until the safest maximum dose has been identified. Part 1 also includes a second phase of the study which is called the Dose-Expansion phase, during which more participants will be treated at this dose level to obtain additional information on safety.
- In Part 2, the Dose-Escalation phase is where the combination of venetoclax and azacitidine will be given after transplantation at different schedules.
- For both the Dose-Escalation or Dose-Expansion phase of this study, there will be a screening period, a pre-transplant period, a transplant period, and a post-transplant follow up period.
In this research study, participants will receive venetoclax plus chemotherapy. Participants in Part 1 and Part 2 of this study will receive chemotherapy immediately prior to transplantation, which is called the "conditioning regimen." The conditioning regimen chemotherapy will suppress the immune system and may help to destroy cancer cells. During this process normal bone marrow cells are destroyed as well, thus making way for donor stem cells.
- Fludarabine and busulfan (FluBu2) are both chemotherapies and a common conditioning regimen.
- In this study, Venetoclax is added to the conditioning regimen (FluBu2) prior to transplantation to eliminate leftover blood cancer cells prior to transplant.
- Participants in Part 2 of the study will also have the opportunity to receive venetoclax plus azacitidine after transplantation. The combination of these two drugs is called "maintenance therapy," which is treatment given after transplant to potentially reduce the chance of disease relapse. Relapse is a cause of transplant failure and can occur when there are leftover blood cancer cells.
- The FDA (U.S. Food and Drug Administration) has approved Venetoclax in combination with cytarabine, azacitidine or decitabine for the treatment of newly diagnosed acute myeloid leukemia, but not for use in with conditioning chemotherapy prior to transplantation or after transplant with maintenance chemotherapy. Venetoclax is an oral drug that selectively inhibits Bcl-2, which is critical for keeping cancer cells alive.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 Study of Adding Venetoclax to a Reduced Intensity Conditioning Regimen and to Maintenance in Combination With Azacitidine After Allogeneic Hematopoietic Cell Transplantation for Patients With High Risk AML, MDS, and MDS/MPN Overlap Syndromes|
|Actual Study Start Date :||October 24, 2018|
|Estimated Primary Completion Date :||February 1, 2023|
|Estimated Study Completion Date :||December 1, 2023|
This study has three periods: 1) Screening, 2) Treatment including venetoclax + FluBu2 conditioning chemotherapy and transplantation; and 3) Post-Transplant follow up. For Part 1, the post-transplant period will include routine follow-up. For Part 2, the post-transplant period will include investigational therapy with azacitidine and venetoclax and follow-up.
Dose escalation in Part 1 will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation/de-escalation.
Dose escalation in Part 2 will occur using a 10+10 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation/de-escalation.
Part 1 and 2: 6-7 total doses depending on dose level assigned
Other Name: ABT199
◦Fludarabine : given once daily for 4 days
Other Name: Fludara
◦Busulfan: given twice daily for 4 days
Part 2: 14 doses for 8-12 cycles depending on dose level assigned
Other Name: ABT199
Part 2: 5 doses for 8-12 cycles depending on dose level assigned
- MTD of Venetoclax with Busulfan and Fludarabine [ Time Frame: 37 Days ]Determine safe dose and schedule of venetoclax
- MTD of Venetoclax with Azacitidine as Maintenance Therapy [ Time Frame: 28 Days from Maintenance Therapy Start ]Determine safe dose and schedule of venetoclax
- Overall Survival [ Time Frame: 12 Months ]Time from treatment start until death
- Progression Free Survival [ Time Frame: 12 Months ]Time from treatment start until relapse
- Overall Response Rate [ Time Frame: At day 100, 6 months and 12 months ]IWG response criteria
- Remission Duration Rate [ Time Frame: from start of the treatment until disease relapse (assessed at day 100, 6 months and 12 months) ]Duration of remission from treatment start until relapse
- Rate of Disease Relapse [ Time Frame: 12 Months ]Frequency of disease recurrence on trial
- Rate of Non-Relapse Mortality [ Time Frame: 12 Months ]Frequency of death that is not due to disease recurrence on trial
- Donor granulocyte chimerism percentage [ Time Frame: 28 Days Post-Transplant ]Percentage of donor blood cells
- Donor granulocyte chimerism percentage [ Time Frame: 100 days Post-Transplant ]Percentage of donor blood cells
- Donor granulocyte chimerism percentage [ Time Frame: 12 Months Post-Transplant ]Percentage of donor blood cells
- Cumulative incidence of acute graft versus host disease (GVHD) and chronic GVHD following allo-HCT [ Time Frame: 12 Months ]Frequency of GVHD events
- Number of Maintenance Treatment Cycles Safely Administered [ Time Frame: From Initiation of Maintenace Therapy up to 12 months ]
- Compare Incidences of Mortality and Survival Between Participants in Part 1 and Part 2 [ Time Frame: 12 months ]Compare cumulative instances of mortality and survival between participants on Part 1 and Part 2
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): NCT03613532
|Contact: Jacqueline S. Garcia, MD||617-632-1906||Jacqueline_garcia@dfci.harvard.edu|
|United States, Massachusetts|
|Dana-Farber Cancer Institute||Recruiting|
|Boston, Massachusetts, United States, 02215|
|Contact: Jacqueline S Garcia, MD 617-632-1906 email@example.com|
|Principal Investigator: Jacqueline S Garcia, MD|
|Principal Investigator:||Jacqueline S. Garcia, MD||Dana-Farber Cancer Institute|