Venetoclax Added to Fludarabine + Busulfan Prior to Transplant and to Maintenance Therapy for AML, MDS, and MDS/MPN

STATUS

Recruiting
End date

Dec 1, 2024
participants needed

78
sponsor

Jacqueline Garcia, MD

Send

Updated on 7 April 2023

See if I qualify

cancer

remission

myeloid leukemia

fludarabine

bone marrow transplant

busulfan

myelodysplasia

flow cytometry

chronic myelomonocytic leukemia

decitabine

leukemia

hematologic disorder

gilbert's syndrome

transplant conditioning

residual tumor

azacitidine

venetoclax

KIT

KRAS

NRAS

TP53

human chorionic gonadotropin

myelomonocytic leukemia

allogeneic hematopoietic stem cell transplant

Summary

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, (2) to test the safety of combination Venetoclax and azacitidine as "maintenance therapy" after transplant to possibly prevent disease recurrence and (3) to test the safety of combination Venetoclax and oral decitabine/cedazuridine 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 68 people will take part in this research study.

Description

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 three 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. Part 2 is to determine the safety of post-transplant maintenance therapy with the combination of azacitidine and venetoclax. Part 3 is to determine the safety of post-transplant maintenance therapy with the combination of oral decitabine/cedazuridine 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 and Part 3 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.
- All 3 Parts 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.
- In Part 3, the Dose-Escalation phase is where the combination of venetoclax and oral decitabine/cedazuridine 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, Part 2 and Part 3 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.
- Participants in Part 3 of the study will also have the opportunity to receive venetoclax plus oral decitabine/cedazuridine 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.

Details

Condition	Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), MDS/Myeloproliferative Neoplasm-unclassifiable (MDS/MPN-unclassifiable), Hematopoietic Stem Cell Transplant
Treatment	busulfan, Fludarabine, Azacitidine, venetoclax, Decitabine/cedazuridine
Clinical Study Identifier	NCT03613532
Sponsor	Jacqueline Garcia, MD
Last Modified on	7 April 2023

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Age 18 years and older
	Patients must have a prior diagnosis of one of the following
	(Note: Mutational and cytogenetic studies performed at sites other than Dana-Farber Cancer Institute or Brigham and Women's Hospital will require review of the outside cytogenetic and/or molecular pathology reports by the overall PI.)
	High-risk MDS, which is defined as one of the following subsets
	IPSS Intermediate-2 or higher
	Presence of a mutation in TP53
	Prescence of mutation in the RAS pathway including NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT
	Therapy-related MDS
	High-risk AML, which is defined as one of the following subsets
	AML with adverse risk disease according to ELN guidelines including one of the following features
	a history of mutation in TP53, RUNX1, or ASXL1
	t(6;9)(p23;q34.1); DEK-NUP214
	t(v;11q23.3); KMT2A rearranged
	t(9;22)(q34.1;q11.2); BCR-ABL1
	inv(3)(q21.3q26.2) or t(3;3)(q21.3;26.2); GATA2,MECOM(EVI1)
	or del(5q)
	abn(17p)
	Complex karyotype
	Monosomal karyotype
	Wild-type NPM1 and FLT3-ITDhigh
	Secondary AML, which is defined as a history of antecedent hematologic
	Secondary-type" AML, which is defined by the presence of a mutation in any of the following eight genes with high specificity for the presence of antecedent myelodysplastic syndrome including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2
	disorder (an MPN or MDS), a diagnosis of therapy-related myeloid neoplasm
	including t-MDS and t-AML, or AML with myelodysplasia-related changes, OR
	Measurable disease is not required for eligibility
	Patients with AML with evidence of measurable residual disease by multiparameter flow cytometry (≥ 0.1%) despite morphologic remission on the pre-transplant/screening bone marrow biopsy. Review required by overall PI
	Patient is determined to be a suitable candidate for an allo-HCT using a reduced intensity conditioning (RIC) regimen using peripheral blood stem cell as stem cell source
	High-risk chronic myelomonocytic leukemia (CMML) or MDS/MPN unclassifiable
	(MDS/MPN-U), which is defined by the presence of trisomy 8, chromosome 7
	Patient must have a matched related or an 8/8 unrelated donor option for his/her allo-HCT
	abnormalities or complex karyotype (3 or more abnormalities); or by the
	presence of a mutation in ASXL1
	There are no limitations or minimum on the amount of prior therapy for patient's advanced myeloid malignancy. Prior exposure to venetoclax is allowed
	Patient must have normal organ function as defined below
	Patient must have an ECOG performance status ≤ 2
	Ability to understand and the willingness to sign a written informed consent document
	Total bilirubin ≤ 2.0 x institutional upper limit of normal (In patients with Gilbert's Syndrome, Total Bilirubin ≥ 2.0 is permitted.)
	AST(SGOT)/ALT(SGPT) ≤ 3 × institutional upper limit of normal
	Creatinine clearance ≥ 30 mL/min using Cockcroft Gault formula
	The effects of venetoclax on the developing human fetus are unknown. For this
	reason, women of child-bearing potential and men must agree to use adequate
	contraception (hormonal or barrier method of birth control; abstinence) prior
	to study entry and for the duration of study participation. Should a woman
	become pregnant or suspect she is pregnant while she or her partner is
	participating in this study, she should inform her treating physician
	immediately. Men treated or enrolled on this protocol must also agree to use
	adequate contraception prior to the study, for the duration of study
	participation, and 4 months after completion of venetoclax administration. For
	women who are of child-bearing potential, they must have a negative serum
	beta-HCG (human chorionic gonadotropin) test to be eligible
Exclusion Criteria
	Patients who have had chemotherapy (with the exception of hydroxyurea and/or dexamethasone) or radiotherapy or investigational therapy within 14 days prior to starting treatment on study. Exceptions: Patients already on venetoclax therapy prior to transplant need a three day wash out prior to first treatment dose on study. Patients on BCR-ABL, IDH and FLT3 small molecule inhibitors can stay on this treatment up until 5 days prior to first treatment dose on study
	Patients with > 10% morphologic blasts on bone marrow biopsy if they have a diagnosis of MDS or MDS/MPN. Patients > 5% morphologic blasts on bone marrow biopsy if they have a diagnosis of AML
	Patients recommended to receive a myeloablative conditioning regimen prior to transplantation (since there is a known survival advantage for AML using higher intensity)
	Patients who have a history of prior allogeneic stem cell transplantation
	Symptomatic or untreated known CNS involvement of disease
	Patients with active heart disease (New York Heart Association class 3-4 as assessed by history and physical exam, or a critical event including unstable angina/stroke/myocardial infarction within the last 6 months prior to first dose on study)
	Patients who have consumed grapefruit, grapefruit products, Seville oranges or starfruit within 3 days prior to study treatment. Patients who a strong or moderate inducer within 7 days prior to the first dose of study drug
	Malabsorption syndrome or other clinically significant condition that would preclude enteral administration
	Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
	Patients with known active hepatitis B virus (HBV) infection should be excluded because of potential effects on immune function and/or drug interactions. However, if a patient has HBV history with an undetectable HBV load by polymerase chain reaction (PCR), no liver-related complications, and is on definitive HBV therapy that is not contraindicated on this study, then he/she would be eligible for study
	Patients with known active hepatitis C virus (HCV) infection. However, if a patient with a history of HCV infection has received definitive therapy (and is now HCV viral load negative), or if a patient has a reactive HCV antibody test but has an undetectable viral load by PCR, then he/she would be eligible
	Patients with known active HIV infection out of concern for the drug-drug interaction with venetoclax and HAART therapy
	Pregnant or breastfeeding women or those intending to become pregnant during the study or within 3 months after the final dose of study treatment are excluded from this study. Women of childbearing potential must have a negative serum pregnancy test resulted during screening and repeated within 7 days prior to study drug (local labs are allowed)
	Vaccination with live, attenuated vaccines within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study
	Patients with uncontrolled infection at time of first dose of treatment on study. Patients receiving anti-microbial agents including antibiotics, antiviral and antifungal therapies are allowed if hemodynamically stable
	No DLT event (including delay in neutrophil engraftment) due to the addition of venetoclax to conditioning chemotherapy prior to start of maintenance therapy
	No morphologic evidence of relapse (defined as 5% or more morphologic blasts) prior to start of maintenance therapy confirmed by bone marrow biopsy after day +28
	Absence of overall grade II-IV acute GVHD per investigator. Upon acute GVHD resolution, patients are eligible. Patients that are on prednisone 0.5 mg/kg daily dose or lower are allowed to initiate maintenance
	Total bilirubin less than or equal to 2 x institutional ULN (unless has known Gilbert's disease)
	AST and ALT less than or equal to 3 x ULN
	No concurrent illnesses that would prevent taking oral therapy and interfere with safety assessment
	Part 2 and Part 3 only: Patients recommended to receive FLT3 inhibitor therapy or any other antileukemic therapy for AML as maintenance post allo-HCT
	Part 2 and Part 3 Eligibility Criteria
	ANC ≥ 1.0 K/uL without growth factor support and platelet level ≥ 50 K/uL without platelet transfusion within 7 days of starting maintenance therapy
	\--Exception: Patients without morphologic evidence of disease relapse but
	with evidence of persistent molecular or cytogenetic residual disease at the
	time of assessment can start maintenance therapy as long as ANC ≥ 0.75 K/uL
	without growth factor support and platelet level ≥ 25 K/uL
	Cr Cl ≥ 30 mL/min or higher (Cockgroft Gault formula)

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Venetoclax Added to Fludarabine + Busulfan Prior to Transplant and to Maintenance Therapy for AML, MDS, and MDS/MPN