A Phase 1 interventional study of Venetoclax and Fludarabine in Leukemia, Myeloid, Acute, Leukemia, Lymphoblastic, Acute, L1 and Leukemia, Lymphoblastic, Acute, L2, sponsored by Melbourne Health. Recruiting at 1 site in Australia. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2023-08-01.
Sponsored by Melbourne Health · Phase 1, Interventional, and Treatment
This is a Phase 1, open-label, single center study of short-course oral venetoclax therapy prior to non-myeloablative conditioning with fludarabine and cyclophosphamide in subjects with haematological malignancies who are planned for allogeneic stem cell transplantation (alloSCT). The primary study objective is to determine the safety and maximum tolerated dose of venetoclax when used in combination with fludarabine and cyclophosphamide conditioning. Secondary objectives were to evaluate the transplant outcomes and donor/recipient engraftment of this regimen.
Eligible patients are to be enrolled sequentially into one of 4 treatment Dose Levels (beginning with Dose Level A) to receive short-course venetoclax on day -11 to -6, followed by intravenous fludarabine 30mg/m2 daily (day -5 to -3) and intravenous cyclophosphamide 750mg/m2 daily (day -5 to -3). Allogeneic stem cell infusion will occur on day 0. In the dose-escalation phase of this 3+3 study, three patients are planned for each Dose Level.
Dose Level A: venetoclax 100mg daily administered on day -11 to -6 (total venetoclax dose: 600mg)
Dose Level B: venetoclax 100mg daily administered on day -11, followed by 200mg daily administered on day -10 to -6 (total venetoclax dose: 1100mg)
Dose Level C: venetoclax 100mg daily administered on day -11, followed by 200mg daily administered on day -10, 400mg daily administered on day -9 and 600mg daily administered on day -8 to -6 (total venetoclax dose: 2500mg)
Protocol-specific dose-limiting toxicitues (DLTs) will be assessed from the first dose of venetoclax up to day 30 post-transplant. Subjects will not be treated in a new cohort until all subjects in the previous cohort had completed the DLT evaluation period and ≤ 1 of 6 subjects had experienced a DLT. If ≥ 2 of 6 subjects experienced a DLT at Dose Level C, subjects will be treated at Dose B' as part of the dose-escalation phase of this study.
Dose Level B': venetoclax 100mg daily administered on day -11, followed by 200mg daily administered on day -10 and 400mg daily administered on day -9 to -6 (total venetoclax dose: 1900mg)
The maximum tolerated dose (MTD) is defined as the highest Dose Level at which ≤ 1 of 6 subjects had experienced a DLT. The dose-expansion phase involves recruitment of up to 12 patients at the MTD.
Patients are eligible for inclusion if all of the following criteria are met:
Adequate renal and hepatic function at screening as follows:
Disease status at the time of transplantation as follows:
Exclusion Criteria:
Patients will be excluded from this study if any of the following criteria are met:
Moderate or high risk of tumour lysis syndrome prior to conditioning for allogeneic transplantation, defined as:
Prior intolerance of venetoclax or another BCL-2 inhibitor with the exception of cytopenias. Patients with prior clinical tumour lysis syndrome following venetoclax or other BCL-2 inhibitor will be excluded from the study if at the time of prior TLS their disease burden was as follows:
Subjects will receive receive short-course venetoclax on day -11 to -6 \[venetoclax 100mg daily administered on day -11 to -6 (total venetoclax dose: 600mg)\], followed by intravenous fludarabine 30mg/m2 daily (day -5 to -3) and intravenous cyclophosphamide 750mg/m2 daily (day -5 to -3). Allogeneic stem cell infusion will occur on day 0.
Drug: Venetoclax · Drug: Fludarabine · Drug: Cyclophosphamide
Subjects will receive receive short-course venetoclax on day -11 to -6 \[venetoclax 100mg daily administered on day -11, followed by 200mg daily administered on day -10 to -6 (total venetoclax dose: 1100mg)\], followed by intravenous fludarabine 30mg/m2 daily (day -5 to -3) and intravenous cyclophosphamide 750mg/m2 daily (day -5 to -3). Allogeneic stem cell infusion will occur on day 0.
Drug: Venetoclax · Drug: Fludarabine · Drug: Cyclophosphamide
Subjects will receive receive short-course venetoclax on day -11 to -6 \[venetoclax 100mg daily administered on day -11, followed by 200mg daily administered on day -10, 400mg daily administered on day -9 and 600mg daily administered on day -8 to -6 (total venetoclax dose: 2500mg)\], followed by intravenous fludarabine 30mg/m2 daily (day -5 to -3) and intravenous cyclophosphamide 750mg/m2 daily (day -5 to -3). Allogeneic stem cell infusion will occur on day 0.
Drug: Venetoclax · Drug: Fludarabine · Drug: Cyclophosphamide
Subjects will receive receive short-course venetoclax on day -11 to -6 \[venetoclax 100mg daily administered on day -11, followed by 200mg daily administered on day -10 and 400mg daily administered on day -9 to -6 (total venetoclax dose: 1900mg)\], followed by intravenous fludarabine 30mg/m2 daily (day -5 to -3) and intravenous cyclophosphamide 750mg/m2 daily (day -5 to -3). Allogeneic stem cell infusion will occur on day 0.
Drug: Venetoclax · Drug: Fludarabine · Drug: Cyclophosphamide
Venetoclax is administered as an oral tablet once daily.
Also known as: Venclaxta
Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.
Cyclophosphamide is administered as an intravenous infusion at a dose of 750mg/m2 daily, to be administered over 30 minutes and to commence 1 hour after fludarabine infusion.
The development of any dose-limiting toxicities
Dose-limiting toxicities (DLT), defined as any of the following which cannot be clearly attributed to a concurrent illness, concomitant medication or those expected as part of standard allogeneic stem cell transplant (alloSCT) complications: * Any grade 3-4 non-haematological adverse events between day -11 to day -1 * Primary failure of neutrophil engraftment by day 30 post-alloSCT. The date of neutrophil engraftment is defined as the first of 3 consecutive days of neutrophil count ≥ 0.5 x 10\^9/L. * Primary failure of platelet engraftment by day 30 post-alloSCT. The date of platelet engraftment is defined as the first day of platelet count ≥ 20 x 10\^9/L, with no transfusions for at least 7 days prior. * Grade 3-4 acute graft-versus-host disease (GVHD) prior to day 30 post-alloSCT * Development of Clinical Tumour Lysis Syndrome
Time frame: Time point between time of first dose of venetoclax to day 30 post-alloSCT
Acute GVHD incidence and severity
Acute GVHD (grade 1-4 and grade 3-4) is classified according to the Przepiorka criteria
Time frame: 180 days post allo-SCT
Chronic GVHD incidence and severity
Chronic GVHD (mild, moderate or severe) is classified according to the Filipovich criteria
Time frame: 1-year post-alloSCT
GVHD, relapse-free survival (GRFS) incidence
GRFS is defined as freedom from grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse or death in the first year following alloSCT
Time frame: 1-year post-alloSCT
Relapse and non-relapse mortality incidence
Relapse is defined as recurrence of disease, determined by radiological or histological grounds. Non-relapse mortality is defined as all-cause mortality without recurrence or progressive disease following alloSCT.
Time frame: 1-year post-alloSCT
Donor/recipient chimerism
Myeloid and T-cell chimerism by fragment analysis and capillary electrophoresis of shor tandem repeat markers.
Time frame: Measured at days 30, 60, 100, 1 year and 2 years following alloSCT
Plan to share: No
No publications or documents are linked to this record.
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Melbourne Health