Short-course treatment with venetoclax prior to non-myeloablative conditioning allogeneic stem cell transplantation for patients with haematological malignancies.
A phase 1 study to assess the safety of short-course treatment with venetoclax prior to non-myeloablative stem cell transplantation for patients with haematological malignancies.
Melbourne Health
18 participants
Jun 8, 2022
Interventional
Conditions
Summary
The purpose of this study is to investigate the safety of oral venetoclax treatment prior to fludarabine and cyclophosphamide non-myeloablative conditioning allogeneic stem cell transplantation for patients with haematological malignancies. Who is it for? You may be eligible to join this study if you are aged 18 years or above, and have been diagnosed with with either acute leukaemia (myeloid and/or lymphoid, or biphenotypic), myelodysplastic syndrome, chronic lymphocytic leukaemia, B-cell non-Hodgkin lymphoma or plasma cell myeloma. Study details: All participants in thus study will undergo a short course of oral venetoclax between day -11 to -6 prior to fludarabine and cyclophosphamide conditioning allogeneic stem cell transplantation. The dose of venetoclax in this study will commence at 100mg daily for 5 days (total dose of 500mg), with subsequent groups increasing to a total dose of 1100mg over 5 days, 1900mg over 5 days and 2500mg over 5 days. Each participant will be assigned to received one dose level for the entire study. The safety of venetoclax treatment will be assessed by the incidence of side effects 30 days after starting the first dose of venetoclax. The study will determine the safest dose of venetoclax to be used prior to allogeneic stem cell transplantation for patients with haematological malignancies.
Eligibility
Inclusion Criteria18
- Patients are eligible for inclusion if all of the following criteria are met:
- Age greater than or equal to 18 years
- Planned to undergo allogeneic stem cell transplantation for one of the following haematological malignancies: acute leukaemia (including myeloid and/or lymphoid lineage or biphenotypic), myelodysplastic syndrome, chronic lymphocytic leukaemia (CLL), B-cell non-Hodgkin lymphoma (NHL), plasma cell myeloma and Hodgkin lymphoma
- Physician preference for a non-myeloablative conditioning regimen
- Available 10/10 HLA-matched related or unrelated haematopoietic stem cell donor
- Transplantation to be performed from a peripheral blood stem cell source
- Adequate renal and hepatic function at screening as follows:
- a) Calculated creatinine clearance >50ml/min as measured by Cockroft Gault formula
- b) AST and ALT less than or equal to 3.0 x ULN
- c) Bilirubin less than or equal to 1.5 x ULN (except patients with Gilbert’s Syndrome)
- Able to tolerate oral medications
- Disease status at the time of transplantation as follows:
- a) Acute leukaemia in complete morphologic remission
- b) Myelodysplastic syndrome with less than 10% bone marrow blasts
- c) CLL in complete remission (CR), partial response (PR) or PR with lymphocytosis
- d) NHL or HL in CR or PR
- e) Plasma cell myeloma in CR, very good partial response (VGPR) or PR within 3 months of prior autologous stem cell transplantation as part of a tandem auto-allo transplant approach
- ECOG performance status 0-1
Exclusion Criteria18
- Patients will be excluded from this study if any of the following criteria are met:
- Moderate or high risk of tumour lysis syndrome (TLS) prior to conditioning for allogeneic stem cell transplantation, defined as:
- a) CLL:
- Diameter of any lymph node or tumour mass >5cm OR absolute lymphocyte count greater than or equal to 25x10^9/L
- b) NHL or HL:
- Diameter of any lymph node or tumour mass >5cm
- 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:
- a) CLL:
- Diameter of any lymph node or tumour mass <5cm OR absolute lymphocyte count less than or equal to 25x10^9/L
- b) NHL or HL:
- Diameter of any lymph node or tumour mass 3
- Any currently active malignancy other than the primary indication for alloSCT (except localized basal cell carcinoma or squamous cell carcinoma of the skin)
- Uncontrolled systemic infection
- Known malabsorption syndrome
- Has received within 7 days prior to the first dose of venetoclax CYP3A4 inducers such as rifampicin, carbamazepine, phenytoin and St John’s wort
- Has received within 7 days prior to the first dose of venetoclax CYP3A4 inhibitors
- Known positivity to HIV
- Significant physical or psychiatric comorbid illness that in the investigator’s opinion would impair the patient’s ability to participate in the study.
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Interventions
This is a Phase 1, single-arm, open-label, single centre, dose escalation study of short-course oral venetoclax in addition to fludarabine and cyclophosphamide conditioning prior to allogeneic stem cell transplantation (alloSCT). This study will have a 3+3 study design for dose escalation of venetoclax, followed by a dose expansion phase. Three patients will be recruited into the first dose level. If there are no dose limiting toxicities (DLTs) among these 3 patients, then recruitment into the next dose level will be permitted. If one patient develops one DLT, then a further 3 patients will be recruited into the same dose level. If fewer than 2 out of the 6 patients develop a DLT, then escalation to the next dose level will be permitted. The maximum tolerated dose (MTD) will be defined as the highest dose level at which less than 2 out of 6 patients experience a DLT. For participants receiving fludarabine and low-dose cyclophosphamide, oral venetoclax tablets are administered from day -11 to day -6, as per the dosing level described below: Dose Level A - Day -11 to -6: 100mg daily - Total dose: 600mg Dose Level B - Day -11: 100mg daily - Day -10 to -6: 200mg daily - Total dose: 1100mg Dose Level B' - Day -11: 100mg daily - Day -10: 200mg daily - Day -9 to -6: 400mg daily - Total dose: 1900mg Dose Level C - Day -11: 100mg daily - Day -10: 200mg daily - Day -9: 400mg daily - Day -8 to -6: 600mg daily - Total dose: 2500mg For participants receiving fludarabine and high-dose cyclophosphamide, oral venetoclax tablets are administered from day -14 to day -9, as per the dosing level described below: Dose Level A - Day -14 to -9: 100mg daily - Total dose: 600mg Dose Level B - Day -14: 100mg daily - Day -13 to -9: 200mg daily - Total dose: 1100mg Dose Level B' - Day -14: 100mg daily - Day -13: 200mg daily - Day -12 to -9: 400mg daily - Total dose: 1900mg Dose Level C - Day -14: 100mg daily - Day -13: 200mg daily - Day -12: 400mg daily - Day -11 to -9: 600mg daily - Total dose: 2500mg Participants will only be enrolled to one dose level as per standard 3+3 study design. Adherence to study drug will be monitored by a combination of witnessed drug administration by trial staff members and participant self-reporting.
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ACTRN12622000308796