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Venetoclax in Combination With Non-myeloablative Conditioning Allogeneic Haematopoietic Stem Cell Transplantation

PHASE1RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Age ≥ 18 years

Planned to undergo alloSCT 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) and plasma cell myeloma

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: 1. Calculated creatinine clearance >50ml/min as measured by Cockroft Gault formula 2. AST and ALT ≤ 3.0 x ULN 3. Bilirubin ≤ 1.5 x ULN (except patients with Gilbert's Syndrome)

Able to tolerate oral medications

Disease status at the time of transplantation as follows: 1. Acute leukaemia in complete morphologic remission 2. Myelodysplastic syndrome with less than 10% bone marrow blasts 3. CLL in complete remission (CR), partial response (PR) or PR with lymphocytosis 4. NHL in CR or PR 5. 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 criteria

Moderate or high risk of tumour lysis syndrome prior to conditioning for allogeneic transplantation, defined as: 1. For CLL: Diameter of any lymph node or tumour mass >5cm OR absolute lymphocyte count≥25x10^9/L 2. For NHL: 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: 1. For CLL: Diameter of any lymph node or tumour mass <5cm OR absolute lymphocyte count≤25x10^9/L 2. For NHL: Diameter of any lymph node or tumour mass <5cm

Reticulin fibrosis of the marrow of grade MF 2-3

Prior allogeneic stem cell transplantation

Haemopoietic cell transplantation - comorbidity index (HCT-CI) score > 5

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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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2022-06-08

Primary completion: 2026-03-31

Study completion finish: 2026-03-31

Study type

TREATMENT

Phase

PHASE1

Trial ID

NCT05005299

Intervention or treatment

DRUG: Venetoclax

DRUG: Fludarabine

DRUG: Cyclophosphamide

Conditions

• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Plasma Cell Myeloma
• Leukemia, Lymphoblastic, Acute, L1
• Leukemia, Lymphoblastic, Acute, L2
• Non-hodgkin Lymphoma

Image related to Leukemia, Myeloid, Acute

Condition: Leukemia, Myeloid, Acute, Myelodysplastic Syndromes and more
DRUG: Venetoclax and other drugs
Melbourne, Victoria, Australia
Sponsor: Melbourne Health

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Closest Location:

Melbourne Health

Research sites nearby

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Melbourne Health
Melbourne, Victoria, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Dose Level A 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 Venetoclax is administered as an oral tablet once daily.
EXPERIMENTAL: Dose Level B 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 Venetoclax is administered as an oral tablet once daily.
EXPERIMENTAL: Dose Level C 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 Venetoclax is administered as an oral tablet once daily.
EXPERIMENTAL: Dose Level B' 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 Venetoclax is administered as an oral tablet once daily.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
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 point between time of first dose of venetoclax to day 30 post-alloSCT

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Acute GVHD incidence and severity	Acute GVHD (grade 1-4 and grade 3-4) is classified according to the Przepiorka criteria	180 days post allo-SCT
Chronic GVHD incidence and severity	Chronic GVHD (mild, moderate or severe) is classified according to the Filipovich criteria	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	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.	1-year post-alloSCT
Donor/recipient chimerism	Myeloid and T-cell chimerism by fragment analysis and capillary electrophoresis of shor tandem repeat markers.	Measured at days 30, 60, 100, 1 year and 2 years following alloSCT

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References

Clinical Trials Gov: Venetoclax in Combination With Non-myeloablative Conditioning Allogeneic Haematopoietic Stem Cell Transplantation