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

NCT05005299 | Recruiting Phase 1 DMC

• 1 other identifier: 2021.238
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Keywords

Venetoclax; Reduced intensity conditioning; Non-myeloablative conditioning; Allogeneic stem cell transplant; Acute leukemia; Myelodysplastic syndrome; Non-Hodgkin Lymphoma; Plasma Cell Myeloma; Graft-versus-host Disease; Engraftment; Graft-versus-Leukemia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Acute GVHD incidence and severity

  180 days post allo-SCT

• Chronic GVHD incidence and severity

  1-year post-alloSCT

• GVHD, relapse-free survival (GRFS) incidence

  1-year post-alloSCT

• Relapse and non-relapse mortality incidence

  1-year post-alloSCT

• Donor/recipient chimerism

  Measured at days 30, 60, 100, 1 year and 2 years following alloSCT

Study Arms (4)

Dose Level A

EXPERIMENTAL

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

Dose Level B

EXPERIMENTAL

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

Dose Level C

EXPERIMENTAL

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

Dose Level B'

EXPERIMENTAL

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

Interventions

Venetoclax DRUG

Venetoclax is administered as an oral tablet once daily.

Also known as: Venclaxta

Dose Level A; Dose Level B; Dose Level B'; Dose Level C

Fludarabine DRUG

Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.

Dose Level A; Dose Level B; Dose Level B'; Dose Level C

Cyclophosphamide DRUG

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.

Dose Level A; Dose Level B; Dose Level B'; Dose Level C

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Calculated creatinine clearance \>50ml/min as measured by Cockroft Gault formula
• AST and ALT ≤ 3.0 x ULN
• 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:
• Acute leukaemia in complete morphologic remission
• Myelodysplastic syndrome with less than 10% bone marrow blasts
• CLL in complete remission (CR), partial response (PR) or PR with lymphocytosis
• NHL in CR or PR

You may not qualify if:

• 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:
• For CLL: Diameter of any lymph node or tumour mass \>5cm OR absolute lymphocyte count≥25x10\^9/L
• 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:
• For CLL: Diameter of any lymph node or tumour mass \<5cm OR absolute lymphocyte count≤25x10\^9/L
• 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

Sponsors & Collaborators

• Melbourne Health: lead

Study Sites (1)

Melbourne Health

Melbourne, Victoria, 3050, Australia

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Lymphoma, Non-Hodgkin; Multiple Myeloma; Graft vs Host Disease

Interventions

venetoclax; fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Bone Marrow Diseases; Lymphoma; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• David Ritchie

  Melbourne Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David Ritchie

CONTACT

+61393427000; David.Ritchie@mh.org.au

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase 1 study, 3+3 design with dose expansion phase.

Study Record Dates

• First Submitted: August 8, 2021
• First Posted: August 13, 2021
• Study Start: June 8, 2022
• Primary Completion: March 31, 2026
• Study Completion: March 31, 2026
• Last Updated: August 1, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)