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

The VICTORY Study: A Phase I Study of Venetoclax in Combination With Non-myeloablative Conditioning Allogeneic Haematopoietic Stem Cell Transplantation

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.

Study Overview

• Status: Recruiting
• Conditions: Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Plasma Cell Myeloma; Non-hodgkin Lymphoma; Leukemia, Lymphoblastic, Acute, L1; Leukemia, Lymphoblastic, Acute, L2
• Intervention / Treatment: Drug: Venetoclax; Drug: Fludarabine; Drug: Cyclophosphamide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: David Ritchie; Phone Number: +61393427000; Email: david.ritchie@mh.org.au

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Recruiting
      • Melbourne Health
      • Contact: David Ritchie, MBBS, PhD; Phone Number: +61393427000; Email: David.Ritchie@mh.org.au
      • Principal Investigator: David Ritchie, MBBS, PhD
      • Sub-Investigator: Ray Mun Koo, MBBS
      • Sub-Investigator: Rachel Koldej, PhD
      • Sub-Investigator: Eric Wong, MBBS, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients are eligible for inclusion if all of the following criteria are met:

• 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:

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:

  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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

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.; Other Names: Venclaxta; Drug: Fludarabine; Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.; Drug: Cyclophosphamide; 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.
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.; Other Names: Venclaxta; Drug: Fludarabine; Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.; Drug: Cyclophosphamide; 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.
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.; Other Names: Venclaxta; Drug: Fludarabine; Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.; Drug: Cyclophosphamide; 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.
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.; Other Names: Venclaxta; Drug: Fludarabine; Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.; Drug: Cyclophosphamide; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	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 Measures

Outcome Measure	Measure Description	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

Collaborators and Investigators

• Sponsor: Melbourne Health
• Investigators: Principal Investigator: David Ritchie, Melbourne Health

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2022
• Primary Completion (Estimated): March 31, 2026
• Study Completion (Estimated): March 31, 2026

Study Registration Dates

• First Submitted: August 8, 2021
• First Submitted That Met QC Criteria: August 12, 2021
• First Posted (Actual): August 13, 2021

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 28, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Venetoclax; Non-Hodgkin Lymphoma; Allogeneic stem cell transplant; Myelodysplastic syndrome; Graft-versus-host Disease; Plasma Cell Myeloma; Engraftment; Acute leukemia; Reduced intensity conditioning; Non-myeloablative conditioning; Graft-versus-Leukemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Precancerous Conditions; Leukemia, Lymphoid; Lymphoma; Myelodysplastic Syndromes; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Venetoclax; Fludarabine
• Other Study ID Numbers: 2021.238

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No