Back to results

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

Primary Purpose

Leukemia, Myeloid, Acute, Leukemia, Lymphoblastic, Acute, L1, Leukemia, Lymphoblastic, Acute, L2

Status

Recruiting

Phase

Phase 1

Locations

Australia

Study Type

Interventional

Intervention

Venetoclax

Fludarabine

Cyclophosphamide

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute focused on measuring 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

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Melbourne HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Dose Level A

Dose Level B

Dose Level C

Dose Level B'

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Acute GVHD incidence and severity

Acute GVHD (grade 1-4 and grade 3-4) is classified according to the Przepiorka criteria

Chronic GVHD incidence and severity

Chronic GVHD (mild, moderate or severe) is classified according to the Filipovich criteria

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

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.

Donor/recipient chimerism

Myeloid and T-cell chimerism by fragment analysis and capillary electrophoresis of shor tandem repeat markers.

Full Information

NCT ID

NCT05005299

First Posted

August 8, 2021

Last Updated

July 28, 2023

Sponsor

Melbourne Health

1. Study Identification

Unique Protocol Identification Number

NCT05005299

Brief Title

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

Acronym

VICTORY

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Recruiting

Study Start Date

June 8, 2022 (Actual)

Primary Completion Date

March 31, 2026 (Anticipated)

Study Completion Date

March 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Melbourne Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Model Description

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

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Dose Level A

Arm Type

Experimental

Arm Description

Arm Title

Dose Level B

Arm Type

Experimental

Arm Description

Arm Title

Dose Level C

Arm Type

Experimental

Arm Description

Arm Title

Dose Level B'

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Venetoclax

Other Intervention Name(s)

Venclaxta

Intervention Description

Venetoclax is administered as an oral tablet once daily.

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Intervention Description

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.

Primary Outcome Measure Information:

Title

The development of any dose-limiting toxicities

Description

Time Frame

Time point between time of first dose of venetoclax to day 30 post-alloSCT

Secondary Outcome Measure Information:

Title

Acute GVHD incidence and severity

Description

Acute GVHD (grade 1-4 and grade 3-4) is classified according to the Przepiorka criteria

Time Frame

180 days post allo-SCT

Title

Chronic GVHD incidence and severity

Description

Chronic GVHD (mild, moderate or severe) is classified according to the Filipovich criteria

Time Frame

1-year post-alloSCT

Title

GVHD, relapse-free survival (GRFS) incidence

Description

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

Title

Relapse and non-relapse mortality incidence

Description

Time Frame

1-year post-alloSCT

Title

Donor/recipient chimerism

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: 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 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: 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 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

David Ritchie

Phone

+61393427000

David.Ritchie@mh.org.au

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David Ritchie

Organizational Affiliation

Melbourne Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

Melbourne Health

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

3050

Country

Australia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David Ritchie, MBBS, PhD

Phone

+61393427000

David.Ritchie@mh.org.au

First Name & Middle Initial & Last Name & Degree

David Ritchie, MBBS, PhD

First Name & Middle Initial & Last Name & Degree

Ray Mun Koo, MBBS

First Name & Middle Initial & Last Name & Degree

Rachel Koldej, PhD

First Name & Middle Initial & Last Name & Degree

Eric Wong, MBBS, PhD

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

We'll reach out to this number within 24 hrs