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Trial registered on ANZCTR


Registration number
ACTRN12622000308796
Ethics application status
Approved
Date submitted
24/01/2022
Date registered
18/02/2022
Date last updated
3/04/2024
Date data sharing statement initially provided
18/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Short-course treatment with venetoclax prior to non-myeloablative conditioning allogeneic stem cell transplantation for patients with haematological malignancies.
Scientific title
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.
Secondary ID [1] 304874 0
Nil.
Universal Trial Number (UTN)
Trial acronym
VICTORY study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute leukaemia (myeloid and/or lymphoid, or biphenotypic) 322994 0
Myelodysplastic syndrome 322995 0
Chronic lymphocytic leukaemia 322996 0
B-cell non-Hodgkin lymphoma 322997 0
Plasma cell myeloma 322998 0
Condition category
Condition code
Blood 320560 320560 0 0
Haematological diseases
Cancer 320561 320561 0 0
Leukaemia - Acute leukaemia
Cancer 320562 320562 0 0
Leukaemia - Chronic leukaemia
Cancer 320563 320563 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 320564 320564 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 320565 320565 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 321266 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328383 0
The primary endpoint the development of any 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 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 greater than or equal to 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 greater than or equal to 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 (Przepiorka criteria)
• Development of Clinical Tumour Lysis Syndrome (TLS)

The DLT window is defined as the time point between time of first dose of venetoclax to day 30 post-alloSCT.

Outcomes will be assessed through routine inpatient and outpatient clinical assessment by study doctors, standard of care blood investigations and additional investigations as deemed necessary by study doctors.
Timepoint [1] 328383 0
30 days post-transplant
Secondary outcome [1] 398825 0
Acute GVHD and severity (Przepiorka criteria)
Timepoint [1] 398825 0
180 days post-transplant
Secondary outcome [2] 398826 0
Chronic GVHD incidence and severity (Filipovich criteria)
Timepoint [2] 398826 0
1-year post-transplant
Secondary outcome [3] 398827 0
Graft-versus-host disease relapse-free survival incidence.

This outcome will be assessed through trial-mandated routine clinical assessment of study participants at pre-determined timepoints.
Timepoint [3] 398827 0
1-year post-transplant
Secondary outcome [4] 398830 0
Peripheral blood donor/recipient chimerism (myeloid and T-cell)
Timepoint [4] 398830 0
At days 30, 60, 100, 1 year and 2 years post-transplant; and at relapse.

Eligibility
Key inclusion criteria
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) 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:
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 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 (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:
• 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:
• 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 > 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
A 3+3 study design for dose escalation of venetoclax, followed by a dose-expansion phase.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
There will be a maximum of 18 patients enrolled on this study. This takes into account the 4 possible dosing levels, with a possible 3 patients that may be enrolled if a dose-limiting toxicity (DLT) is experience at the highest dose level. Rates of accrual reflect safety requirement for the DLT period of 30 days.

Patient and disease characteristics, donor engraftment assessed by peripheral blood donor/recipient chimerism measured at day 30, 60 and 100 will be reported descriptively. Severity of acute GVHD will be categorized according to established criteria. The cumulative incidence of grade 1 and grade 2-4 acute GVHD will be determined, taking into account death due to non-GVHD causes as a competing risk. Chronic GVHD will be assessed using NIH consensus criteria and reported as a cumulative incidence function taking into account non-GVHD death as a competing risk. Overall survival, relapse-free survival and GRFS will be assessed using the Kaplan-Meier method. Safety and data will be reviewed and reported.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
28/02/2022
Actual
8/06/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
18
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 20076 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 20077 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 34784 0
3050 - Parkville
Recruitment postcode(s) [2] 34785 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 309248 0
Government body
Name [1] 309248 0
The Commonwealth of Australia - Medical Research Future Fund (MRFF)
Country [1] 309248 0
Australia
Primary sponsor type
Hospital
Name
Melbourne Health
Address
Royal Melbourne Hospital
Grattan Street
Parkville 3050
Victoria
Country
Australia
Secondary sponsor category [1] 310218 0
None
Name [1] 310218 0
NA
Address [1] 310218 0
NA
Country [1] 310218 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309093 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 309093 0
Royal Melbourne Hospital
Grattan Street, Parkville
Victoria 3050
Ethics committee country [1] 309093 0
Australia
Date submitted for ethics approval [1] 309093 0
16/08/2021
Approval date [1] 309093 0
15/11/2021
Ethics approval number [1] 309093 0

Summary
Brief 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112950 0
Prof David Ritchie
Address 112950 0
Clinical Haematology
Royal Melbourne Hospital
Grattan Street, Parkville
Victoria 3050
Country 112950 0
Australia
Phone 112950 0
+61433052317
Fax 112950 0
Email 112950 0
[email protected]
Contact person for public queries
Name 112951 0
Prof David Ritchie
Address 112951 0
Clinical Haematology
Royal Melbourne Hospital
Grattan Street, Parkville
Victoria 3050
Country 112951 0
Australia
Phone 112951 0
+61 3 93427000
Fax 112951 0
Email 112951 0
[email protected]
Contact person for scientific queries
Name 112952 0
Dr Rachel Koldej
Address 112952 0
Australian Cancer Research Foundation (ACRF) Translational Research Laboratory
Level 10, Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 112952 0
Australia
Phone 112952 0
+61 3 93427000
Fax 112952 0
Email 112952 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will remain confidential


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.