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

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.

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.

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.