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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 study, 3+3 design with dose expansion phase.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level A<br>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<br>* Venetoclax is administered as an oral tablet once daily.<br>* Other names: Venclaxta;Drug: Fludarabine<br>* Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.<br>Drug: Cyclophosphamide<br>* 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.<br>|
| Experimental: Dose Level B<br>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<br>* Venetoclax is administered as an oral tablet once daily.<br>* Other names: Venclaxta;Drug: Fludarabine<br>* Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.<br>Drug: Cyclophosphamide<br>* 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.<br>|
| Experimental: Dose Level C<br>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<br>* Venetoclax is administered as an oral tablet once daily.<br>* Other names: Venclaxta;Drug: Fludarabine<br>* Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.<br>Drug: Cyclophosphamide<br>* 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.<br>|
| Experimental: Dose Level B'<br>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<br>* Venetoclax is administered as an oral tablet once daily.<br>* Other names: Venclaxta;Drug: Fludarabine<br>* Fludarabine is administered as an intravenous infusion at a dose of 30mg/m2 daily, to be administered over 30 minutes.<br>Drug: Cyclophosphamide<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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