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Leukemia, Myeloid

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Cyclophosphamide

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Fludarabine phosphate

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Alkylating Agents

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Antitubercular Agents

Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -5 Busulfan 1 mg/kg po qid x 2 days Days -4 through -3 Thymoglobulin 2,5 mg/kg po qd x 2 days Days -1 through +30: Mycophenolate mofetil 30 mg/kg/day, maximum 2 g/day, iv or po x 30 days Days -1 through +150: Tacrolimus 0.03 mg/kg/day with further correction by concentration

Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -4 through -3: Busulfan 1 mg/kg po qid x 2 days Day 0: Infusion of unmanipulated graft Day +3 and +4: Cyclophosphamide 50 mg/kg/day iv Days +5 through +35: Mycophenolate mofetil 30 mg/kg/day, maximum 2 g/day, iv or po x 30 days Days +5 through +120: Tacrolimus 0.03 mg/kg/day with further correction by concentration

Unrelated allogeneic stem cell transplantation

Fludarabine monophosphate

Mycophenolate mofetil

Boris V. Afanasyev, Professor

Purpose There is a growing evidence of high efficacy of post-transplantation cyclophocphomide (PTCy)-based GVHD prophylaxis in haploidentical and matched related and unrelated bone marrow transplantation. There is limitted, but growing data on safety and efficacy of this prophylaxis in unrelated and peripheral blood stem cell transplantations. Use of PTCy in chronic myeloproliferative neoplasms and myelodisplatic syndrome is of particular interest. On the one hand, PTCy could reduce the incidence of chronic GVHD and long-term bormidity. On the other hand, there is a concern, that PTCy can increase the incidence of graft failures in this group of patients. Currently published data indicate that low-dose Thymoglobulin-based prophylaxis is the most promissing compatitor in terms of acute and chronic GVHD control. So there is a rationale to randomize Thymoglobulin and PTCy as GVHD prophilaxis. Pre-transplant assesment of moratlity (PAM)-index will be used as the strata for randomization, as it is the paramter that takes into account the most important factors effecting survival. The conditioning regimen and the other two components of GVHD prophylaxis (mycophenolate mofetil and tacrolimus) will be identical in the two arms of the study.

Trial of GVHD Prophylasxis With PTCy or Thymoglobulin in Unrelated SCT

Randomized Trial of GVHD Prophylasxis With Post-transplantation Cyclophocphomide (PTCy) or Thymoglobulin in Unrelated SCT Recepients With Chronic Myeloproliferative Neoplasms and Myelodisplatic Syndrome

Toxicity parameters based on NCI CTCAE 4.03 grades: hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), mucositis (attending physician assessment), hemorrhagic cystitis (attending physician assessment), cardiotoxicity (ECG, echocardiography). Additional toxicity parameters: incidence and severity of veno-occlusive disease, incidence of transplant-associated microangiopathy

St. Petersburg State Pavlov Medical University

Head of adolescent and adult department of oncology, heamatology and transplantation

Leukemia, Myeloid, Acute

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Leukemia, Lymphocytic, Chronic, B-Cell

Graft vs Host Disease

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Chronic Lymphocytic Leukemia

Homologous Wasting Disease

Acute Graft Versus Host Disease

Days -8 through -4: Busulfan 1 mg/kg po qid x 4 days Days -3 through -2: Cyclophosphamide 50mg/kg/day iv x 2 days Or Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -4 through -3: Busulfan 1 mg/kg po qid x 2 days Day 0: Infusion of unmanipulated graft Day +3 and +4: Cyclophosphamide 50 mg/kg/day iv

Days -8 through -4: Busulfan 1 mg/kg po qid x 4 days Days -3 through -2: Cyclophosphamide 50mg/kg/day iv x 2 days Or Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -4 through -3: Busulfan 1 mg/kg po qid x 2 days Day 0: Infusion of unmanipulated graft Day +3 and +4: Cyclophosphamide 50 mg/kg/day iv Days +5 through +35: Mycophenolate mofetil 30 mg/kg/day, maximum 2 g/day, iv or po x 30 days Days +5 through +120: Tacrolimus 0.03 mg/kg/day with further correction by concentration

Days -8 through -4: Busulfan 1 mg/kg po qid x 4 days Days -3 through -2: Cyclophosphamide 50mg/kg/day iv x 2 days Or Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -4 through -3: Busulfan 1 mg/kg po qid x 2 days Day 0: Infusion of unmanipulated graft Day +3 and +4: Cyclophosphamide 50 mg/kg/day iv Days +5 through +35: Mycophenolate mofetil 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days Days +5 through +120: Tacrolimus 0.03 mg/kg/day with further correction by concentration

Allogeneic hematopoietic stem cell transplantation

Boris V Afanasyev, MD, Prof.

This study evaluates the efficacy of high-dose post-transplantation cyclophosphomide as graft-versus-host disease (GVHD) prophylaxis after allogeneic stem cell transplantation in patients with different risk of GVHD. The risk-adapted strategy involves using single-agent cyclophosphomide in recipients of matched bone marrow graft, and combining cyclophosphomide with tacrolimus and mycophenolate mofetil in recipients of matched peripheral blood stem cells and mismatched bone marrow.

Post-transplantation Cyclophosphamide as GVHD Prophylaxis After HSCT

High-dose Post-transplantation Cyclophosphamide as Graft Versus-host Disease Prophylaxis After Allogeneic Hematopoietic Stem Cell Transplantation

Ivan S Moiseev

Vice-director for science of R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation

Leukemia, Biphenotypic, Acute

Acute Leukemia of Ambiguous Lineage

Bendamustine Hydrochloride

10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3 and +4: Bendamustine 140 mg/m2/day iv.

10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3 and +4: Bendamustine 100 mg/m2/day iv

10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3, +4: Bendamustine 70 mg/m2/day iv.

Allogeneic stem cell transplantation

Bendamustine

Several groups have demonstrated very low incidence of acute and chronic graft-versus-host disease (GVHD) with post-transplantation cyclophosphamide (PTCy) in haploidentical, unrelated and related allogeneic stem cell transplantation (SCT). Nonetheless for majority of the grafts, except for 10/10 HLA-matched bone marrow, with this type of prophylaxis require concomitant administration of calcineurin inhibitors±MMF, which delays immune reconstitution and development of graft-versus-leukemia (GVL) effect. So, despite reduction of transplant-related mortality, use of PTCy doesn't lead to the reduction of relapse incidence. This is particularly important for relapsed or refractory acute leukemia patients, where, despite all efforts to intensify conditioning regimens, relapses after SCT occur in more than 50% of patients, and long-term survival rarely exceeds 10-20%. In preclinical model of haploidentical SCT the substitution of post-transplantation cyclophosphamide with bendamustine, led to comparable GVHD control, but significantly augmented GVL effect. To test this hypothesis and improve the outcome of allogeneic SCT in refractory acute leukemia patients we initiated a pilot trial with high-dose post-transplantation bendamustine for GVHD prophylaxis. The selection of doses is based on the previous dose-escalation studies. Additional immunosuppression could be added for mismatched grafts.

GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

Dose-escalation Study of Graft-versus-host Disease Prophylaxis With High-dose Post-transplantation Bendamustine in Patients With Refractory Acute Leukemia

Consultations are ongoing about how IPD initiative fits the local law "About personal data 152-fz".

Engraftment is defined as the first of 3 consecutive days with an ANC\>500 per μl and WBC\>1000 per μl. Platelet engraftment is not mandatory for the endpoint.

Acute Disease

Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days; Days -7 through -6: Bendamustine 130 mg/m2 iv x 2 days; Days -5 through -3: Busulfan 1 mg/kg po qid x 3 days; Days +3 through +4: Cyclophosphamide 50 mg/kg iv x 2 days; Days +5 through +35: Mycophenolate mofetil 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days; Days +5 through +150: Tacrolimus 0.03 mg/kg/day with further correction by concentration

30 mg/m2/day iv x 6 days, days -7 through -2 of HSCT

130 mg/m2 iv x 2 days, Days -7 through -6 of HSCT

1 mg/kg po qid x 3 days, Days -5 through -3

45 mg/kg/day, maximum 3 g/day, iv or po x 30 days, Days +5 through +35

Mycophenolate Mofetil

0.03 mg/kg/day iv or po, Days +5 through +100 with with further correction by concentration. Target concentration 5-15 ng/ml.

Tacrolimus 5Mg Cap

Haploidentical hematopoietic stem cell transplantation irrespective of the conditioning and graft-versus-host disease prophylaxis is associated with high frequency of primary and secondary graft failure. Different technologies of with replete or depleted graft are associated with 10-20% of graft failures. Fludarabine and busulfan conditioning is the most commonly used approach for a variety of disease. Furthermore combination of fludarabine and bendamustine was sufficient to facilitate engraftment in patients with chronic lymphocytic leukemia and lymphomas. The aim of the study is to evaluate whether addition of bendamustine to fladarabine and busulfan conditioning reduces the risk of primary graft failure after haploidentical allograft.

Benadamustine, Fludarabine and Busulfan Conditioning in Recipients of Haploidentical Stem Cell Transplantation (FluBuBe)

Request for sharing data with the study plan for the data will be evaluated under common conditions by Pavlov University Ethical Committee.

Proportion of patients with primary and secondary graft failure defined by the absence of donor chimerism

Toxicity assessment is based on NCI CTC AE 5.0 grades. Veno-occlusive disease incidence and severity assessment is based on EBMT criteria 2016. Transplant-associated microangiopathy incidence assessment is based on Cho et al. criteria. All toxicity measurements will be aggregated as severity scores.

Proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease

Cumulative incidence of patients with acute GVHD II-IV grade

Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria.

Cumulative incidence of patients with mortality without hematological relapse of malignancy

Kaplan-Meier estimate of death from all causes

Kaplan-Meier estimate of death or relapse

Cumulative incidence of patients with relapse

Vice-pdirector for science RM Gorbacheva Institute

Lymphoma, Non-Hodgkin

Lymphoma, T-Cell

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Lymphoma, Large-Cell, Anaplastic

B-cell Lymphoma

Anaplastic Large Cell Lymphoma

Anti-Inflammatory Agents

Antibodies

Antibodies, Monoclonal

Doxorubicin

Liposomal doxorubicin

Prednisone

Vincristine

Immunoglobulins

Brentuximab Vedotin

Carbamide Peroxide

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immunotoxins

Immunoconjugates

Monoclonal antibody SGN-30 monotherapy: SGN-30 12 mg/kg weekly intravenously(IV) over 2 hours once weekly for 3 weeks.

SGN-30 and CHOP chemotherapy: Beginning 1 week after completion of monoclonal antibody SGN-30 monotherapy, SGN-30 12 mg/kg IV over 2 hours on day 1 and CHOP chemotherapy comprising cyclophosphamide IV over 1 hour, doxorubicin hydrochloride IV over 15 minutes, and vincristine IV over 15 minutes on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 6-8 courses.

Doxorubicin hydrochloride

vincristine sulfate

prednisone

12 mg/kg weekly IV over 2 hours once weekly for 3 weeks.

SGN-30

Michelle Fanale, MD

This phase II trial is studying how well giving SGN-30 together with combination chemotherapy works in treating patients with newly diagnosed anaplastic large cell lymphoma. Monoclonal antibodies, such as SGN-30, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving SGN-30 together with combination chemotherapy may kill more cancer cells

PRIMARY OBJECTIVES:

I. Determine the efficacy of monoclonal antibody SGN-30 in combination with cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (CHOP) in patients with newly diagnosed anaplastic large cell lymphoma (ALCL).

II. Determine the safety of combining monoclonal antibody SGN-30 with CHOP chemotherapy.

SECONDARY OBJECTIVES:

I. Determine whether monoclonal antibody SGN-30 can induce apoptosis of ALCL cells in vivo.

II. Determine the response duration in patients treated with this regimen.

III. Correlate response with pretreatment serum CD30 levels.

IV. Determine response to single-agent monoclonal antibody SGN-30.

OUTLINE: This is a multicenter study. Patients are stratified according to anaplastic large cell kinase (ALK) status (positive vs negative).

Monoclonal antibody SGN-30 monotherapy: Patients receive monoclonal antibody SGN-30 IV over 2 hours once weekly for 3 weeks.

Monoclonal antibody SGN-30 and CHOP chemotherapy: Beginning 1 week after completion of monoclonal antibody SGN-30 monotherapy, patients receive monoclonal antibody SGN-30 IV over 2 hours on day 1 and CHOP chemotherapy comprising cyclophosphamide IV over 1 hour, doxorubicin hydrochloride IV over 15 minutes, and vincristine IV over 15 minutes on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 6-8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for at least 5 years.

SGN-30 and Combination Chemotherapy in Treating Patients With Newly Diagnosed Anaplastic Large Cell Lymphoma

A Phase II Study of SGN-30 in Combination With CHOP in Anaplastic Large Cell Lymphoma

Objective response rate (ORR) defined as the proportion of participants experiencing a Complete Response (CR) or Partial Response to a regimen of SGN-3- + CHOP using International Workshop Response Criteria (IWG) for Non-Hodgkin's Lymphomas (NHL). The IWG criteria (Cheson et al 2007) for a CR is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A PR is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed.

National Cancer Institute (NCI)

Monoclonal antibody SGN-30 monotherapy: SGN-30 12 mg/kg weekly intravenously (IV) over 2 hours once weekly for 3 weeks.

SGN-30 and CHOP chemotherapy: Beginning 1 week after completion of monoclonal antibody SGN-30 monotherapy, SGN-30 12 mg/kg IV over 2 hours on day 1 and CHOP chemotherapy comprising cyclophosphamide IV over 1 hour, doxorubicin hydrochloride IV over 15 minutes, and vincristine IV over 15 minutes on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 6-8 courses.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Trial of GVHD Prophylasxis With PTCy or Thymoglobulin in Unrelated SCT	NCT02627573	Leukemia, Chron... Myelodysplastic... Leukemia, Myelo...	Unrelated allog... Busulfan Fludarabine mon... Tacrolimus Mycophenolate m... Cyclophosphamid... Thymoglobulin	18 Years - 75 Years	St. Petersburg State Pavlov Medical University
Post-transplantation Cyclophosphamide as GVHD Prophylaxis After HSCT	NCT02294552	Acute Myeloid L... Acute Lymphoid ... Lymphoma Myelodysplastic... Chronic Lymphoc... Immune System D...	Cyclophosphamid... Busulfan Fludarabine mon... Tacrolimus Mycophenolate m... Allogeneic hema...	18 Years - 65 Years	St. Petersburg State Pavlov Medical University
GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia	NCT02799147	Leukemia, Acute... Acute Myeloid L... Mixed-Lineage A...	Allogeneic stem... Fludarabine mon... Busulfan Bendamustine	18 Years - 60 Years	St. Petersburg State Pavlov Medical University
Benadamustine, Fludarabine and Busulfan Conditioning in Recipients of Haploidentical Stem Cell Transplantation (FluBuBe)	NCT04942730	Leukemia, Acute... Myeloid Leukemi... Biphenotypic Ac... Lymphoblastic L... Myelodysplastic... Myeloproliferat...	Fludarabine Bendamustine Hy... Busulfan Cyclophosphamid... Mycophenolate M... Tacrolimus 5Mg ...	18 Years - 75 Years	St. Petersburg State Pavlov Medical University
SGN-30 and Combination Chemotherapy in Treating Patients With Newly Diagnosed Anaplastic Large Cell Lymphoma	NCT00365274	Anaplastic Larg...	Cyclophosphamid... Doxorubicin hyd... vincristine sul... prednisone SGN-30	18 Years -	National Cancer Institute (NCI)

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