Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Hematologic Neoplasms

Graft vs Host Disease

Hematologic Diseases

Homologous Wasting Disease

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Dermatologic Agents

Reproductive Control Agents

Anti-Infective Agents

Micronutrients

Hematinics

Vitamins

Cyclophosphamide

Methotrexate

Cyclosporine

Cyclosporins

Lenograstim

Mycophenolic Acid

Mesna

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Immunologic Factors

Folinic Acid

Folate

Vitamin B9

GVHD prophylaxis will consist of high-dose PTCy (50 mg/kg i.v. on days +3 and +4) with mesna, cyclosporine (initiated on day +5) and methotrexate i.v (see doses on the right). Cyclosporine will be dosed with a target trough of 200 to 250 ng/mL and discontinued without taper at D+60 (if bone marrow graft) or until D+90 (is peripheral blood graft), unless acute GVHD is present. Filgrastim will be administered from day +5 until neutrophil recovery to ≥ 1,000/mcL for 3 days.

GVHD prophylaxis will consist of high-dose PTCy (50 mg/kg i.v. on days +3 and +4) with mesna, cyclosporine (initiated on day +5) and mycophenolate mofetil (15 mg/kg/dose p.o. t.i.d. initiated on day +5). Cyclosporine will be dosed with a target trough of 200 to 250 ng/mL and discontinued without taper at D+60 (if bone marrow graft) or until D+90 (is peripheral blood graft), unless acute GVHD is present.

Phase 1:

* Level -1: Methotrexate 7.5 mg/m2 on D+6 and D+9\*. Level -1 will be explored only if the starting dose is too toxic (reduced dose).
* Level 0 \[Starting Dose\]: Methotrexate 10 mg/m2 on D+6 and 7.5 mg/m2 on D+9
* Level +1: Methotrexate 10 mg/m2 on D+6 and D+9
* Level +2: Methotrexate 15 mg/m2 on D+6 and 10 mg/m2 on D+9

Phase 2: dose determined in the phase 1 trial

Methotrexate Injectable Solution

Giancarlo Fatobene, MD

Maria Claudia R Moreira, MD

Afonso Vigorito, MD, PhD

Iago Colturato, MD

Bruna Carvalho

Vanderson Rocha, MD, PhD

Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic strategy for many malignant and benign hematologic diseases. Haploidentical HCT has been increasingly used in patients lacking a HLA-matched donor due to its prompt availability, possibly lower cost and results comparable with other donor types. Graft-versus-host disease (GVHD) is the main cause of morbidity and mortality after HSCT, and prophylactic strategies are routinely used. In the context of haploidentical HCT, posttransplant cyclophosphamide plus cyclosporine and mycophenolate mofetil (MMF) is the most common platform used in Brazil. Data comparing MMF and methotrexate (MTX) as GVHD prophylaxes have proved controversial in other donor types, yet some large studies have showed that MTX is associated with lower risk of GVHD and improved long-term outcomes. Moreover, it is known that MMF is a potent inhibitor of natural killer (NK) cells, possibly interfering with the graft-versus-leukemia effect in haploidentical HCT. Given the possible advantages and the absence of consistent evidence regarding safety, efficacy and ideal dosage of MTX as GVHD prophylaxis in this setting, we propose a phase I / II study evaluating this drug in adult patients with hematologic malignancies undergoing haploidentical HCT with posttransplant cyclophosphamide.

Phase I / II multicenter open-label clinical trial with prospective nonrandomized arm and historical control group

GVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide

GVHD Prophylaxis With Methotrexate and Cyclosporine in Haploidentical Stem Cell Transplantation Using Posttransplant Cyclophosphamide in Hematologic Malignancies: Phase I/II Trial

The methotrexate dose to be used in the subsequent phase 2 will be equal to or lower than the maximum tolerated dose (MTD). MTD will be considered exceeded if at least 2 out of 6 subjects on a certain dosing level develop dose-limiting toxicity (DLT). DLT consists of gastrointestinal tract perforation, mediastinitis, airway obstruction requiring orotracheal intubation, severe gastrointestinal bleeding (without evidence of GVHD), graft failure, or hyperbilirubinemia or increase in alanine transaminase \[ALT\] / aspartate transaminase \[AST\] levels \> 5x the upper limit of normal.

Relapse, grade 3-4 GVHD and 2014 NIH Chronic GVHD will be considered events, and non-relapse related mortality will be a competing event.

Neutrophil engraftment will be the first of three consecutive daily absolute neutrophil counts \> 500 / mcL after transplantation. Disease relapse will be a competitive event. Platelet engraftment will be considered as the first of seven daily consecutive platelet counts \> 20,000 / mcL without transfusion support. Disease relapse will be a competitive event.

Time to primary or secondary graft failure. Primary graft failure will be defined as failure to reach neutrophils \> 500 / mcL for three consecutive days or donor chimerism \<5% in any hematopoietic compartment (lymphocyte chimerism or total bone marrow / peripheral blood chimerism) and requiring additional hematopoietic cells. Secondary graft failure will be defined as the need for additional hematopoietic cells due to declining hematopoietic recovery in a patient with previous neutrophil engraftment.

Time to onset of grade II-IV acute GVHD according to the MAGIC criteria. Death without previous acute GVHD will be a competing event.

Time to onset of grade III-IV acute GVHD according to the MAGIC criteria. Death without previous acute GVHD will be a competing event.

Time to onset of disease relapse or progression (imaging, morphologic or molecular). Non-relapse related mortality will be a competing event.

Time to onset of 2014 NIH Chronic GVHD. Non-relapse related mortality will be a competing event.

Change in mean subscale response of the SF-36 Survey version 2.0 (Physical functioning, Role limitations due to physical health, Role limitations due to emotional problems, Energy/fatigue, Emotional well-being, Social

Change in mean subscale response of the FACT-BMT survey

Adverse events will be classified according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), Version 5.0

Libbs Farmacêutica LTDA

University of Sao Paulo General Hospital

Head and Neck Neoplasms

Pembrolizumab

Cisplatin

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Pembrolizumab 200 mg q3w i.v. until disease progression or non-tolerable toxicity (maximum 2 years)

Arm B: Methotrexate (MTX) 40 mg/m2 weekly i.v. until disease progression or non-tolerable toxicity (maximum 2 years)

Pembrolizumab Injection

Methotrexate 40 mg/m2 weekly i.v. until disease progression or non-tolerable toxicity (maximum 2 years)

The study is designed as an open-label, randomized, prospective, multicenter, phase II study comparing pembrolizumab with methotrexate in elderly, frail or cisplatin-ineligible patients with squamous carcinoma of the head and neck (HNSCC)

Patients recieve pembrolizumab or methotrexate

Study Comparing Pembrolizumab With Methotrexate in Elderly, Frail or Cisplatin-ineligible Patients With Head and Neck Cancers

A Randomized Phase II Study Comparing Pembrolizumab With Methotrexate in Elderly, Frail or Cisplatin-ineligible Patients With Head and Neck Cancers

objective response rate (ORR) according to RECIST 1.1

molecular-genetic pro-inflammatory markers

defined as death, progressive disease (PD), treatment discontinuation ( or deterioration of Instrumental Activities of Daily Living (IADL score) by 2 points.

Objective response rate (ORR) according to RECIST 1.1

Adverse event rates due to treatment with MTX and pembrolizumab in SCCHN measured according to CTCAE 4.03

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
GVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide	NCT04622956	Graft Vs Host D... Hematopoietic N...	Methotrexate In...	18 Years - 70 Years	University of Sao Paulo General Hospital
Study Comparing Pembrolizumab With Methotrexate in Elderly, Frail or Cisplatin-ineligible Patients With Head and Neck Cancers	NCT03193931	Cancer of Head ...	Pembrolizumab I... Methotrexate In...	18 Years -	AIO-Studien-gGmbH

Spots Global Cancer Trial Database for methotrexate injectable solution