Symptoms and General Pathology

All Conditions

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Red-Cell Aplasia, Pure

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Acute Graft Versus Host Disease

Congenital Aplastic Anemia

Diamond-Blackfan Anemia

Pure Red Cell Aplasia

Rimiducid: to treat uncontrolled GVHD in patients who have received rivogenlecleucel Rimiducid will be given at 0.4 mg/kg weight (intravenous infusion)

No further rivogenlecleucel infusions are planned. Patients who received rivogenlecleucel in the BP-004 study will be evaluated for long-term safety and efficacy.

Rimiducid is administered to treat chronic graft versus host disease

Rimiducid

donor T-cells modified with iCasp safety switch

rivogenlecleucel

Bellicum Pharmaceuticals

This is a long-term follow up study evaluating the safety of BPX-501 T cells (rivogenlecleucel) and infused in pediatric patients previously enrolled on the BP-004 study.

Subjects enrolled on the BP-004 study who have completed or discontinued from the study, and are beyond Day 180 will be requested to enroll on this long-term follow up protocol. Long term follow up for gene therapy clinical and safety endpoints will continue up to 15 years.

Long Term Follow-up Study for Patients Enrolled on the BP-004 Clinical Study

Follow-up of Phase 1/2 Study of CaspaCIDe T Cells (BPX-501) From an HLA-partially Matched Family Donor After Negative Selection of TCR αβ+T Cells in Pediatric Patients Affected by Hematological Disorders

Overall survival (OS) in both malignant and non-malignant subpopulations at 1 and 2 years in the Intent-to-Treat (ITT) Population

KM Parameter Estimates of disease-free survival (DFS) in the non-malignant subpopulation at 1 and 2 years in the Intent-to-Treat (ITT) Population

Kaplan-Meier Parameter Estimates of Relapse-free survival rate (number of patients survived without experiencing a recurrence) at the 1-year and 2-year timepoints in the Intent-to-Treat (ITT) Population in the malignant study arm (patients with a malignant reason for their transplant).

ITT Population: Includes all patients treated with HSCT who received rivogenlecleucel at the dose of 1×10E6 cells/kg

All patients who received HSCT and went on to receive any dose of rivogenlecleucel.

Rivogenlecleucel (BPX-501) Safety Population

All patients who received at least 1 dose of rimiducid for the treatment of acute or chronic GvHD refractory to SoC treatment after rivogenlecleucel administration.

Rimiducid Safety Population

Rimiducid and Rivogenlecleucel

Subject eligibility criteria: patients less than or equal to 18 years of age and greater than or equal to 1 month of age.

Age, Continuous

< 2 years

2 to < 12 years

12 to ≤ 18 years

18 to ≤ 26 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

HSCT safety population: All enrolled patients who received hematopoietic stem cell transplantation

Rivogenlecleucel Study Team

1 Year

2 Years

Malignant

Non-malignant

ITT Population: Includes all patients treated with HSCT who received rivogenlecleucel at the dose of 1×10E6 cells/kg

Study BP-404 is the long-term follow-up study of patients of the BP-004 study who were enrolled at the Italian and Saudi Arabia sites. There is a second long-term follow-up study (BP-004 UK) for patients enrolled at the UK sites. The below results include data from both the BP-404 study and the BP-004 UK study. Individual results for either study are not available.

Overall Survival

Incidence of Disease-free Survival

Relapse-free Survival

Overall Study

Musculoskeletal Diseases

Skin and Connective Tissue Diseases

Osteopetrosis

Osteosclerosis

Osteochondrodysplasias

Mucopolysaccharidosis IV

Bone Diseases

Bone Diseases, Developmental

Mucopolysaccharidosis Type IV

Hematinics

All Drugs and Chemicals

Liver Extracts

TCR alpha beta depleted graft infusion with addback of BPX-501 T cells (rivogenlecleucel).

Rimiducid/AP1903: Dimerizer drug administered to subjects who develop Grade III-IV acute GVHD, Grade II gut/liver acute GVDH or Grade I/II skin-only acute GvHD which is non-responsive after 7 days of standard of care treatment

BPX-501 T cells

This study will evaluate pediatric patients with malignant or non-malignant blood cell disorders who are having a blood stem cell transplant depleted of T cell receptor (TCR) alfa and beta cells that comes from a partially matched family donor. The study will assess whether immune cells, called T cells, from the family donor, that are specially grown in the laboratory and given back to the patient along with the stem cell transplant can help the immune system recover faster after transplant. As a safety measure these T cells have been programmed with a self-destruct switch so that they can be destroyed if they start to react against tissues (Graft versus host disease).

This is a Phase I/II study evaluating the safety and feasibility of BPX-501 T cells infused after partially mismatched, related, TCR alpha beta T cell depleted hematopoietic stem cell transplant (HSCT) in pediatric patients. The purpose of this clinical trial is to determine whether BPX-501 infusion can enhance immune reconstitution in those patients with hematologic disorders, with the potential for reducing the severity and duration severe acute graft versus host disease (GvHD).

The trial will also evaluate the treatment of GvHD by the infusion of dimerizer drug (AP1903/rimiducid) in those subjects who present with GVHD who progress or do not respond to standard of care treatment.

Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant

Phase I/II Study of CaspaCIDe T Cells (BPX-501; Rivogenlecleucel) From an HLA Partially Matched Family Donor After Negative Selection of TCRαβ+ T Cells in Paediatric Patients Affected by Haematological Disorders

Events included transplant-related mortality (TRM) / non-relapse mortality (NRM), severe GvHD (acute Grades 2-4 organ or extensive chronic GvHD) and life-threatening infections (Grade 4). Time to the first event only is represented in the primary endpoint, if a subsequent event occurred in the same patient this was not captured in this outcome.

There were no protocol-specified primary endpoints for Phase I of the study.

Analysis of All Cause Mortality was performed with the HSCT Safety Population (all patients who received a HSCT).

Analysis of safety, regardless of study treatment and in relation to BPX-501, was conducted with the BPX-501 Safety Population (patients who received HSCT and subsequently received any dose of BPX-501) Analysis of safety in relation to rimiducid treatment was performed with the Rimiducid Population, (patients who received at least 1 dose of rimiducid)

BPX-501 (rivogenlecleucel): TCR alpha beta depleted graft infusion with addback of BPX-501 T cells

BPX-501 T cells: 1x10E6 cells/kg infused on Day 0

BPX-501

Rimiducid/AP1903: Dimerizer drug administered to subjects who develop Grade III-IV acute GVHD, Grade II gut/liver acute GVDH or Grade I/II skin-only acute GvHD which is non-responsive after 7 days of standard of care treatment

Rimiducid: 0.4mg/kg administered IV to treat GVHD

TCR alpha beta depleted graft infusion with addback of BPX-501 T cells (rivogenlecleucel).

Rimiducid/AP1903: Dimerizer drug administered to subjects who develop Grade III-IV acute GVHD, Grade II gut/liver acute GVDH or Grade I/II skin-only acute GvHD which is non-responsive after 7 days of standard of care treatment

BPX-501 T cells: 1x10E6 cells/kg infused on Day 0

Rimiducid: 0.4mg/kg administered IV to treat GVHD

BPX-501 T Cells and Rimiducid

One patient was enrolled under a protocol version for which the inclusion criterion was \<= 21 years and ≥ 3 months. The age range was revised in a subsequent protocol to \< 18 years and ≥ 1 month (\< 1 month upon approval by Sponsor).

All enrolled patients iwho received HSCT (HSCT safety population)

ITT population: All patients treated with HSCT who received 1×10\^6 cells/kg BPX-501

Event-free Survival (EFS) at 180 Days After Transplant

Infections

Communicable Diseases

Epstein-Barr Virus Infections

Virus Diseases

Anti-Arrhythmia Agents

Channel Blockers

Analgesics

Anticonvulsants

Central Nervous System Depressants

Reproductive Control Agents

Bone Density Conservation Agents

Magnesium Sulfate

Anesthetics

Calcium

Calcium Channel Blockers

Calcium, Dietary

Hormones

Tocolytic Agents

In phase 1, participants received oral magnesium L-threonate for 12 weeks then crossover to placebo for 12 weeks, followed by a 2-week washout period. In phase 2, all participants received 3 days of intravenous MgSO4 in 3 daily doses totaling 30 mg/kg/day followed by oral magnesium L-threonate for 24 weeks.

In phase 1, participants received oral placebo for 12 weeks then crossover to oral magnesium L-threonate for 12 weeks, followed by a 2-week washout period. In phase 2, all participants received 3 days of intravenous MgSO4 in 3 daily doses totaling 30 mg/kg/day followed by oral magnesium L-threonate for 24 weeks.

In Part I, participants will receive 12 weeks of oral magnesium L-threonate; will be dose escalated based on weight.

In Part 2, participants will receive 24 weeks of oral magnesium L-threonate; will be dose escalated based on weight.

Magnesium L-threonate

In Part I, participants will receive 12 weeks of oral placebo; will be dose escalated based on weight.

Placebo

In Part II, participants will be hospitalized to receive 3 days of IV magnesium sulfate (MgS04).

Intravenous (IV) magnesium sulfate (MgSO4)

Juan C Ravell Aumaitre, M.D.

Background:

- X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia syndrome is called XMEN syndrome. In this genetic condition, the cells have less magnesium than normal. This makes it hard for the body to fight infections. Researchers want to see if magnesium supplements can make it easier for the body to fight infection.

Objective:

- To see if magnesium supplements can strengthen the immune system and reduce the amount of Epstein-Barr virus in people with XMEN syndrome.

Eligibility:

- People ages 6 and older who have XMEN syndrome

Design:

* Participants will be screened with:
* Medical history
* Physical exam
* CT scan: Participants will drink a contrast and may get dye through an IV in the arm. They will lie in a machine that takes pictures of the body.
* EKG: Small sticky patches on the body will trace heart rhythm.
* Blood tests
* The study has 2 parts.
* Participants doing both parts will participate for 1 year and visit the clinic about 15 times. These visits will include a physical exam and blood and urine tests.
* Participants doing only the first part finish in 6 months and have fewer visits.
* For study part 1, participants will take magnesium pills for 3 months and placebo pills for another 3 months.
* At 3 and 6 months, they will have physical exam, medical history, blood and urine tests, and an EKG.
* If the magnesium pills are not helpful, participants will do study part 2.
* They will be admitted to the hospital for 4 5 days to get magnesium for 3 days through an arm vein.
* They will take magnesium pills for another 6 months.

X-linked immunodeficiency magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) syndrome is a primary immunodeficiency caused by the loss of expression of the magnesium transporter 1 (MAGT1). This syndrome is associated with cluster of differentiation 4 (CD4) lymphopenia, chronic EBV infection in most patients, and EBV-related lymphoproliferative disorders. The loss of MAGT1 leads to impaired T cell activation and decreased expression of the activator receptor, NKG2D on natural killer (NK) cells and CD8 T cells, leading to decreased EBV-specific cytolytic function of these cells. Results of previous studies suggest that magnesium supplementation may be a viable therapeutic option for patients with XMEN.

The proposed study has 2 parts, and patients will be divided into 2 cohorts. Patients in cohort 1 (high EBV group) will have baseline blood EBV viral load greater than or equal to 5,000 copies/mL or EBV log greater than or equal to 3.7 IU/mL. Patients in cohort 2 (low/no EBV group) will have baseline blood EBV viral load \<5,000 copies/mL or EBV log \<3.7 IU/mL. Part I is a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of oral magnesium L-threonate in patients with XMEN syndrome. Within each cohort, patients will be randomized to receive escalating doses of either placebo or oral magnesium L-threonate for 12 weeks. Patients will then receive the crossover treatment (magnesium or placebo) for an additional 12 weeks. For patients who experience a 0.5-log decrease in the number of EBV-infected B cells (cohort 1) or a greater than or equal to 2-fold increase in NKG2D receptor expression on cluster of differentiation 8 (CD8+) T cells (cohort 2) with oral magnesium as compared to placebo, the study will be complete. Patients who do not meet this efficacy outcome will undergo a 2-week washout period and proceed to Part II, an open-label, non-randomized evaluation of intravenous magnesium sulfate (MgSO4) followed by oral magnesium L-threonate. These patients will be hospitalized to receive 3 days of intravenous MgSO4 in 3 daily doses totaling 30 mg/kg/day. They will then restart escalating doses of oral magnesium L-threonate and continue for the remaining 24 weeks of Part II. If conducted, Part II will allow for secondary analyses to compare different durations of magnesium supplementation.

Magnesium Supplementation in People With XMEN Syndrome

A Double-blind, Placebo-controlled, Crossover Study of Magnesium Supplementation in Patients With XMEN Syndrome

Participants with a ≥ 0.5 log decrease in the absolute number of Epstein-Barr virus (EBV) infected B-cells by flow cytometric Fluorescence in situ hybridization (FISH) assay after 12 weeks of oral magnesium supplementation compared to 12 weeks of placebo.

Participants with difference of a 2-fold or greater increase in NKG2D expression in cluster of differentiation 8 (CD8+) T cells after 12 weeks of oral magnesium supplementation versus 12 weeks of placebo.

Participants with a ≥ 0.5 log decrease in the absolute number of Epstein-Barr virus (EBV) infected B-cells by flow cytometric Fluorescence in situ hybridization (FISH) assay before and after 24 weeks of magnesium supplementation

Participants with a 2-fold or greater increase in NKG2D expression in CD8+ T cells before and after magnesium supplementation for 24 weeks in phase 2 of study

Participants with adverse events by grade using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4) grading criteria.

* Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated
* Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL)
* Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL
* Grade 4 Life-threatening consequences; urgent intervention indicated
* Grade 5 Death related to adverse event (AE)

Participants with severe adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4) to evaluate severity.

National Institute of Allergy and Infectious Diseases (NIAID)

In phase 1, participants received oral magnesium L-threonate for 12 weeks

Phase 1 - Oral Magnesium

Participants received oral placebo for 12 weeks

Phase 1 - Placebo

In phase 2, participants received 3 days of intravenous MgSO4 in 3 daily doses totaling 30 mg/kg/day

Phase 2 - IV MgSO4

In phase 2, participants received oral magnesium L-threonate for 24 weeks

Phase 2 - Oral Magnesium

Magnesium, Then Placebo

Placebo, Then Magnesium

Total

Age, Categorical

Ravell Aumaitre, Juan

Participants received oral magnesium L-threonate for 12 weeks

Magnesium

The analyses included only EBV positive subject who completed Phase 1 of the study. In this phase, two participants were EBV positive, but only one participant completed Phase 1.

Participants With a ≥0.5 Log Reduction in the Number of EBV-infected B Cells After Magnesium Supplementation as Compared to Placebo - Phase 1

The analyses included only EBV negative subjects who completed phase 1 of the study, which is the crossover phase.

Participants With 2-fold or Greater Increase in NKG2D Expression in CD8 T+ Cells After Magnesium Supplementation as Compared to Placebo - Phase 1

In phase 2, participants received 3 days of intravenous MgSO4 daily at 30 mg/kg/day followed by oral magnesium L-threonate for 24 weeks.

Analysis included all EBV positive participants who completed phase 2 of study

Participants With a Decrease in the Absolute Number of EBV Infected B Cells Before and After Magnesium Supplementation - Phase 2

Analysis included all participants who completed phase 2 of study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Long Term Follow-up Study for Patients Enrolled on the BP-004 Clinical Study	NCT03733249	Acute Lymphobla... Leukemia, Acute... Lymphoma, Non-H... Myelodysplastic... Primary Immunod... Anemia, Aplasti... Hemoglobinopath... Cytopenia Fanconi Anemia Diamond Blackfa... Thalassemia Anemia, Sickle ...	Rimiducid rivogenlecleuce...	1 Month - 18 Years	Bellicum Pharmaceuticals
Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant	NCT02065869	Acute Lymphobla... Leukemia, Acute... Lymphoma, Non-H... Myelodysplastic... Primary Immunod... Anemia, Aplasti... Osteopetrosis Hemoglobinopath... Cytopenia Fanconi Anemia Diamond Blackfa... Thalassemia Anemia, Sickle ...	BPX-501 T cells Rimiducid	1 Month - 18 Years	Bellicum Pharmaceuticals
Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant	NCT02065869	Acute Lymphobla... Leukemia, Acute... Lymphoma, Non-H... Myelodysplastic... Primary Immunod... Anemia, Aplasti... Osteopetrosis Hemoglobinopath... Cytopenia Fanconi Anemia Diamond Blackfa... Thalassemia Anemia, Sickle ...	BPX-501 T cells Rimiducid	1 Month - 18 Years	Bellicum Pharmaceuticals
Long Term Follow-up Study for Patients Enrolled on the BP-004 Clinical Study	NCT03733249	Acute Lymphobla... Leukemia, Acute... Lymphoma, Non-H... Myelodysplastic... Primary Immunod... Anemia, Aplasti... Hemoglobinopath... Cytopenia Fanconi Anemia Diamond Blackfa... Thalassemia Anemia, Sickle ...	Rimiducid rivogenlecleuce...	1 Month - 18 Years	Bellicum Pharmaceuticals
Magnesium Supplementation in People With XMEN Syndrome	NCT02496676	XMEN	Magnesium L-thr... Placebo Intravenous (IV...	6 Years -	National Institutes of Health Clinical Center (CC)
Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant	NCT02065869	Acute Lymphobla... Leukemia, Acute... Lymphoma, Non-H... Myelodysplastic... Primary Immunod... Anemia, Aplasti... Osteopetrosis Hemoglobinopath... Cytopenia Fanconi Anemia Diamond Blackfa... Thalassemia Anemia, Sickle ...	BPX-501 T cells Rimiducid	1 Month - 18 Years	Bellicum Pharmaceuticals

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