Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Digestive System Diseases

Skin and Connective Tissue Diseases

Neoplasms

Rare Diseases

Syndrome

Anemia

Anemia, Aplastic

Bone Marrow Failure Disorders

Pancytopenia

Disease Susceptibility

Fanconi Syndrome

Fanconi Anemia

Congenital Bone Marrow Failure Syndromes

Shwachman-Diamond Syndrome

Anemia, Diamond-Blackfan

Dyskeratosis Congenita

Hemoglobinuria

Hemoglobinuria, Paroxysmal

Hematologic Diseases

Bone Marrow Diseases

Anemia, Hypoplastic, Congenital

Genetic Diseases, Inborn

DNA Repair-Deficiency Disorders

Metabolic Diseases

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Kidney Diseases

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Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Cytopenia

Hemolysis

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Preleukemia

Myelodysplastic Syndromes

Red-Cell Aplasia, Pure

Congenital Abnormalities

Skin Abnormalities

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Skin Diseases

Skin Diseases, Genetic

Exocrine Pancreatic Insufficiency

Pancreatic Diseases

Gastrointestinal Diseases

Metabolism, Inborn Errors

Lipid Metabolism, Inborn Errors

Lipid Metabolism Disorders

Lipomatosis

Lipomatosis, Multiple Symmetrical

Infant, Newborn, Diseases

Aplastic Anemia

Congenital Aplastic Anemia

Diamond-Blackfan Anemia

Pure Red Cell Aplasia

Multiple Symmetric Lipomatosis

All families with a member who has one of the relevant syndromes.

NCI Family Study Referrals

Neelam Giri, M.D.

Background:

A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders.

Pathogenic variant(s) in IBMFS genes are relevant to carcinogenesis in sporadic cancers.

Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer.

These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer.

Carriers of IBMFS pathogenic variant(s) are at increased risk of cancer.

The prototype disorder is Fanconi's Anemia (FA); other IBMFS will also be studied.

Objectives:

To determine the types and incidence of specific cancers in patients with an IBMFS.

To investigate the relevance of IBMFS pathogenic variant(s) in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers.

To identify risk factors for IBMFS-related cancers in addition to the primary germline pathogenic variant(s).

To determine the risk of cancer in IBMFS carriers.

Eligibility:

North American families with a proband with an IBMFS.

IBMFS suspected by phenotype, confirmed by pathogenic variant(s) in an IBMFS gene, or by clinical diagnostic test.

Fanconi's anemia: birth defects, marrow failure, early onset malignancy; positive chromosome breakage result.

Diamond-Blackfan anemia: pure red cell aplasia; elevated red cell adenosine deaminase.

Dyskeratosis congenita: dysplastic nails, lacey pigmentation, leukoplakia; marrow failure.

Shwachman-Diamond Syndrome: malabsorption; neutropenia.

Amegakaryocytic thrombocytopenia: early onset thrombocytopenia.

Thrombocytopenia absent radii: absent radii; early onset thrombocytopenia.

Severe Congenital Neutropenia: neutropenia, pyogenic infections, bone marrow maturation arrest.

Pearson's Syndrome: malabsorption, neutropenia, marrow failure, metabolic acidosis; ringed sideroblasts.

Other bone marrow failure syndromes: e.g. Revesz Syndrome, WT, IVIC, radio-ulnar synostosis, ataxia-pancytopenia.

First degree relatives of IBMFS-affected subjects as defined here, i.e. siblings (half or full), biologic parents, and children.

Grandparents of IBMFS-affected subjects.

Patients in the general population with sporadic tumors of the types seen in the IBMFS (head and neck, gastrointestinal, and anogenital cancer), with none of the usual risk factors (e.g. smoking, drinking, HPV).

Design:

Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory test, review of medical records, cancer surveillance.

Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS.

Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones....

Study Description:

This is a natural history study involving questionnaires, clinical and research evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance. A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders.

Pathogenic variant(s) in IBMFS genes are relevant to carcinogenesis in sporadic cancers.

This study will determine whether patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer.

These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer.

Carriers of IBMFS gene pathogenic variant(s) are at increased risk of cancer.

The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied.

Objectives:

To determine the types and incidence of specific cancers in patients with an IBMFS.

To investigate the relevance of IBMFS gene pathogenic variants in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers.

To identify risk factors for IBMFS-related cancers in addition to the primary germline pathogenic variant(s).

To determine the risk of cancer in IBMFS carriers.

Endpoints:

Primary Endpoint:

-All cancers, solid tumors, and cancers specific to each type of IBMFS.

Secondary Endpints:

-Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

Cancer in Inherited Bone Marrow Failure Syndromes

Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study

Establish a cohort of families with IBMFS

Compare biology of IBMFS patients with general populations

Identify differences between patients with IBMFS who develop cancer and those who don't

Determine risk of cancer in IBMFS patients with specific gene mutations

National Cancer Institute (NCI)

Immune System Diseases

Leukemia

Anemia, Sickle Cell

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Lymphoma, Non-Hodgkin

Thalassemia

Hematologic Neoplasms

Immunologic Deficiency Syndromes

Hemoglobinopathies

Primary Immunodeficiency Diseases

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Anemia, Hemolytic, Congenital

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Acute Graft Versus Host Disease

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

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

Thrombocytopenia

beta-Thalassemia

Hodgkin Disease

Blood Platelet Disorders

Beta-thalassemia

Hodgkin Lymphoma

Sickle Cell Anemia

Severe Congenital Neutropenia

Matched allogeneic donor stem cells will be processed utilizing α/β CD3+/CD19+ cell depletion with the Prodigy system. Standard pre-conditioning and post-transplant motioning will be given.

donor cells will be collected and subsequently undergo α/β CD3+/CD19+ cell depletion.

alpha beta depletion

Mitchell S Cairo, MD

Lauren Harrison, RN

Lauren Harrison, MSN

Mitchell S Cairo

Children, adolescents, and young adults with malignant and non-malignant conditionsundergoing an allogeneic stem cell transplantation (AlloSCT) will have the stem cells selected utilizing α/β CD3+/CD19+ cell depletion. All other treatment is standard of care.

Patients wiith selected malignant or non-malignant conditions meeting eligibility criteria will be enrolled on this study. Patients will receive one of either full intensity, reduced intensity, or reduced toxicity conditioning appropriate based on disease, disease status, organ function and performance status and will undergo α/β T-cell and CD 19+ B cell depleted alloSCT.

Patients will be following for engraftment, chimerism, immune reconstitution, GVHD and QOL.

AlloSCT for Malignant and Non-malignant Hematologic Diseases Utilizing Alpha/Beta T Cell and CD19+ B Cell Depletion

Allogeneic Stem Cell Transplantation for Malignant and Non-malignant Hematologic Diseases Utilizing Alpha/Beta T Cell and CD19+ B Cell Depletion - NYMC 588

patients will be monitored for any adverse events related to administration of α/β CD3+/CD19+ cell depleted stem cells

patients will have routine chimerism performed to monitoring engraftment of donor cells

patients will be monitored post transplant for signs of acute and chronic GVHD

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cancer in Inherited Bone Marrow Failure Syndromes	NCT00027274	Diamond Blackfa... Dyskeratosis Co... Fanconi Anemia Shwachman Diamo... Inherited Bone ...		-	National Institutes of Health Clinical Center (CC)
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
AlloSCT for Malignant and Non-malignant Hematologic Diseases Utilizing Alpha/Beta T Cell and CD19+ B Cell Depletion	NCT04099966	Acute Leukemia Severe Aplastic... Non-hodgkin Lym... Hodgkin Lymphom... Kostmann Diamond Blackfa... Amegakaryocytic... Sickle Cell Dis... Beta-Thalassemi...	alpha beta depl...	1 Day - 30 Years	New York Medical College
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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