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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)

Hematologic Neoplasms

Blood Platelet Disorders

Disease Attributes

Familial Platelet Disorder With Associated Myeloid Malignancy

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Escalating doses of imatinib to determine the MTD

Collection of blood or marrow only. No treatment.

Imatinib at 100-400 mg PO QD based on arm assignment/dose level

imatinib

Assay sequencing platform to identify pathogenic genetic mutations in DNA and RNA

TruSight Oncology

Rebecca Alexander

Lea C Cunningham, M.D.

National Cancer Institute Referral Office

Background:

Runt-related transcription factor 1 (RUNX1) gene regulates the formation of blood cells. People with mutations of this gene may bleed or bruise easily; they are also at higher risk of getting cancers of the blood, bone marrow, and lymph nodes.

Objective:

To test a drug (imatinib) in people with RUNX1 mutations that cause symptoms.

Eligibility:

Adults aged 18 and older with RUNX1 mutations. Healthy people without this mutation, including family members of affected participants, are also needed.

Design:

Participants with the RUNX1 mutation will be screened. They will have a physical exam with blood and urine tests. They will have a test of their heart function. They may need a new bone marrow biopsy: A sample of soft tissue will be removed from inside a bone.

Imatinib is a tablet taken by mouth once a day, every day, at home. Affected participants in different parts of the study will take imatinib for either 28 days or up to 84 days.

Participants will visit the clinic once a week for the first 28 days that they are taking the imatinib. Then they will come once every 2 weeks if they are taking the drug for 84 days. Blood, urine, and tests of heart function will be repeated. They may opt to have the bone marrow biopsy repeated after they finish their course of imatinib.

Participants will have a follow-up visit 30 days after they stop taking imatinib.

Participants who do not have the RUNX1 mutation will have 1 clinic visit. They will have blood tests. They will fill out questionnaires. They may opt to have a bone marrow biopsy....

Background:

* Runt-related transcription factor 1 (RUNX1) gene is located on chromosome 21 and encodes an important regulator of hematopoiesis. People normally inherit one functional copy from each parent.
* RUNX1 function is highly dose dependent as both too little as well as too much RUNX1 activity is associated with development of hematologic malignancy. The focus of this protocol is participants with germline RUNX1 mutations resulting in too little RUNX1 activity.
* Germline heterozygous RUNX1 mutations are inherited in an autosomal dominant manner and cause a disorder called Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM). Patients with one deleterious germline RUNX1 mutation often have haploinsufficiency although some mutations are associated with a dominant negative effect.
* Clinically, patients with germline RUNX1 mutations have aberrant megakaryocytic development, which often results in quantitative and/or qualitative platelet defects. Patients often have easy bleeding or bruising, although some cases are subclinical, and they may present to clinicians with hematologic malignancy.
* Patients with germline RUNX1 mutations have 35-45% lifetime risk of developing myeloid hematologic malignancies including MDS and AML. Increased risk of B-ALL, T-ALL and other hematologic malignancies is also associated with deleterious germline RUNX1 mutations.
* Deleterious RUNX1 mutations are known to be associated with high-risk malignancy with poor response to upfront chemotherapy and require hematopoietic stem cell transplantation (HSCT).
* Imatinib is a dual SFK and ABL inhibitor that is FDA approved and indicated for treatment of CML, ALL, MDS/MPD, aggressive systemic mastocytosis (ASM) as well as hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL).
* ABL physically associates with RUNX1, phosphorylates key tyrosines within the RUNX1 inhibitory domain and negatively regulates RUNX1 transcriptional activity.
* We hypothesize that imatinib will decrease RUNX1 tyrosine phosphorylation thereby increasing RUNX1 protein activity to a level closer to that expected for 2 normal copies of RUNX1. We also hypothesize that normal levels of RUNX1 protein activity will ameliorate platelet dysfunction and bleeding symptoms via objective measures.
* We expect this study to inform the biologically relevant endpoints for a subsequent phase II efficacy study, which would also seek to determine if longer term imatinib administration could prevent malignant transformation.

Objectives:

* To determine the dose of imatinib for dose expansion in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose escalation phase
* To determine the safety of imatinib in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose expansion phase

Eligibility:

* Age \>=18 years
* Participants with deleterious germline RUNX1 mutations as defined by ClinGen with adequate organ function and no history of hematologic malignancy.

Design:

* This is a phase Ib study with 2 cohorts (participants with and without pathogenic or likely pathogenic RUNX1 mutations) and 3 arms (2 for imatinib administration and 1 for biobanking control).
* A standard 3+3 non-randomized dose-escalation design will be used in the first arm, with orally administered imatinib tested at 4 dose levels from 100 to 400 mg daily for 28 days for participants with pathogenic or likely pathogenic germline RUNX1 mutations.
* Participants will have PK/PD evaluations at all dose levels.
* An expansion cohort will be treated at the maximum tolerated dose (MTD) in Arm 2, daily for 12 weeks. Participants who are treated on the dose escalation phase may also be treated in the expansion phase after an appropriate wash out period of 28 days.
* The third arm is for unaffected family control participants with wildtype RUNX1 or healthy volunteers who may choose to enroll to donate blood or marrow but will not be treated.
* 12-24 participants will be enrolled for dose escalation, 12 participants in the expansion cohort, and up to 80 unaffected controls contemporaneously whenever feasible.

Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

Phase Ib Study of Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.@@@@@@

Safety will be evaluated by the number of DLTs identified at each dose level. The number of DLTs at each dose level will be reported and used to determine the RP2D.

Safety will be evaluated by the number of DLTs identified at each dose level.

AEs are reported by type and grade, and frequency.

Change in measurement; assessed for statistical significance by an appropriate paired test.

Change in measurement of drug levels in blood; assessed for statistical significance by an appropriate paired test.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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)
Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency	NCT06090669	Inherited Bone ... Familial Platel...	imatinib TruSight Oncolo...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for ibmfs

Every month we try and update this database with for ibmfs cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for ibmfs

Every month we try and update this database with for ibmfs cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for ibmfs cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.