Fanconi's AnemiaPhase 1NCT00001399
Gene Therapy for the Treatment of Fanconi's Anemia Type C
A Phase 1 study testing Transduced CD34+ Cells in people with Fanconi's Anemia and Pancytopenia, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
Fanconi's Anemia is an inherited disorder that can produce bone marrow failure. In addition, some patients with Fanconi's anemia have physical defects usually involving the skeleton and kidneys. Read more about this study
- Who is it for?
- Ages 5 years and older
- Conditions the study is for
- Fanconi's Anemia, Pancytopenia
- What is being tested?
- Transduced CD34+ Cells
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Dec 1993to 11 Feb 2009
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients must meet the following criteria within 30 days prior to study entry (Day 0) unless otherwise noted.
- Males or females, age greater than or equal to 5 years of age.
- Diagnosis of Fanconi anemia, complementation group C, as confirmed by 1) Diepoxybutane or mitomycin C testing and 2) DNA analysis indicating FACC mutations.
- Adequate baseline organ function as assessed by the following laboratory values within 30 days prior to study entry (day -30 to 0).
- Adequate renal function with estimated creatinine clearance greater than 50 ml/min. (This will be determined by serum creatinine and 24-hour urine creatinine ordered concurrently).
- Adequate liver function with SGOT, SGPT and alkaline phosphatase less than or equal to 5 times the ULN (if transaminases greater than the upper limit of normal (ULN), patients should have a hepatitis B surface antigen (HBsAG) test prior to study entry. Patients may not enter the study if HBsAG is positive).
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- PT and PTT not more than 1.5 times the ULN.
- Serum Amylase less than or equal to 1.5 times the ULN.
- Bilirubin less than or equal to 3.0 mg/dL.
- Triglyceride less than 400 mg/dl.
- Ability to give informed consent.
- Normal cardiac function by history and exam.
- Resting transcutaneous oxygen saturation greater than 90 percent on room air.
- Karnofsky Performance Status greater than or equal to 40.
- Although there are no blood count criteria for inclusion in this study, preference will be given to patients with significant marrow failure as reflected by anemia, neutropenia, and/or thrombocytopenia. Furthermore, we intend to first enroll adults and older children, to the extent possible, before enrolling younger children.
Who cannot join
- Patients who meet any one of the following criteria will be excluded from study entry:
- Patients presenting with acute leukemia or bone marrow aspirate revealing greater than 10 percent blasts.
- Pregnant or lactating females (all patients must practice adequate birth control and females of child-bearing potential must have a negative serum beta-HCG pregnancy test (within Day -7 to Day 0).
- Acute infection: any acute viral, bacterial, or fungal infection which requires specific therapy. Acute therapy must have been completed within 14 days prior to study treatment.
- Hepatitis-B surface antigen positive patients.
- HIV-infected patients.
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- Acute medical problems such as ischemic heart or lung disease that may be considered an unacceptable anesthetic or operative risk.
- No patients with any underlying conditions which would contraindicate therapy with study treatment (or allergies to reagents used in this study).
- Patients less than 25 kg in weight .
- Patients who elect bone marrow transplantation.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Retroviral Mediated Gene Transfer of the Fanconi Anemia Complementation Group C Gene to Hematopoietic Progenitors of Group C Patients
Fanconi's Anemia is an inherited disorder that can produce bone marrow failure. In addition, some patients with Fanconi's anemia have physical defects usually involving the skeleton and kidneys. The major problem for most patients is aplastic anemia, the blood counts for red blood cells, white blood cells, and platelets are low because the bone marrow fails to produce these cells. Some patients with Fanconi's anemia can develop leukemia or cancers of other organs.
Many laboratory studies have suggested that Fanconi's anemia is caused by an inherited defect in the ability of cells to repair DNA. Recently, the gene for one of the four types of Fanconi's anemia, type C, has been identified. It is known that this gene is defective in patients with Fanconi's anemia type C.
Read more
Researchers have conducted laboratory studies that suggest Fanconi's anemia type C may be treatable with gene therapy. Gene therapy works by placing a normal gene into the cells of patients with abnormal genes responsible for Fanconi's anemia type C. After the normal gene is in place, new normal cells can develop and grow. Drugs can be given to these patients kill the remaining abnormal cells. The new cells containing normal genes and will not be harmed by these drugs.
The purpose of this study is to test whether researchers can safely place the normal Fanconi's anemia type C gene into cells of patients with the disease. The gene will be placed into special cells in the bone marrow called stem cells. These stem cells are responsible for producing new red blood cells, white blood cells, and platelets.
Read the detailed description
Fanconi anemia (FA) is a rare genetic disorder characterized by progressive pancytopenia, congenital abnormalities, and predisposition to malignancy. Therapy is currently limited to allogeneic marrow transplantation; patients lacking a suitable donor usually die from aplasia or acute leukemia. Recently, mutation in a novel gene named FACC (Fanconi anemia C-complementing) has been identified as causing one type of FA. FACC mutations, which introduce splicing errors or stop codons, have been identified in 15% of FA patients. We have recently been successful in functional complementation of four FA cell lines using retroviral vectors to transfer a copy of the normal FACC gene. We also analyzed the ability of four viral vectors to functionally correct hematopoietic progenitor cells from a patient bearing a splice donor mutation. As for the lymphoid cell lines, these CD34 enriched cells were extremely sensitive to MMC. After injection of these progenitor cells with viral vectors bearing normal FACC, the progenitors gave rise to increased numbers of colonies both in the absence and presence of up to 5 nM MMC, whereas control cells were completely destroyed by 1 nM MMC. In summary, we have demonstrated that: (1) retroviral vectors can be engineered to transfer a normal FACC gene to FA(C) lymphoid cell lines and primary hematopoietic cells; (2) introduction of a normal FACC gene into CD34+ progenitors markedly enhances their growth in the absence and presence of MMC.
This study is designed to determine whether hematopoietic progenitors transduced with the normal FACC gene can be re-infused safely into FA(C) patients. CD34+ cells obtained from G-CSF mobilized peripheral blood will be transduced ex vivo over a 72 hour period in the presence of IL-3, IL-6, and stem cell factor with the FACC retroviral vector. These transduced cells will be re-infused into FA(C) patients. Patients will be monitored for toxicities as well as evidence of successful gene transfer and expression. The procedure will be repeated up to a total of 4 times with each treatment 2-4 months apart. Theoretically, these rescued stem cells should have a selective growth advantage within the hypoplastic FA marrow environment in vivo.
- Conditions
- Fanconi's Anemia, Pancytopenia
- Being tested
- Transduced CD34+ Cells
- Keywords
- Gene Therapy, Stem Cell Rescue, Bone Marrow Failure, Fanconi Anemia
- Medical subject headings
- Fanconi Anemia, Pancytopenia, Bone Marrow Failure Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transduced CD34+ CellsDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 1999 (estimated)
- Study start3 Dec 1993
- Study completion11 Feb 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Fanconi's AnemiaStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00001399
- Sponsor's protocol ID
- 940033
- Other IDs
- 94-H-0033
- Status last verified
- 11 Feb 2009
- First submitted
- 3 Nov 1999
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Whitney MA, Saito H, Jakobs PM, Gibson RA, Moses RE, Grompe M. A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews. Nat Genet. 1993 Jun;4(2):202-5. doi: 10.1038/ng0693-202.
PubMed 8348157Strathdee CA, Gavish H, Shannon WR, Buchwald M. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature. 1992 Apr 30;356(6372):763-7. doi: 10.1038/356763a0.
PubMed 1574115Strathdee CA, Duncan AM, Buchwald M. Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9. Nat Genet. 1992 Jun;1(3):196-8. doi: 10.1038/ng0692-196.
PubMed 1303234Martinez-Balsalobre E, Guervilly JH, van Asbeck-van der Wijst J, Perez-Oliva AB, Lachaud C. Beyond current treatment of Fanconi Anemia: What do advances in cell and gene-based approaches offer? Blood Rev. 2023 Jul;60:101094. doi: 10.1016/j.blre.2023.101094. Epub 2023 Apr 28.
PubMed 37142543
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Retroviral Mediated Gene Transfer of the Fanconi Anemia Complementation Group C Gene to Hematopoietic Progenitors of Group C Patients
- ClinicalTrials.gov ID
- NCT00001399
- Acronym / sponsor ID
- 940033
- Conditions
- Fanconi's Anemia, Pancytopenia
- Keywords
- Gene Therapy, Stem Cell Rescue, Bone Marrow Failure, Fanconi Anemia
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 3 Dec 1993
- Study completion
- 11 Feb 2009
- First posted
- 4 Nov 1999 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Fanconi's Anemia is an inherited disorder that can produce bone marrow failure. In addition, some patients with Fanconi's anemia have physical defects usually involving the skeleton and kidneys. The major problem for most patients is aplastic anemia, the blood counts for red blood cells, white blood cells, and platelets are low because the bone marrow fails to produce these cells. Some patients with Fanconi's anemia can develop leukemia or cancers of other organs.
Many laboratory studies have suggested that Fanconi's anemia is caused by an inherited defect in the ability of cells to repair DNA. Recently, the gene for one of the four types of Fanconi's anemia, type C, has been identified. It is known that this gene is defective in patients with Fanconi's anemia type C.
Researchers have conducted laboratory studies that suggest Fanconi's anemia type C may be treatable with gene therapy. Gene therapy works by placing a normal gene into the cells of patients with abnormal genes responsible for Fanconi's anemia type C. After the normal gene is in place, new normal cells can develop and grow. Drugs can be given to these patients kill the remaining abnormal cells. The new cells containing normal genes and will not be harmed by these drugs.
The purpose of this study is to test whether researchers can safely place the normal Fanconi's anemia type C gene into cells of patients with the disease. The gene will be placed into special cells in the bone marrow called stem cells. These stem cells are responsible for producing new red blood cells, white blood cells, and platelets.
Detailed description
Fanconi anemia (FA) is a rare genetic disorder characterized by progressive pancytopenia, congenital abnormalities, and predisposition to malignancy. Therapy is currently limited to allogeneic marrow transplantation; patients lacking a suitable donor usually die from aplasia or acute leukemia. Recently, mutation in a novel gene named FACC (Fanconi anemia C-complementing) has been identified as causing one type of FA. FACC mutations, which introduce splicing errors or stop codons, have been identified in 15% of FA patients. We have recently been successful in functional complementation of four FA cell lines using retroviral vectors to transfer a copy of the normal FACC gene. We also analyzed the ability of four viral vectors to functionally correct hematopoietic progenitor cells from a patient bearing a splice donor mutation. As for the lymphoid cell lines, these CD34 enriched cells were extremely sensitive to MMC. After injection of these progenitor cells with viral vectors bearing normal FACC, the progenitors gave rise to increased numbers of colonies both in the absence and presence of up to 5 nM MMC, whereas control cells were completely destroyed by 1 nM MMC. In summary, we have demonstrated that: (1) retroviral vectors can be engineered to transfer a normal FACC gene to FA(C) lymphoid cell lines and primary hematopoietic cells; (2) introduction of a normal FACC gene into CD34+ progenitors markedly enhances their growth in the absence and presence of MMC.
This study is designed to determine whether hematopoietic progenitors transduced with the normal FACC gene can be re-infused safely into FA(C) patients. CD34+ cells obtained from G-CSF mobilized peripheral blood will be transduced ex vivo over a 72 hour period in the presence of IL-3, IL-6, and stem cell factor with the FACC retroviral vector. These transduced cells will be re-infused into FA(C) patients. Patients will be monitored for toxicities as well as evidence of successful gene transfer and expression. The procedure will be repeated up to a total of 4 times with each treatment 2-4 months apart. Theoretically, these rescued stem cells should have a selective growth advantage within the hypoplastic FA marrow environment in vivo.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 5 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (15 listed)
- Patients must meet the following criteria within 30 days prior to study entry (Day 0) unless otherwise noted.
- Males or females, age greater than or equal to 5 years of age.
- Diagnosis of Fanconi anemia, complementation group C, as confirmed by 1) Diepoxybutane or mitomycin C testing and 2) DNA analysis indicating FACC mutations.
- Adequate baseline organ function as assessed by the following laboratory values within 30 days prior to study entry (day -30 to 0).
- Adequate renal function with estimated creatinine clearance greater than 50 ml/min. (This will be determined by serum creatinine and 24-hour urine creatinine ordered concurrently).
Key exclusion criteria (10 listed)
- Patients presenting with acute leukemia or bone marrow aspirate revealing greater than 10 percent blasts.
- Pregnant or lactating females (all patients must practice adequate birth control and females of child-bearing potential must have a negative serum beta-HCG pregnancy test (within Day -7 to Day 0).
- Acute infection: any acute viral, bacterial, or fungal infection which requires specific therapy. Acute therapy must have been completed within 14 days prior to study treatment.
- Hepatitis-B surface antigen positive patients.
- HIV-infected patients.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transduced CD34+ Cells | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 8348157Whitney MA, Saito H, Jakobs PM, Gibson RA, Moses RE, Grompe M. A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews. Nat Genet. 1993 Jun;4(2):202-5. doi: 10.1038/ng0693-202.
- Background: PubMed 1574115Strathdee CA, Gavish H, Shannon WR, Buchwald M. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature. 1992 Apr 30;356(6372):763-7. doi: 10.1038/356763a0.
- Background: PubMed 1303234Strathdee CA, Duncan AM, Buchwald M. Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9. Nat Genet. 1992 Jun;1(3):196-8. doi: 10.1038/ng0692-196.
- Derived from this study: PubMed 37142543Martinez-Balsalobre E, Guervilly JH, van Asbeck-van der Wijst J, Perez-Oliva AB, Lachaud C. Beyond current treatment of Fanconi Anemia: What do advances in cell and gene-based approaches offer? Blood Rev. 2023 Jul;60:101094. doi: 10.1016/j.blre.2023.101094. Epub 2023 Apr 28.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Transduced CD34+ Cells in people with Fanconi's Anemia and Pancytopenia, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00001399, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.