A clinical trial using cell transplantation as treatment for bone marrow failure due to dyskeratosis congenita / telomere disease, inherited genetic conditions.

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2018-001489-41-SE
• Date of registration: 08/05/2018
• Prospective Registration: Yes
• Primary sponsor: Karolinska Universitetssjukhuset
• Public title: A clinical trial using cell transplantation as treatment for bone marrow failure due to dyskeratosis congenita / telomere disease, inherited genetic conditions.
• Scientific title: Radiation- and alkylator-free hematopoietic cell transplantation for bone marrow failure due to dyskeratosis congenita / telomere disease
• Date of first enrolment: 02/07/2018
• Target sample size: 40
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001489-41
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Sweden, United States

Contacts

• Name: Mikael Sundin
• Affiliation: Karolinska Universitetssjukhuset

• Name: Mikael Sundin
• Affiliation: Karolinska Universitetssjukhuset

Key inclusion & exclusion criteria

Inclusion criteria:
1. Patients 30 days to 65 years of age at the time of inclusion with a diagnosis of severe aplastic anemia or single lineage cytopenia, defined as follows:
- Bone marrow hypocellular for age on biopsy based on review at the enrolling institution within 90 days of protocol inclusion
AND
- One or more of the following (in peripheral blood):
-neutrophils < 0.5 x 109/L
-platelets < 30 x 109/L, or platelet transfusion dependence*
-reticulocytes < 50 x 109/L in anemic patients, or red cell transfusion dependence*
*transfusion dependence will be defined as greater than ONE transfusion of platelets or red blood cells in the last year prior to protocol inclusion
AND

2. Diagnosis with one of the following DC categories on any prior evaluation:
A. age-adjusted mean telomere length < 1%ile in peripheral blood lymphocytes by flow-FISH on any occasion, as reported by a CLIA-approved laboratory
B. pathogenic mutation(s) in DKC1,TERC, TERT, NOP10, NHP2, TCAB1, TINF2, CTC1, RTEL1, ACD, or PARN as reported by a CLIA-approved laboratory
C. Dyskeratosis congenita diagnosed by:
1. clinical triad: abnormalities of skin pigmentation, nail dystrophy, oral leukoplakia
OR
2. one of clinical triad and presence of two or more associated features:
epiphora, developmental delay, mental retardation, pulmonary disease, short stature, dental caries/loss, esophageal stricture, grey hair, hyperhidrosis, malignancy, intrauterine growth retardation (IUGR), liver disease, enteropathy, ataxia/cerebellar hypoplasia, hypogonadism, microcephaly, urethral stricture, osteoporosis/AVN, scoliosis, deafness
D. Hoyeraal Hreidarsson syndrome: cerebellar hypoplasia, microcephaly, IUGR, “T+B-NK-“ immunodeficiency
E. Revesz syndrome: exudative retinopathy, cerebral calcifications, IUGR, fine sparse hair, ataxia

3. Availability of a HLA-compatible related or unrelated donor, defined as a 7/8 or 8/8 match for HLA-A, B, C, and DRB1. Related donors must be ruled out for telomere disease by appropriate clinical and diagnostic measures (for example, clinical evaluation, flow-FISH telomere length testing, genetic testing, and/or bone marrow examination).

4. For patients under 18 both parents must give a written informed consent.

5. Matched unrelated donor must consent to provide a bone marrow allograft.

6. The diagnosis of Fanconi anemia must be excluded by mitomycin C or diepoxybutane (DEB) chromosomal breakage testing on peripheral blood at a CLIA-approved laboratory on any prior evaluation. This evaluation is not required for patients with a pathogenic mutation in a known DC-associated gene as defined in 5.1.1.2.B above.

7. Adequate renal function with glomerular filtration rate equal to or greater than 30 ml/min/1.73 m2 measured within 30 days of protocol inclusion.

8.Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they are using effective methods of contraception during the study. Acceptable bi
Exclusion criteria:
1. Clonal cytogenetic abnormalities associated with MDS or AML on bone marrow examination performed within 90 days of protocol inclusion.

2. Karnofsky performance status < 40% for patients 16 years old or older; or Lansky < 40% for patients < 16 years old.

3. Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms). Patients with fever despite broad-spectrum antimicrobials but no clinical or hemodynamic evidence of sepsis will be allowed.

4. Positive for the human immunodeficiency virus (HIV) by nucleic acid testing.

5. Pregnancy (positive B-HCG) or breastfeeding.

6. Known severe or life-threatening allergy or intolerance to fludarabine, alemtuzumab, cyclosporine, or mycophenolate mofetil.

7. In HLA mismatched transplants: positive patient anti-donor HLA antibody, defined as clinically significant based on institutional standards.

8. Prior allogeneic marrow or stem cell transplantation.

9. Prior solid organ transplantation.

10. Non-hematological co-morbid condition(s) or other factors (for example, psychological or social factors) that preclude the patient?s candidacy for performing BMT under the protocol regimen, in the opinion of the treating physician



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Dyskeratosis congenita / telomere disease
MedDRA version: 20.0 Level: PT Classification code 10001756 Term: Allogenic bone marrow transplantation therapy System Organ Class: 10042613 - Surgical and medical procedures

Intervention(s)

Trade Name: Lemtrada
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Alemtuzumab
CAS Number: 216503-57-0
Other descriptive name: ALEMTUZUMAB
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 0,2-

Trade Name: Fludarabine
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: FLUDARABINE
CAS Number: 21679-14-1
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: equal
Concentration number: 30-

Primary Outcome(s)

Main Objective: To evaluate the ability to achieve an acceptable primary engraftment rate using a reduced intensity conditioning regimen in allogeneic HCT for BMF due to DC.

Secondary Objective: Secondary objectives are to describe the following after allogeneic HCT for BMF due to DC:
Survival to day+100 post-transplant
- Rate of secondary graft failure
- Regimen-related toxicity (RRT)
- Incidence of acute and chronic graft-versus-host disease (GVHD)
- Rates of viral reactivation and infection
- Peripheral blood and bone marrow engraftment
- Changes in pulmonary function
- Late effects including disease progression, incidence of secondary malignancies, and long-term survival
- Immune reconstitution

Primary end point(s): - Neutrophil engraftment
- Primary Graft Failure
- Primary engraftment

Timepoint(s) of evaluation of this end point: - Neutrophil engraftment: an ANC = 0.5 x 10e9/L for three consecutive measurements on different days. The day of engraftment will be the day of the first of these three measurements.

- Primary graft failure: A) the lack of neutrophil engraftment as of Day +42; i.e., ANC was not = 0.5 x 10e9/L for three consecutive measurements on different days with day +42 post-transplant or earlier as the first day of engraftment. B) Peripheral blood chimerism = 50% donor neutrophil cells on two occasions from Day +30 to Day +100 post-transplant.

For the calculation of the primary engraftment rate, a patient will be considered to have, engrafted? if the patient has neutrophil engraftment per section 7.1.1 and if the patient does not have primary graft failure per either 7.1.2.1A or 7.1.2.1B.

Secondary Outcome(s)

Secondary end point(s): - Day +100 Post-transplant
Survival
- Secondary Graft Failure
- Toxicities
- Acute GVHD of Grades 2-4 and
3-4
- Chronic GVHD
- Viral reactivation/infection and
disease
- Engraftment monitoring
(chimerism)
- Pulmonary function testing
(PFTs)
- Immune function and
reconstitution
- Late effects

Timepoint(s) of evaluation of this end point: -Post-transplant survival: 100 days from the time of transplant
-Secondary Graft Failure: Decline in the ANC to < 0.5 x 109/L for 3 consecutive measurements
-The assessment for toxicities will be carried out until day +365 post-transplant.
-Acute GVHD of Grades 2-4 and 3-4 will be monitorered during the course of the study
-Chronic GVHD will be monitorered during the course of the study
-Viral monitoring weekly by quantitative for CMV, EBV, and adenovirus from day 0 to day +100.
- Engraftment monitoring from Days +15 to +365; and when possible yearly thereafter.
-PFTs: within 90 days of treatment start; Day +365; and when possible yearly thereafter
-Immune function and - disease progression within 90 Days of study initiation, at Day +365 and at Day +365 if possible.

Secondary ID(s)

P00003466

Source(s) of Monetary Support

Karolinska Universitetssjukhuset

Ethics review

Status: Approved
Approval date:
Contact: