To evaluate safety and tolerability of AMG 531 in patients with low or intermediary-1 risk MDS and thrombocytopenia and to evaluate thrombocyte response at AMG 531 in these patients.
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) Incidence ans severtity of all adverse events. 2) To define the maximum
tolerated dose. 3) To evaluate anti-AMG 531 antibodies.
Secondary outcome
Percentage of patients with a complete (increase of thrombocytes to 100 x 109/l
or more) or major (absolute increase of thrombocytes of 30 x109/l or more)
thrombocyte response.
Background summary
Myelodysplastic syndrome (MDS) is a heterogenous group of clonal disorders in
the hematopoietic stem cell characterised by a varying degree of cytopenia in
one or more cell lines. Prognosis can be expressed by the International
Prognostic Scoring System (IPSS) score. Patients with a low or intermediary-1
risk according to the IPSS are often treated with supportive care. About 30 %
of these patients have thrombocytopenia at presentation, in the others it
develops during the course of the disease. Thrombocytopenia can give rise to
bleeding, often of the oral mucosa, and spontaneous hematomas. This negatively
affects the quality of life of these patients. Thrombocyte transfusions are
only effective for a few days and are given only in case of serious bleeding.
Other than by thrombocyte transfusion, a thrombocytopenia cannot be treated at
the moment. AMG 531 is a recombinantly expressed protein in E. Coli which
offers a possible new treatment for thrombocytopenia in MDS patients.
Study objective
To evaluate safety and tolerability of AMG 531 in patients with low or
intermediary-1 risk MDS and thrombocytopenia and to evaluate thrombocyte
response at AMG 531 in these patients.
Study design
Phase 1-2, multicenter, open label sequential cohort dosis escalation study of
AMG 531. Five patients will be enrolled into each of 4 or 5 seqential cohorts
of increasing dose levels. Patients will receive 3 weekly injections of AMG
531. The effect will be evaluated weekly until week 4. After completion of each
cohort, defined as the fifth subject completing the week 4 visit, the Safety
Review Panel (SRP) will decide wether the next cohort will begin or not and at
which dosage. In the SRP are members of AMGEN (study sponsor) and 3
investigators.
Dose limiting toxicity (DLT) is defined as the dose at which 3 or more of 5
patients in a cohort experience a study-related CTCAE grade 3-4 toxicity (not
a thrombocytopenia), or if no toxicity is experienced at the maximum dose of
AMG 531 (1500 ug). In this case, dose escalation will stop. If 2 out of 5
patients in a cohort experience a CTCAE grade 3 or 4 toxicity, the cohort will
expanded with another 5 patients. If in this expanded cohort 2 patients
experience a CTCAE grade 3-4 toxicity, dose escalation will continue.
Otherwise, there is DLT at this dose level. In that case, another 20 patients
will be added to the appropiate lower dose level that the SRP has recommended
as the potential maximum tolerated dose (MTD). The MTD is defined as the
highest dose at which < 34 % of patients experience a DLT.
In week 4, an individual patient can choose to continue AMG 531 at the same
dose level in an extension arm.
Intervention
Weekly subcutaneous injection of AMG 531.
Study burden and risks
Patients will visit the hospital 6 times (more if the patient participates in
the extension study). At first and fifth visit, a bone marrow aspirate and
biopsy will be done. This will be repeated every twelve weeks in the extension
study. Physical examination and laboratory evaluations will be regularly done.
At first visit, a pregnancy test, if applicable, will be done.
AMG 531 has been studied in 2 phase 1 studies in healthy volunteers and 2 phase
2 studies in ITP patients. Most adverse events were mild or moderate in
severity. In healthy volunteers the most common adverse events were headache,
fatigue and flu-like symptoms. In ITP patients these were headache and
epistaxis. In 2 patients with ITP an increase in bone marrow reticulin was
reported. In one of these 2 patients, the bone marrow reticulin was decreased 6
months after discontinuation of AMG 531.
Minervum 7061
4717 ZK Breda
Nederland
Minervum 7061
4717 ZK Breda
Nederland
Listed location countries
Age
Inclusion criteria
Diagnosis of MDS using the World Health Organization classification.
Low or intermediate-1 MDS using the IPSS.
Mean of two platelet counts taken within 1 week prior to dosing must be equal to or less than 50 x 10 9/l and no individual count higher than 55 x 10 9/L.
Exclusion criteria
Currently receiving any treatment for MDS other than supportive care.
Clinically significant bleeding within 2 weeks of screening (i.e. GI bleeds, intracranial hemorrhage)
Prior malignancy (other than controlled prostate cancer, in situ cervical cancer or basal cell cancer of the skin) unless treated with curative intent and without evidence of disease for 3 or more years.
History of heart disease or thrombo-embolic disease
Untreated B12 or folate deficiency.
Received hypomethylating agents, immunomodulating agents, histone deacetylase inhibitors, cyclosporine or mycophenolate within 6 weeks of screening.
Concurrent use of granulocyte growth factors
Received IL-11 within 4 weeks of screening
Have ever previously received rTPO, PEG-rHuMGDF, eltrombopag or AMG 531.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-000144-92-NL |
| CCMO | NL12944.091.06 |