Primary: To determine the MTD and/or RDE of LGH447 with or without midostaurin. Secondary: 1. To characterize the safety and tolerability of LGH447 with or without midostaurin at the MTD and/or RDE.2. To assess any observed antitumor activity of…
ID
Source
Brief title
Condition
- Haematological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence rate of dose limiting toxicities during the first cycle of LGH447
with or without midostaurin treatment.
Secondary outcome
Clinical response, adverse events, dose interruptions, dose reductions, and
dose intensity.
Background summary
Currently, treatment of patients with AML includes intensive remission
induction and consolidation therapies, including stem cell transplantation.
Approximately 60-70% of adults with AML can be expected to attain complete
remission following appropriate induction therapy. More than 25% of adults with
AML can be expected to survive 3 or more years and may be cured. Remission
rates in adult AML are inversely related to age. Data suggest that once
attained, duration of remission may be shorter in older patients. Despite the
improvements in standard chemotherapy and supportive case, more effective
therapeutic modalities to improve the survival of patients with AML are needed.
MDS are a heterogenous group of chronic myeloid disorders that involve
persistent peripheral blood cytopenias and an increased prevalence of leukemic
transformation. Patients are grouped into five risk categories based prognostic
factors. As the disease evolves to AML, AML-based therapies are utilized.
However, similar to patients with relapsed AML, patients with transformed MDS
respond poorly to standard therapeutic regimens and additional treatment
options are needed for MDS.
Elevated levels of PIM1 and PIM2 are seen in various hematologic malignancies.
Deregulation of PIM gene expression is frequently associated with commonly
occurring genetic alterations and it is thought that the resulting increased
PIM kinase activity contributes to disease progression. There are indications
that PIM2 is significantly over-expressed in hematological malignancies
relative to the levels in solid tumors.
The PIM kinase gene family encodes three Serine/Threonine protein kinases that
have roles in cell cycle progression and survival.
LGH447 is a potent, selective, and orally bioavailable inhibitor of the PIM
kinase. In vitro, LGH447 demonstrates inhibition of proliferation in cell lines
derived from a variety of hematological malignancies, including multiple
myeloma, AML, and B-Cell NHL. In vivo, LGH447 is efficacious in mouse models of
MM and AML.
In September 2016 a protocol amendement has been issued. Sofar 41 subjects iwth
AML or MDS have been included in the study.
The objective of this amendement is to assess whether combined targeting of Pim
kinase and FMS-like tyrosine kinase 3 (FLT3) signaling patheways promotes
greater sustained reduction in tumor burden compared with either monotherapy in
patients with AML. this amendement will evaluate the combination of LGH447 with
the multi-kinase inhibitor midostaurin in patients with AML. To better
understand whether the combination of LGH447 and midostaurin exhibits
immunomodulatory activity in AML blood samples and tumor samples will be
evaluated for immunomodulation.
Study objective
Primary:
To determine the MTD and/or RDE of LGH447 with or without midostaurin.
Secondary:
1. To characterize the safety and tolerability of LGH447 with or without
midostaurin at the MTD and/or RDE.
2. To assess any observed antitumor activity of LGH447 with or without
midostaurin.
3. To assess pharmacodynamics effects of LGH447 with or without midostaurin.
4. To evaluate the pharmacokinetics of LGH447 with or without midostaurin and
its metabolites if appropriate.
Study design
The study includes a phase 1 dose escalation portion to define the MTD/RDE for
LGH447 with or without midostaurin, followed by an expansion at the MTD/RDE to
further characterize the safety and efficacy of LGH447 with or without
midostaurin.
41 subjects have been included in the monotherapy part and 52 will be included
in the combination therapy part (12 in dose escalation and 40 in dose
expansion).
Intervention
Treatment with LGH447 with or without midostaurin.
Study burden and risks
Risk:
Adverse events of LHG447. The drug is still in a very early stage of development
Burden:
Cycle 1-2: 5 visits, thereafter 2 visits/cycle. 2 visits after termination of
study medication.
Physical examination1-3x per cycle.
Blood draws approx. 5 ml screening, every visit during cycle 1 and 2, therafter
twice.
2 days with long PK sampling up to 8 h after administration of LGH447.
Bone aspirate/-biopsy screening, once during cycle 1 and once during the next
cycles.
Pregnancy test screening and startin in cycle 2 once every cycle..
ECG (3 registrations with an interval of 5-10 min.) screening and cycle 1-6
once per cycle.
CT-/MRI-scan in case of extramedullary disease during screening and to be
repeated if indicated.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Male or female patients *18 years.with refractory/relapsed AML (see protocol page 44 for details).
2. Patients with active CNS disease are eligible and may be treated concurrently with intrathecal (or intra Ommaya) chemotherapy.
3. Patients are eligible as long as previous and concomitant medications are in line with the with the list of approved concomitant medications (see protocol appendix 5 for details).
4. ECOG performance status 0-2.
Exclusion criteria
1. Systemic antineoplastic therapy or any experimental therapy within 7 days or 5 half-lives, whichever is longer, before the first dose of LGH447 with or without midostaurin (see protocol page 45 for further details).
2. Radiotherapy with a wide field of radiation within 28 days or radiotherapy with a limited
field of radiation for palliation within 7 days of the first dose of LGH447 with or without midostaurin.
3. CNS irradiation for meningeal leukemia, except if radiotherapy occurred > 3 months previously.
4. Ongoing systemic therapy with corticosteroids greater than 10 mg of prednisone or its equivalent
per day.
5. Uncontrolled cardiovascular condition within the past 6 months.
6. Active infection requiring systemic therapy or other severe infection with 2 weeks before the first dose of LGH447.
7. Currently receiving hydroxyurea to control peripheral blood leukemic
blasts that cannot be discontinued for at least 48 hours prior to obtaining PD biomarkers at
screening/baseline and during the study.
8. Other prohibited medications (see protocol page 27 for details).
9. Pregnancy, lactation.
10. Inadequate contraception for women of childbearing potential (see protocol page 46 for details).
11 Sexually active males must use a condom during intercourse while taking the drug and for
96 days after stopping treatment and should not father a child in this period.
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| Other | clinicaltrials.gov; registratienummer n.n.b. |
| EudraCT | EUCTR2013-003756-20-NL |
| CCMO | NL46781.029.13 |