This is a phase I/II pediatric dose-ranging study that will evaluate the safety, tolerability and pharmacokinetics of midostaurin in children = 3 months who have relapsed or refractory leukemias that may benefit from administration of midostaurin…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the maximum tolerated dose (MTD) or to identify the recommended
dose for expansion (RDE) for two age groups (>=3 months to <=2 years: >2years to
<18 years) of pediatric patients with AML or MLL based on the rate of
dose-limiting toxicity (DLT) of midostaurin administered orally in dose ranges
studied in adults.
Secondary outcome
• To characterize the safety and tolerability of midostaurin, including acute
and chronic toxicities
• To characterize the population PK of single and repeated doses of midostaurin
and its metabolite(s),
• To determine the response rates, time to relapse and overall survival of
patients treated with midostaurin.
Background summary
The survival of children with refractory or relapsed Mixed Lineage Leukemia
(MLL) gene rearranged Acute Lymphoblastic Leukemia (ALL) or with refractory or
second relapse of Acute Myeloid Leukemia (AML) is poor, with recovery rates of
10-20%. Further intensification of upfront therapy is not possible because it
leads to very high toxic-death rates in these children Thus, there is need to
develop new modalities of treatment for these subtypes of leukemia, which may
be added to standard chemotherapy, to further reduce relapse rate without
increasing toxicity.
FLT3 activation plays a role in the development of leukemias and is related to
a poor outcome. The addition of a targeted agent against FLT3 may offer the
possibility for significant therapeutic advantage as demonstrated in adult AML
patients expressing FLT3. Childhood MLL shows overexpression of FLT3 compared
to other types of leukemia, and AML shows activating FLT3 mutations in a
significant percentage of patients. Therefore, FLT3 has the potential to be a
promising target for therapy in these subtypes of childhood leukemia. So far,
no other FLT3 inhibitors have been developed for use in children in Europe. In
the United States of America studies are being conducted with CEP701, however
results are not known yet.
Midostaurin inhibits a number of tyrosine kinases, such as the class III
tyrosine protein kinase FLT3, and has documented antiproliferative and
pro-apoptotic activities in cell systems expressing and depending on mutated
FLT3 receptor signaling or in wild-type FLT3 over-expressing cells. In vitro
cytotoxicity studies on samples derived from pediatric patients showed
that cells from MLL patients were significantly ~5 fold more sensitive to
midostaurin than cells from children with conventional ALL. In addition to its
activity as a single agent, [Study CPKC412A2104], midostaurin can be combined
with standard chemotherapeutic agents used in leukemia resulting in synergism
or additivity [Study CPKC412A2106].
In order to support dosing pediatric patients a drink solution has been
developed. The relative bioavailability of the drink solution was demonstrated
to be biocomparable to the oral capsule in [Study CPKC412A2108], with no
conversion factor required.
Study objective
This is a phase I/II pediatric dose-ranging study that will evaluate the
safety, tolerability and pharmacokinetics of midostaurin in children <18 years
of age and >= 3 months who have relapsed or refractory leukemias that may
benefit from administration of midostaurin including MLL-rearranged ALL and AML
with FLT3 mutations.
Treatment with single agent midostaurin may have potential therapeutic benefit
in pediatric AML patients similar to the response seen in adults with the
disease, as was shown in [Study CPKC412A2104], summarized in section 1.3.4.2.
of the protocol. A similar effect may be seen in MLL cases, although there are
no adult data to support this, as high FLT3-overexpression in the absence of
mutations is mainly limited to infant ALL.
Given midostaurin*s limited potential to induce complete remissions in adults
with AML, it is anticipated that in future protocols, midostaurin will be used
mainly in combination with regular chemotherapy. This will be addressed
in future phase II trials in MLL and AML. However, before doing so, sufficient
background data are needed on its safety and preliminary evidence of
activity/efficacy as a single agent. Therefore in this study, only a limited
number of dose-levels will be assessed, based on availability of adult data,
and non-efficacious dose-levels will be avoided. Also a Bayesian logistic
model is being used to limit the number of patients that has to be included.
Study design
This is a phase I/II, open-label, dose-escalating study to determine the
safety, tolerability, and pharmacokinetics of twice daily oral midostaurin and
to determine the preliminary clinical and pharmacodynamic response in pediatric
patients with relapsed or refractory leukemia. The dose escalation will be
stratified into two age groups, patients aged greater than 2 years and less
than 18 years, and those 2 years or younger but greater than or equal to 3
months. Besides this MLL-ALL and AML will be analysed separately. The maximum
treatment dose administered in the adult population on monotherapy is 100 mg
b.i.d., and in combination with chemotherapy 50mg b.i.d., and for this reason
the maximum of midostaurin in the pediatric population will not exceed 60
mg/m2, equivalent to 100 mg b.i.d.
Once the Maximum Tolerated Dose (MTD) or the recommended dose for expansion
(RDE) has been established in each stratum of the dose-escalation part
additional patients might need to be included in order to have a total of 10
patients within each of the two indications (AML/MLL)treated across all dose
levels. A minimum of 10 patients per indication have been enrolled and
received at least one dose of midostaurin. The eligibility criteria and
assessments for patients enrolled in this dose-expansion phase will be
the same as those used during the dose-escalation phase.
An exploratory analysis will also be performed (see protocol)
Intervention
Children will be treated orally with midostaurin (25mg/ml). As long as they
experience benefits from treatment with midostaurin, they can continue to take
it. De respons evaluation takes place every 2 weeks.
Study burden and risks
Most of the assessments belong to the standard care in child oncology treatment.
Patient can get side effects of midostaurin, in adults the most common side
effects were nausea and vomiting. For this reason patients will be treated with
antiemetics. Other potential side effects are tiredness, headache, anorexia,
indigestion, diarrhea, flatulence and dehydration. Other less frequent side
effects are abdominal cramps, constipation, pain, gout, hypertension, viral
infection, rash, increased sweating, urinary tract infection, coughing, bad
taste in the mouth, itching, indreased dreams, dizziness and pain in the
joints.
The extra blooddraws for the study will be taken from the central line which
these patients have.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Patients must have a documented diagnosis of one of the following
leukemias:
• MLL-rearranged ALL, refractory to standard induction treatment or in
first or subsequent relapse
• FLT3-mutated AML refractory to standard induction (after failure of at
least 2 different induction chemotherapy regimens) or refractory to reinduction
at 1st relapse (after failure of the first re-induction course), or
in second or greater relapse
2. Patients must be less than 18 years of age and >=3 months of age.
3. Patients must have a Lansky/Karnofsky performance status >= 60.
4. Patients must have the following laboratory values reflecting appropriate
organ function:
• AST and ALT <= 5x Upper Limit of Normal (ULN),
• Serum Bilirubin <= 1.5 x ULN,
• Serum Creatinine <= 2 x ULN.
5. Patients must have an expected survival of greater than 8 weeks.
6. Parent or legal quardian and/or patient must give written informed consent, according to local law and regulations
Exclusion criteria
1. Patients with symptomatic leukemic CNS involvement.
2. Patients with isolated extramedullary leukemia.
3. Patients must have recovered from prior cytotoxic chemotherapy, and a
minimum wash-out time of previous chemotherapy of 72 hours should be
taken into account. For intrathecal chemotherapy, the minimum wash-out time is 48 hours
4. Patients who had prior allogeneic, syngeneic or autologous bone marrow
or stem cell transplant less than 2 months from Day 1
5. Patients who have received any investigational agent within 30 days or 5
half lives, whichever is greater, prior to Day 1.
6. Patients who have had prior treatment with a FLT3 inhibiting drug or
investigational agent, except for sorafenib
7. Use of CYP3A4/5 enzyme inducing or inhibiting drugs or CYP3A4/5 enzyme inducing or
inhibiting herbal supplements while on study treatment
8. The use of corticosteroids while on study drug (exceptions are noted in the protocol section 6.6.5)
9. Patients who have had any surgical procedure, excluding central venous
catheter placement or other minor procedures (e.g. skin or bone marrow
biopsy), within 14 days of Day 1.
10. Patients with any other known disease concurrent severe and/or
uncontrolled medical condition (e.g. cardiovascular disease including
congestive heart failure or active uncontrolled infection) which could
compromise participation in the study.
11. Patients with an abnormal chest X-ray and/or any pulmonary infiltrate
including those suspected to be of infectious origin. In particular, patients
with resolution of clinical symptoms of pulmonary infection but with
residual pulmonary infiltrates on chest x-ray are not eligible until
pulmonary infiltrates have completely resolved.
12. Patients with known impairment of gastrointestinal (GI) function or GI
disease that may significantly alter the absorption of midostaurin,
including active graft-versus-host disease of the liver or the gut.
13. Patients with a known confirmed diagnosis of HIV infection or active viral
hepatitis.
14. Patients with a left ventricular shortening fraction < 27% as determined by
MUGA scan or echocardiogram
15. Patients with abnormal ECG including:
• QTcF >= 450 ms, PR >=200 msec, QRS complex >=110 msec, at
screening or prior to first dosing
• Any cardiac conduction abnormality
• Any morphologic abnormality
• Any ST/T wave abnormality
• Any atrial or ventricular arrhythmia
16. Female patients who are pregnant or breast feeding or patients of
reproductive potential not employing an effective method of birth control.
Barrier contraceptives must be used throughout the trial by both sexes, if
applicable.
17. Males of reproductive potential unwilling to comply with contraceptive
requirements
18. Patients/parents unwilling or unable to comply with the protocol
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 |
|---|---|
| EudraCT | EUCTR2008-006931-11-NL |
| ClinicalTrials.gov | NCT00866281 |
| CCMO | NL28605.078.09 |