Primary:• Phase I part: to define the recommended dose (RD) of nilotinib and vinblastine when used in combination• Phase II part: to evaluate the efficacy of vinblastine in combination with nilotinib (VINILO) at the RD, as compared to vinblastine…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase I part - Safety assessment
Dose-Limiting Toxicity (DLT), assessed over the first 28-day cycle, defined as
• Grade > 3 neutropenia (<1 x 109/L) for more than 7 days;
• Grade > 2 thrombopenia (<75 x 109/L) or thrombocytopenia requiring
transfusions for more than 7 days.
• Grade 3 or grade 4 non-hematological toxicity, excluding grade 3 nausea,
vomiting, fever, and hepatic toxicity that is rapidly reversible (i.e. returns
to < 2.5 x ULN within 2 weeks after study drug discontinuation), and symptoms
that are related to tumor progression.
and: Any study drug related toxicity occuring during the first cycle leading
to a significant dose reduction considering the 1st cycle
plus the following week (1st week of cycle 2), i.e.:
o If the patient receive less than 80% of the planned
dose of Nilotinib
o If the patient receive less than 75% of the planned
dose of Vinblastine
Phase II part - Efficacy assessment
PFS computed as the time interval between the date of study entry and the date
of tumor progression or death (whatever the cause of death). The progression
will be defined either radiologically (>25% increase in two-dimension
measurements or appearance of new lesions compared to the baseline or to the
best response after initiation of therapy) or clinically by new symptoms
related to tumor progression (significant decrease of visual acuity, new or
worsening neurological deficit). Hydrocephalus is not considered as progression
per se.
Secondary outcome
1) Safety monitoring during the treatment
Clinical and laboratory toxicities / symptoms will be graded according to
NCI-CTCAE v4.0 over the whole treatment duration. The adverse events which are
not reported in the NCI-CTC will be graded as mild, moderate, severe, and
life-threatening. In particular, cardiac function will be monitored with
echocardiography and ECG.
2) Efficacy criteria
Tumor response will be based on two-dimension measurement and to RANO Criteria
(van den Bent, Lancet Oncol 2011). The radiological imaging will be reanalyzed
after the study by a radiologist panel, according to the RANO criteria and to
the newly defined RAPNO Criteria, once they will be available.
All tumor reduction >25% (CR or PR or MR) will be considered as success.
Morphologic MRI will be performed every 3 months prior to the new cycle, apart
from the week 4 early evaluations in case functional MRI is performed. Primary
objective of the study is PFS and thus objective response does not need to be
confirmed at 4 to 6 weeks. Baseline MRI and that related to the best response
will be centrally reviewed by an independent international radiology panel.
Growth modulation index or progression-free survival time ratio
(PFS2/PFS1-ratio), defined as the ratio of a patient*s progression-free
survival time from start of study treatment (VINILO or Vinblastine alone),
PFS2, relative to the progression-free survival time observed from the
patient*s most recent prior anticancer treatment, PFS1, which serves as the
patient-specific historical control value.
Modification of functionnal status. In particular, for optic pathway glioma,
quantitative assessment of visual acuity and qualitative changes in visual
field will be assessed.
Overall survival computed from the date of study entry to the date of death,
from any cause.
3) Dose intensity of each drug computed on the whole treatment duration and per
month. Duration of treatment and reasons for the end of treatment.
4) Pharmacokinetics dosage of both drugs (for 30 patients of each arm of the
phase II part)
5) Functional MRI (perfusion sequence). This dynamic imaging technique will be
performed with contrast after 1 month and 3 months of treatment and compared to
that performed at study entry. This evaluation will be performed in selected
centers (see Appendix 2).
6) Tumor biomarkers will be studied on paraffin tumor samples (histological
subtype, vascular density with monoclonal antibody anti-CD105/endoglin,
proliferation index MIB1, immunohistochemical expression of c-kit, PDGFR alpha
and beta, and basic protein of myelin or MBP, telomeres length using Q-FISH
technique, BRAF status).
7) Pharmacogenetic biomarker (enzyme polymorphism)
8) Long-term follow-up: height, weight, pubertal growth, phosphor-calcic
evaluation and cardiac function.
Background summary
Low grade gliomas (LGG) are the most frequent brain tumor type in children.
They are often chemosensitive. However, more than 50% of these tumors will
progress within the first 5 years after the start of the treatment and need a
second-line therapy (Laithier, JCO 2003). In most cases, patients are still
young and the risk of side effects from radiation therapy will call for another
medical treatment. If a tumor does not respond to first-line chemotherapy, the
prognosis worsens with 25% of deaths within the first 5 years for optic gliomas
(de Haas, Pediatr Blood Cancer 2009). Vinblastine (Velbe®) is an effective drug
for low grade gliomas with both antiproliferative and antiangiogenic effects.
An update of the Canadian phase II of weekly vinblastine (6 mg/m²/week)
reported one complete response (CR), three partial responses (PR) and 9 minor
responses (MR) in the first 31 patients (Bouffet, JCO, 2012). The 2-year
progression-free survival (PFS) rate was 62%. Tolerance of the treatment is
fair allowing prolonged maintenance therapy as in Langerhans cell histiocytosis
and anaplastic large cell lymphoma (ALCL). These data encourage proceeding with
further testing this approach in pediatric low-grade glioma.Nilotinib is a
tyrosine kinase inhibitor (TKI) known to affect c-Kit, DDR1 and the PDGF
receptors alpha and beta. PDGF is a growth factor for normal and tumoral
astrocytes and oligodendrocytes. In addition, PDGF receptors are expressed on
pediatric low-grade glioma vessels (McLaughlin, J Pediatr Hematol Oncol 2003;
Peyrl, Pediatr Blood Cancer 2009). Tumor response to this class of TKI has been
reported occasionally (Peyrl, Pediatr Blood Cancer 2009; McLaughlin, J Pediatr
Hematol Oncol 2003). When used as monotherapy, this class of TKI was well
tolerated in children, including those with brain tumors (Wayne, Blood 2008;
Baruchel, Eur J Cancer 2009; Geoerger, Eur J Cancer 2009).
Taking advantage of their different antiangiogenic mechanisms, their limited
and non-overlapping toxicities, vinblastine and nilotinib could play an
interesting role in the treatment of pediatric low-grade glioma. Nilotinib via
PDGFRA and c-kit interactions may also interfere with the stroma of the tumor
which is a key factor for tumor growth as shown in the NF1 mouse model
(Daginakatte, Cancer Res 2008; Kim, Neuroscience 2010; Simmons, J Neuropathol
Exp Neurol 2011). Both drugs have also immunostimulating effects especially in
dendritic cells, that will be explored during treatment in selected patients
(Tanaka, Cancer Res 2009; Nishioka Immunotherapy 2011)
Previous to the phase II assessing the efficacy of the combination compared to
vinblastine as single agent, nilotinib and vinblastine have to be administered
by escalating dosages in order to identify the recommended doses of each agent
when given in combination. This phase I part of the trial is justified by a
possible interaction of the two drugs that are substrates of cytochrome P450
CYP3A4. Initial/starting dose of nilotinib (115 mg/m² BID) will be 50% of the
recommended dose when used as monotherapy in adults (800 mg/day: 400 mg BID
=230 mg/m2 BID). Initial/starting dose of vinblastine will be 50% of the
recommended dose when used as monotherapy or in association with other
chemotherapeutic drugs (i.e. 3 mg/m2 once a week). This justifies obtaining
pharmacokinetic data on both drugs when used in combination. A phase I trial
evaluating nilotinib as single agent in pediatrics in hematological
malignancies is ongoing, run by the ITCC and the COG group, exploring the
dose-levels 230 mg/m² to 460 mg/m² BID. The results of this phase I trial,
expected by 2012, and the data of the current trial will be considered to
decide whether a higher dose-level for nilotinib can be opened (350 mg/m² BID).
Study objective
Primary:
• Phase I part: to define the recommended dose (RD) of nilotinib and
vinblastine when used in combination
• Phase II part: to evaluate the efficacy of vinblastine in combination with
nilotinib (VINILO) at the RD, as compared to vinblastine alone, in terms of
progression-free survival, in children, adolescents, and young adults with
refractory or recurrent low grade glioma and in NF1 patients with low grade
glioma at diagnosis.
Secondary:
1. To measure the impact of the VINILO combination compared to vinblastine
alone, in terms of tumor response, functionnal status (visual acuity*),
progression-free survival time ratio (PFS2/PFS1-ratio), and overall survival
(OS)
2. To describe and compare, on the whole duration of treatment, the acute
toxicity related to the VINILO combination with that of vinblastine alone; and
to compare the long-term effects of both regimens
3. To describe the feasibility of the treatment and the compliance
4. To provide pharmacokinetics data on both drugs when given in combination
5. To identify the predictive value of early functional MRI changes
6. To assess the inter-observers agreement of radiologic response assessment
Exploratory:
1. To explore putative predictors of the response to therapy (tumor, serum and
pharmacogenetic biomarkers).
Study design
Multicenter, open label, prospective study including successively a phase I
trial and then a phase II trial
Phase I : Open label, non-randomized, sequential dose escalation of both drugs,
vinblastine and nilotinib.
Phase II : Open label, randomized study of the combination of nilotinib and
vinblastine (VINILO) versus vinblastine alone
Intervention
Phase I part: Nilotinib and Vinblastine dose-escalation
Nilotinib (Tasigna®): 115 to 350 mg/m2 twice daily (BID) orally given
continuously (115 mg/m2 once daily if de-escalation requested). The
administered dose will be defined for a day, and rounded to the nearest 50 mg
dose.
Vinblastine: 3 to 6 mg/m2 once weekly as an IV bolus or in a 15-minute
infusion, on Days 1, 8, 15 and 22 of each cycle according to standard practice.
Each 28-day cycle is repeated on Day 29/Day 1. No intra-patient dose-escalation
is permitted.
Dose allocation will be centrally defined, based on toxicity observed in
patients previously evaluated. Every new patient will be treated at the best
current recommended dose, i.e. the dose associated with an estimated level of
toxicity that is judged acceptable (20% DLT). At least two patients fully
observed with no DLT are requested at a given dose level before dose escalation.
Initial dose-escalation scheme
Dose level (DL) Vinblastine weekly Nilotinib
DL-1 3 mg/m2 115 mg/m2 once daily
DL1 (Starting dose) 3 mg/m2 115 mg/m2 BID
DL2 3 mg/m2 230 mg/m2 BID
DL3 4 mg/m2 230 mg/m2 BID
DL4 5 mg/m2 230 mg/m2 BID
DL5 6 mg/m2 230 mg/m2 BID
This scheme is an initial path within the bidimensional space of doses. We will
first aim at escaladating the vinblastine dose for a dose of
Nilotinib equal to 230 mg/m² (start-up). However, other adjacent dose
combinations to the current dose (excluding the combination with an
increase of both agents) can also be explored as soon as DL2 is deemed safe.
Thus a combination of Vinblastine 3 mg/m² + Nilotinib
350 mg/m² may be explored as soon as DL2 is deemed safe. The decision to
explore the different possible adjacent doses will be basedon the posterior
probability of DLT estimated by the model for all the dose combinations, as
well as on the evaluation of the whole safety data, discussed with the Data and
Safety Monitoring Board
The phase II part of the study may be opened if the RD of vinblastine is equal
or greater than 3 mg/m² and the RD of Nilotinib is equal or
greater than 230 mg/m² BID and if the combination is deemed safe. A report
describing the phase I results will be sent to the DSMB and the
ethics committee. The Phase II part will be opened as a protocol amendment
submitted for authorization to the ethics committee and
the health authorities.
Phase II part: Patients will be randomly allocated (1:1) to one of the
following treatment arms:
A. VINILO-arm: Vinblastine and nilotinib given in combination at the RD defined
in the Phase I part:
• Vinblastine: 3 mg/m2 administered as an IV bolus or in a 15-minute infusion
as per standard practice, once weekly on Days 1, 8, 15 and 22 of each 28-day
cycle.
• Nilotinib (Tasigna®): 230 mg/m2 orally BID given continuously on Days 1-28.
The administered dose will be calculated for a day (460 mg/m²), rounded to the
nearest 50 mg dose, and then divided into two doses, with a possible difference
of 50 mg between morning and evening uptakes.
Recommended doses of the drug combination will be re-considered at an interim
stage of the phase II trial after the analysis of the delayed toxicity
encountered in the first 20 patients treated at the initial RD (adaptive
design).
B. Control Vinblastine only arm:
• Vinblastine 6 mg/m2 given as an IV bolus or in a 15-minute infusion as per
standard practice, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle.
Each 28-day cycle is repeated on Day 29/Day 1.
In both treatment groups, dose reductions and/or administration delays will be
performed in case of severe hematological and/or non hematological toxicities
while on treatment.
Vinblastine will be temporarily stopped in case of neutropenia <1 x 109/L or
thrombopenia <75 x 109/L. It could be re-started at a reduced dose after
complete recovery.
Patients benefiting from study treatment may continue up to 12 cycles as long
as the toxicity-benefit ratio is adequate.
May 2019: Randomization in the trial is stopped. All patients must be treated
according to the current standard, i.e Vinblastine 6 mg/m2 alone.
Study burden and risks
Patients may suffer from regular side-effects such as known for intensive
chemotherapy given for malignancies in children, such as hematological toxicity
and febrile neutropenia. Nilotinib is known for its potential gastrointestinal
side-effects and skin rash. Vinblastin can cause peripheral neuropathy and
constipation. Other not yet known side effects may occur when vinblastin and
nilotinib are combined.
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Listed location countries
Age
Inclusion criteria
1. Written informed consent signed by the patient, or parents or legal
representative and assent of the minor child where appropriate.
2. Age: 6 months to < 21 years of age at time of study entry;
3. Diagnosis: one of the three conditions listed below
• Refractory or recurrent low-grade glioma after at least one first-line
therapy with pathological documentation in non NF1 patients (no further biopsy
is needed at study entry)
• Refractory or recurrent low-grade glioma after at least one first-line
therapy in NF1 patients, with or without pathological documentation. For
patients with NF1 and optic pathway glioma, no biopsy is required to confirm
the radiological diagnosis of the low grade glioma.
• Low grade glioma at diagnosis in NF1 patients when the use of chemotherapy is
considered for the treatment in case of threat to vision or unequivocal
radiological tumor progression. Pathological documentation is advised but not
mandatory.
4. Evaluable Disease on morphologic MRI;
5. Karnofsky performance status score >=70% for patients >12 years of age, or
Lansky score >=70% for patients <=12 years of age, including patients with motor
paresis due to disease.
6. Life expectancy >= 3 months.
7. Administration of stable dose of steroids for at least one week
8. Adequate organ function:
• Adequate hematopoietic function: neutrophils >= 1.0 x 109/L, platelets >= 100
x 109/L; hemoglobin >= 8 g/dL
• Adequate renal function: serum creatinine <= 1.5 x ULN for age. In other
cases where serum creatinine >1.5 ULN according to age. Glomerular filtration
rate or creatinine clearance has to be
> 70ml/min/1.73m2 or > 70% of the expected value.
• Adequate electrolytes levels: potassium, magnesium, phosphate, total calcium
>= Lower Limit of Normal (LLN)
• Adequate hepatic function: total bilirubin <=1.5 x ULN; AST and ALT <=2.5 x ULN.
• Absence of peripheral neuropathy >= grade 2 (Common Toxicity Criteria Adverse
Event, NCI CTCAE v4.0)
9. Adequate cardiac function:
• Shortening Fraction (SF) >= 28% (35% for children <3 years) and Left
Ventricular Ejection Fraction (LVEF) >= 50% at baseline, as determined by
echocardiography;
• Absence of QTc prolongation (QTc QTcF formula) or other clinically significant ventricular or atrial arrhythmia
10. Wash-out period of at least
• 3 weeks in case of preliminary chemotherapy
• 6 weeks in case of nitrosourea-containing chemotherapy
• 2 weeks in the case of treatment with vincristine only
• 6 weeks in case of radiation therapy
11. Possibility of receiving the therapeutic schedule as indicated in the
protocol
12. Patients with reproductive potential must use effective/acceptable birth
method control (as defined per CTFG guidelines) during their treatment and for
up to 90 days after the last dose. Females with reproductive potential must
have a negative pregnancy test <= 7 days before randomization.
13. Patients already treated with one of the two drugs can be enrolled in the
trial provided that rechallenging them with the same drug could be considered
acceptable
Exclusion criteria
1. Concomitant anti-tumor treatment
2. Not recovered to chemotherapy, immunotherapy or radiotherapy
3. Known intolerance or hypersensitivity to Vinblastine;
4. Existence of another severe systemic disease;
5. Uncontrolled infections not responsive to antibiotics, antiviral medicines,
or antifungal medicines
6. Any concurrent illness which in the opinion of the investigator may
interfere with the treatment and evaluation of the patient
7. Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of nilotinib.
8. Simultaneous treatment with strong cytochromes P450 CYP3A4 inhibitors
9. Simultaneous treatment with antiarrythmic drugs and other drugs known to
prolong QT interval
10. Impaired cardiac function including any one of the following
• Clinically significant resting brachycardia
• QTc > 450 msec on baseline ECG. If QTc >450 msec and electrolytes are not
within normal ranges, electrolytes should be corrected and then the patient
re-screened for QTc.
• Other clinically significant uncontrolled heart disease
• History of or presence of clinically significant ventricular or atrial
tachyarrhythmias
11. Positive test for Hepatitis B virus surface antigen
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 | EUCTR2012-003005-10-NL |
| ClinicalTrials.gov | NCT01884922(fase1)&NCT01887522(fase2) |
| CCMO | NL42257.078.13 |