Know Cancer

forgot password


Phase 1
6 Months
20 Years
Open (Enrolling)
Refractory Low-grade Gliomas, Recurrent Low-grade Gliomas

Thank you

Trial Information


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,
Abstract in Neuro-Oncology 2008). The 1-year progressionfree survival (PFS) rate was 57%.
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).

Inclusion Criteria:

1. Written informed consent signed by the patient, or parents or legal representative
and assent of the minor child.

2. Age: 6 months to < 21 years of age at time of study entry

3. Histologically confirmed low-grade glioma in non-NF1 patients (no further biopsy is
needed at study entry). For patients with NF1, no biopsy is required to confirm the
radiological diagnosis of the low grade glioma.

4. Relapse or refractory tumor after at least one first-line therapy, not taking into
account surgery only.

5. Evaluable Disease on morphologic MRI

6. 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.

7. Life expectancy >= 3 months.

8. Adequate organ function:

- Adequate hematopoietic function: neutrophils ³1.0 x 109/L, platelets ³100 x
109/L; hemoglobin ³8 g/dL

- Adequate renal function: serum creatinine < 1.5 x ULN for age 0 - 1 year: <= 40

1 - 15 years: <= 65 µmol/L 15 - 20 years: <= 110 µmol/L In case serum creatinine
>1.5 ULN according to age, creatinine clearance has to be >70 mL/min/1.73 m2 or
glomerular filtration rate measurement >70% of the expected value

- Adequate electrolytes levels: potassium, magnesium, phosphor, 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)

- 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 > 450 msec on baseline ECG, using the QTcF formula)
or other clinically significant ventricular or atrial arrhythmia

9. 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

10. Possibility of receiving the therapeutic schedule as indicated in the protocol

11. Patients with reproductive potential must use effective contraception 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 starting Nilotinib
and/or Vinblastine.

12. 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 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 (e.g.
antiepileptic drugs, see complete list in the Appendix 5).

9. Simultaneous treatment with antiarrythmic drugs and other drugs known to prolong QT
interval (cloroquine, halofantrine, clarithromycin, haloperidol, methadone,
moxifloxacin, bepridil, cisapride and pimozide). A list of QT prolonging compounds
can be found at (Appendix

10. Impaired cardiac function including any one of the following:

- Clinically significant resting brachycardia (<50 beats per minute).

- 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 (e.g. unstable angina,
congestive heart failure or uncontrolled hypertension).

- History of or presence of clinically significant ventricular or atrial
tachyarrhythmias (including congenital long QT syndrome or a known family
history of congenital long QT syndrome)

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety Assessment - Dose-Limiting Toxicity (DLT)

Outcome Description:

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.

Outcome Time Frame:

Assessed over the first 28-day cycle

Safety Issue:


Principal Investigator

Jacques GRILL, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Gustave Roussy, Cancer Campus, Grand Paris


France: Agence Nationale de Sécurité du Médicament et des produits de santé

Study ID:

2012-003005-10 Phase I



Start Date:

May 2013

Completion Date:

May 2019

Related Keywords:

  • Refractory Low-grade Gliomas
  • Recurrent Low-grade Gliomas
  • Children
  • adolescents
  • young adults
  • Glioma