Know Cancer

forgot password

Phase I-II Study of Vinblastine in Combination With Nilotinib in Children, Adolescents, and Young Adults With Refractory or Recurrent Low-Grade Glioma

Phase 2
6 Months
20 Years
Open (Enrolling)
Refractory Low-grade Gliomas, Recurrent Low-grade Gliomas

Thank you

Trial Information

Phase I-II Study of Vinblastine in Combination With Nilotinib in Children, Adolescents, and Young Adults With Refractory or Recurrent Low-Grade Glioma

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. 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. 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. 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. Tumor response to this class of TKI has been reported occasionally . When used as
monotherapy, this class of TKI was well tolerated in children, including those with brain
tumors. 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. Both drugs have also immunostimulating effects especially in
dendritic cells, that will be explored during treatment in selected patients. 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:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression Free Survival (PFS)

Outcome Description:

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). Hydrocephaly is not considered as progression per se.

Outcome Time Frame:

assessed up from randomization to tumor progression or death whatever the cause assessed up to 24 months

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 II



Start Date:

May 2013

Completion Date:

May 2019

Related Keywords:

  • Refractory Low-grade Gliomas
  • Recurrent Low-grade Gliomas
  • Children
  • Adolescents
  • Young Adults
  • Glioma