Clinical Trials /

Study of Vinblastine in Combination With Nilotinib in Children, Adolescents, and Young Adults

NCT01887522

Description:

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.

Related Conditions:
  • Low Grade Glioma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 2012-003005-10 Phase II
  • SECONDARY ID: 2012/1883
  • SECONDARY ID: 022
  • NCT ID: NCT01887522

Conditions

  • Refractory Low-grade Gliomas
  • Recurrent Low-grade Gliomas

Interventions

DrugSynonymsArms
Vinblastine + NilotinibVINILO
VinblastineControl Vinblastine only

Purpose

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.

Detailed Description

      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).
    

Trial Arms

NameTypeDescriptionInterventions
VINILOExperimentalVINILO-arm: Vinblastine and nilotinib given in combination at the RD defined in the Phase I part: Vinblastine: administered in a 15-minute infusion, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle. Nilotinib (Tasigna®): orally BID given continuously on Days 1- 28 Recommended doses of the drug combination will be reconsidered 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).
  • Vinblastine + Nilotinib
Control Vinblastine onlyActive ComparatorControl Vinblastine only arm: · Vinblastine 6 mg/m2 given in a 15-minute infusion, 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 x109/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.
  • Vinblastine

Eligibility Criteria

        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
                  µmol/L

                  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 <Grade 2 from the acute toxic effects of all prior 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 (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 http://www.azcert.org/medical-pros/druglists/drug-lists.cfm (Appendix 6)

         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)
      
Maximum Eligible Age:20 Years
Minimum Eligible Age:6 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:assessed up from randomization to tumor progression or death whatever the cause assessed up to 24 months
Safety Issue:
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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gustave Roussy, Cancer Campus, Grand Paris

Trial Keywords

  • Children
  • Adolescents
  • Young Adults

Last Updated

September 7, 2018