Vinblastine +/- Bevacizumab in Children With Unresectable or Progressive Low Grade Glioma (LGG)

NCT02840409 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: 1000052116
• Study Type: interventional
• Target: 109
• Locations: 4 countries
• Sites: 21

Brief Summary

This is an open-label, randomized, multi-center, comparator Phase II trial looking at the addition of Bevacizumab to Vinblastine in chemotherapy naïve pediatric patients with progressive Low Grade Glioma aged 6 months to less than18 years of age at the time of initiation of therapy. Participants will be randomized to Arm A or Arm B. Arm A includes 68 weeks of single agent Vinblastine administered once weekly IV. Arm B includes 68 weeks of Vinblastine administered weekly IV with the addition of 12 doses of Bevacizumab administered every two weeks IV for the initial 24 weeks. Randomization will take place at the time of registration taking into account NF1 and BRAF-KIAA1549-fusion status.

Conditions

Low Grade Glioma

Outcome Measures

Primary Outcomes (1)

• Efficacy of the addition of Bevacizumab to Vinblastine compared with Vinblastine alone in chemotherapy-naïve pediatric patients with unresectable or progressive Low Grade Gliomas as measured by Response Rate (RR).

  Objective response rate within 6 months of randomisation

  6 months from randomization

Secondary Outcomes (6)

• Overall survival (OS) at the end of study.

  From the date of study completion (approximately 6.5 years (78 months)) up till the date of death.

• To determine 6 month, 12 month and 2 year progression free survival (PFS) between vinblastine alone versus in combination with Bevacizumab.

  At 6 and 12 months and 2 years

• To evaluate the difference in visual outcome measures in children with optic pathway gliomas treated with vinblastine alone or in combination with Bevacizumab.

  Every 3 months during treatment, every 3 months for 1 year after completion of treatment, then every 6 months for 4 years.

• To determine if the prevalence of cognitive deficits in children and adolescents treated for LGG, is significantly higher than the normative population (> 14%) using the NIH Toolbox Cognitive Battery.

  At 1 year off therapy

• To determine the effects of Bevacizumab on cognitive function in the pediatric population using the NIH Toolbox Cognitive Battery.

  During treatment, 28 days after completing treatment, at 6 months and 1 year off therapy

Other Outcomes (11)

• To evaluate the safety of the combination of Vinblastine and Bevacizumab compared with Vinblastine alone in pediatric patients with LGG, focusing on serious adverse events as assessed by CTCAE v 4.03.

  Through study completion which is approximately 6.5 years (78 months)

• To define and describe the toxicities of the agents in combination and of single agent Vinblastine in this treatment naïve population as assessed by CTCAE v 4.03.

  Through study completion which is approximately 6.5 years (78 months)

• To evaluate the effect of Bevacizumab on growth and puberty by recording patient's height and using the Tanner Scale to measure puberty.

  Baseline, 28 days off therapy, and then annually for 5 years off therapy

Study Arms (2)

Arm A

ACTIVE COMPARATOR

68 weeks of single agent Vinblastine administered once weekly IV

Drug: Vinblastine

Arm B

EXPERIMENTAL

68 weeks of Vinblastine administered weekly IV with the addition of 12 doses of Bevacizumab administered every two weeks IV for the initial 24 weeks.

Drug: Vinblastine; Drug: Bevacizumab

Interventions

Vinblastine DRUG

Arm A; Arm B

Bevacizumab DRUG

Also known as: Avastin

Arm B

Eligibility Criteria

• Age: 6 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Children and adolescents aged 6 months to \< 18 years old with Low Grade Glioma (See Appendix I).
• All patients must submit tumour tissue (fresh tumour tissue is recommended) and have pathological confirmation of LGG and determination of BRAF characteristics from the Hospital for Sick Children. Exceptions will be made for patients with neurofibromatosis type 1 who have not previously had a biopsy. NF1 patients are eligible without tissue confirmation but must have definitive clinical or radiographic evidence of tumour progression or risk for significant neurologic deterioration requiring immediate therapy. If a tissue sample for NF1 patients is available from a previous biopsy, it is required to be submitted for Central Review at the Hospital for Sick Children. Please refer to the lab manual for further details.
• Patients must have progressive disease following surgical excision based on clear radiological or clinical evidence of progression, or an incomplete excision (\< 95% or \> 1.0 cm2 residual tumour) with necessity to begin treatment because of a risk of neurological impairment with progression.
• All patients on study must have measurable tumour (\>1.0 cm2 of residual tissue if resection has been performed) within 28 days of enrollment.
• Patients must have received no prior therapy including chemotherapy, biological modifiers and/or radiation treatment for the tumour with the exception of surgery.
• Patient is able to start treatment within 14 working days after randomization.
• Post pubertal teenagers who are sexually active agree to use two methods of contraception during the treatment period and for at least 6 months after the last dose of study drug. Please refer to Appendix V for a list of acceptable methods of contraception.
• Lansky performance status \> 50% for patients \< 16 years of age. Karnofsky performance status \> 50% for patients ≥ 16 years of age.
• Patients with neurologic deficits must have deficits that are stable for a minimum of 1 week prior to enrollment.
• Patients receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment.
• Life expectancy \> 2 months at the time of enrollment.
• Parents/guardians must provide written informed consent and to agree that they (and the patient) will comply with the study protocol.
• Written assent by patient according to institutional guidelines.
• Patients must have adequate bone marrow function within 2 weeks prior to enrollment:
• Hemoglobin ≥ 10 g/dL (may be supported )

You may not qualify if:

• Children under 6 months of age.
• Pregnant or lactating females.
• Use of any investigational agent, systemic, targeted or immunotherapy prior to the first dose of study treatment.
• Any bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation).
• Patients with evidence of new symptomatic CNS hemorrhage (\> grade I) on baseline MRI.
• Any significant cardiovascular disease, e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis, CVAs, transient ischemic attacks (TIAs), and systemic hypertension (i.e., a systolic and diastolic BP ≥ 95th percentile for age, sex), prior history of hypertensive crisis or hypertensive encephalopathy or stroke, uncontrolled cardiac arrhythmia within 6 months prior to enrollment .
• Any previous venous thromboembolism Grade 3 or higher (NCI CTCAE v. 4.03).
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.
• Unresolved infection.
• An active peptic or duodenal ulcer.
• Major surgical procedure (see Table 3 section 6.1.7), brain surgery, open biopsy or significant traumatic injury within 28 days prior to enrollment or the anticipation of the need for major (elective) surgery during the course of the study treatment.
• Intermediate surgical procedure (see Table 3 section 6.1.7) within 2 weeks of enrollment.
• Minor surgical procedures (see Table 3 section 6.1.7) within 3 days prior to the start of treatment (including the placement of a central line, including PICC line). Insertion of a port-a-cath will require a 7-day interval prior to the start of treatment.
• Non-healing surgical wound.
• A bone fracture that has not satisfactorily healed.

Sponsors & Collaborators

• The Hospital for Sick Children: lead
• Hoffmann-La Roche: collaborator

Study Sites (21)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital at Westmead

Westmead, New South Wales, Australia

Location

Queensland Children's Hospital

South Brisbane, Queensland, Australia

Location

Women's and Children's Hospital

North Adelaide, South Australia, Australia

Location

Royal Children's Hospital

Parkville, Victoria, Australia

Location

Perth Children's Hospital

Nedlands, Western Australia, Australia

Location

Alberta Children's Hospital

Calgary, Alberta, Canada

Location

Stollery Children's Hospital

Edmonton, Alberta, Canada

Location

BC Children's Hospital

Vancouver, British Columbia, Canada

Location

Cancer Care Manitoba

Winnipeg, Manitoba, Canada

Location

McMaster Children's Hospital

Hamilton, Ontario, Canada

Location

Children's Hospital - London Health Sciences Centre

London, Ontario, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, Canada

Location

Montreal Children's Hospital

Montreal, Quebec, Canada

Location

CHU du Quebec-Universite Laval

Québec, Quebec, Canada

Location

Starship Children's Hospital

Grafton, Auckland, New Zealand

Location

MeSH Terms

Interventions

Vinblastine; Bevacizumab

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Eric Bouffet, MD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Physician, Paediatric Neuro-Oncology Program

Model Details: Cross over to bevacizumab-vinblastine allowed in case of progression on vinblastine only

Study Record Dates

• First Submitted: January 28, 2016
• First Posted: July 21, 2016
• Study Start: August 1, 2016
• Primary Completion: July 31, 2024
• Study Completion (Estimated): August 1, 2026
• Last Updated: January 31, 2024

Record last verified: 2024-01

Locations

NZ (1); US (5); AU (5); CA (10)