Study of Vinblastine and Sirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors Including Central Nervous System Tumors

This study has been completed.
Sponsor:
Collaborator:
Solving Kids’ Cancer
Information provided by (Responsible Party):
Sylvain Baruchel, The Hospital for Sick Children
ClinicalTrials.gov Identifier:
NCT01135563
First received: June 1, 2010
Last updated: December 2, 2013
Last verified: December 2013
  Purpose

This study is a Phase I study using vinblastine and sirolimus in patients with relapsed solid tumors including selected brain tumors and lymphoma. The investigators hypothesis is that the combination administration of weekly vinblastine and sirolimus is safe.


Condition Intervention Phase
Solid Tumors
Central Nervous System Tumors
Drug: Vinblastine and Sirolimus
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Vinblastine and Sirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors Including CNS Tumors

Resource links provided by NLM:


Further study details as provided by The Hospital for Sick Children:

Primary Outcome Measures:
  • Maximum tolerated dose of vinblastine in combination with sirolimus [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Dose will be escalated every 3 to 6 patients using the 3+3 standard design regimen. Enrollment of the next cohort will occur after the previous cohort has completed a full cycle without any dose limiting toxicity (DLT). If a DLT is observed in 1 out of 3 patients during the first cycle, 3 additional patients will be enrolled to receive the same dose. If a DLT is observed in another patient, 3 additional patients will be enrolled to receive a dose level below this dose. The MTD will be defined as the dose level below which DLTs are seen in ≥ 2 of at least 6 patients dosed.


Secondary Outcome Measures:
  • Safety data [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Safety data will be described for all patients receiving at least one dose of vinblastine and sirolimus. Safety data will include values for hematology, serum chemistry, vital signs, and adverse events. The proportion of patients experiencing adverse events, serious adverse events, dose limiting toxicities and treatment delays will be summarized for each dosing cohort.

  • Response Rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    The proportion of patients experiencing progressive disease, stable disease, partial responses or complete responses will be summarized in tabular format. Progression free survival and duration of any responses will also be summarized.


Estimated Enrollment: 24
Study Start Date: April 2010
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vinblastine and Sirolimus
The standard 3+3 Phase 1 trial design will be used for the conduct of this study. Three to six patients can be concurrently enrolled onto a dose level. Accrual is suspended when a cohort of three has been enrolled until toxicity data for that cohort have been reported, or when the study endpoints have been met.
Drug: Vinblastine and Sirolimus

Patients will be enrolled to receive vinblastine and sirolimus in 28 day cycles. Using the 3+3 standard Phase1 design, vinblastine will be administered via IV push on Days 1, 8, 15, 22. The starting dose of 4 mg/m2 (Dose Level 1) is 67% of the established MTD (6 mg/m2) for this schedule in pediatrics. Dose escalation will take place in a standard 3+3 design, in which doses will increase by approximately 20 to 25% in successive 3-patient cohorts.

Sirolimus (rapamycin) will be given by mouth (tablet or suspension) once daily throughout the cycle. Ideally patients will remain on the same dose form (tablet or suspension) for the duration of the study. All patients will be assigned a target sirolimus serum trough

Other Names:
  • Vinblastine Sulfate Injection
  • Rapamune

Detailed Description:

Published data demonstrating a survival advantage of the vinblastine-sirolimus regimen vs single agent in an orthopotic neuroblastoma mouse model and our unpublished data support a VBL in vitro pro-apoptotic plasma concentration of 1-2 nM range and an anti angiogenic concentration of 2pM. These plasma concentrations are achievable with a 6 mg/m2 (apoptosis) and 1 mg/m2 VBL regimen (anti-angiogenesis) weekly regimen. We expect that vinblastine delivered at any given dose, as described in the protocol, will carry both anti-apoptotic and antiangiogenic activity. Safety and preliminary efficacy of both drugs in pediatric tumors support the development of a clinical trial.

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age: 0-21 years at the time of diagnosis
  2. Diagnosis: Histologic verification at either the time of original diagnosis or relapse of solid tumor including CNS tumors or lymphomas
  3. Disease Status: All refractory/recurrent solid tumors including CNS tumors (all Diffuse Intrinsic Brain Stem Gliomas excluded) and lymphomas that have relapsed after, or are refractory to, a chemotherapy-containing treatment regimen
  4. Measurable disease:

    • Measurable tumor by CT or MRI defined as >10 mm by spiral CT in at least one dimension
  5. Current disease state must be one for which there is currently no known curative therapy
  6. A negative urine pregnancy test is required for female participants of child bearing potential
  7. Organ Function Requirements:

    • adequate liver function as defined by AST or ALT < 5 x upper limit of normal, bilirubin ≤1.5 X upper limit of normal
    • adequate renal function: Serum creatinine < 1.5 X upper limit of normal for age
  8. Adequate Bone Marrow Function Defined as:

    • ANC ≥ 1000/mm3, platelets ≥ 75,000/mm3 and hemoglobin ≥ 90 g/L
    • Transfusions are permitted to meet these platelet and Hgb criteria, if the patient is known to have a history of bone marrow involvement with tumor
    • Patients with platelet counts < 75,000/ mm3 who are refractory to platelet transfusions are not eligible for this study
    • Patients requiring transfusions of platelets or RBC to meet eligibility criteria will not be evaluable for platelet or hgb/hct hematological toxicity
  9. Lansky Play Score (for patients < 16 years of age) must be more than 50 and/or ECOG performance status (for patients ≥ 16 years of age) must be 0 to 2
  10. Specific requirements for Neuroblastoma patients Stratum:

    • MIBG scan with positive uptake at minimum of one site (MIBG not required if subject's neuroblastoma is previously determined to not uptake MIBG and no measurable disease)
    • Bone marrow with tumor cells seen on routine morphology (not by NSE staining only) of bilateral aspirate and /or biopsy on one bone marrow sample
  11. Written informed consent

Exclusion Criteria:

  1. Lansky score <50%
  2. Investigational Drugs: Patients who are currently receiving another investigational drug(s)
  3. Previous treatment with Vinblastine and/or mTor inhibitors
  4. Anti-cancer Agents: Patients who are currently receiving other anticancer agents. Patients must have fully recovered from the effects of prior chemotherapy, generally at least 3 weeks from the most recent administration (6 weeks for nitrosoureas)
  5. Infection: Patients who have an uncontrolled infection are not eligible until the infection is judged to be well controlled
  6. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal
  7. One week from usage of hematopoietic Growth Factor
  8. Patients who are refractory to platelet transfusions
  9. Brain Stem Glioma patients
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01135563

Locations
United States, California
Rady Children's Hospital-San Diego
San Diego, California, United States, 92123
United States, Missouri
SSM Cardinal Glennon Children's Medical Center
St. Louis, Missouri, United States, 63104
United States, Vermont
Fletcher Allen Health Care
Burlington, Vermont, United States, 05401
Canada, Ontario
The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
CHU Sainte-Justine
Montreal, Quebec, Canada, H3T 1C5
Sponsors and Collaborators
The Hospital for Sick Children
Solving Kids’ Cancer
Investigators
Principal Investigator: Sylvain Baruchel, MD The Hospital for Sick Children, Toronto Canada
  More Information

No publications provided

Responsible Party: Sylvain Baruchel, Associate Staff Oncologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT01135563     History of Changes
Other Study ID Numbers: 1000016324
Study First Received: June 1, 2010
Last Updated: December 2, 2013
Health Authority: Canada: Health Canada
United States: Institutional Review Board

Keywords provided by The Hospital for Sick Children:
pediatrics
Solid Tumors
CNS Tumors
Vinblastine
Sirolimus
Recurrent
Refractory

Additional relevant MeSH terms:
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms
Neoplasms by Site
Nervous System Diseases
Vinblastine
Sirolimus
Everolimus
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 19, 2014