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Treatment of Children With Recurrent Refractory Brain/Solid Tumors and Recurrent Ependymoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03206021
Recruitment Status : Recruiting
First Posted : July 2, 2017
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
Vijay Ramaswamy, The Hospital for Sick Children

Tracking Information
First Submitted Date  ICMJE June 21, 2017
First Posted Date  ICMJE July 2, 2017
Last Update Posted Date January 18, 2020
Actual Study Start Date  ICMJE August 1, 2017
Estimated Primary Completion Date July 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 7, 2017)
Establish maximum tolerated dose of carboplatin in combination with 5'azacytidine [ Time Frame: 1 year ]
Number of participants with treatment-related adverse events as assessed by the CTCAE4.0
Original Primary Outcome Measures  ICMJE
 (submitted: June 28, 2017)
  • Establish maximum tolerated dose of carboplatin and 5'azacytidine [ Time Frame: 1 year ]
    Number of participants with treatment-related adverse events as assessed by the CTCAE4.0
  • Determine the safety and tolerability of carboplatin when combined with 5-azacitidine in recurrent/refractory ependymoma [ Time Frame: 3 years ]
    Number of participants with recurrent ependymoma with treatment-related adverse events as assessed by the CTCAE v4.0
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2017)
  • Characterization of the pharmacodynamics of 5'-azacitidine in combination with carboplatin [ Time Frame: 3 years ]
    Plasma pharmacodynamics will be assessed using methylation profiling of whole blood collected before and after administration of 5'Azacytidine, and after administration of carboplatin.
  • Assessment of intratumoral DNA demethylation as a preliminary indication of biological efficacy of this combination. [ Time Frame: 3 years ]
    Where feasible, two cycles of 5'azacytidine and carboplatin will be administered prior to a biopsy and/or gross total resection, and intratumoral DNA methylation profiles will be generated to determine the degree of intratumoral DNA demethylation.
  • Assessment of disease response as a preliminary indication of efficacy of this combination against recurrent, refractory pediatric brain and solid tumors [ Time Frame: 3 years ]
    Response to therapy, particularly in ependymoma will be evaluated to determine if a larger Phase II study is warranted.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Children With Recurrent Refractory Brain/Solid Tumors and Recurrent Ependymoma
Official Title  ICMJE Phase I/Ib Trial of Combined 5'Azacitidine and Carboplatin for Recurrent/Refractory Pediatric Brain and Solid Tumors
Brief Summary Many pediatric brain and solid tumors have altered epigenetic landscapes, and altered DNA methylation. As such this study is a Phase I/Ib study of combined 5'Azacitidine with an escalating dose of carboplatin for all recurrent/refractory pediatric brain and solid tumors. The phase I component will establish with maximum tolerated dose of carboplatin with azacytidine. An expansion cohort will be recruited of up to 30 patients will follow consisting of 20 recurrent posterior fossa ependymoma and 10 recurrent supratentorial ependymoma.
Detailed Description

Aberrant DNA methylation is frequently observed in many pediatric solid tumors, but in particularly several entities such as ependymoma, medulloblastoma, embryonal tumor with multilayered rosettes, atypical/teratoid rhabdoid tumor, neuroblastoma and wilm's tumor have promoter hypermethylation. Treatment with DNMTi (DNA methyltransferase inhibitors) agents such as 5-azacytidine has been shown to be safe and efficacious in adult myelodysplastic syndromes, causing significant decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. However, monotherapy with DNMTi has been shown to result in resistance in leukamia's and efficacy in solid tumours is limited. Synergy between DNMTi and platinum agents has shown promise in pre-clinical models including pediatric ependymoma, and in addition, the combination of demethylating agents with carboplatin has provided promising results in platinum resistant ovarian cancers. However, this approach has not been applied to pediatric solid malignancies, which are attractive targets due to their frequent epigenetic dysregulation.

Platinums are the backbone of therapy for most pediatric solid tumors, and as such it is an attractive hypothesis that part of the reason for resistance to upfront therapies is platinum resistance. Specifically, ependymoma's are highly chemoresistant tumors and studies in preclinical models of ependymoma support that this chemoresistance can be overcome with DNMTi.

There is a clear medical need for new therapies, particularly for relapsed solid tumors, specifically brain tumors. Although pre-clinical data from our group and others suggests DNA demethylase inhibitors to be promising therapies for high risk ependymoma, medulloblastoma and ETMR (embryonal tumor with multilayered rosettes), 5'azacitidine monotherapy has been disappointing in clinical studies of adult solid tumours. Previous studies have suggested that platinum therapy can be effectively combined with azacitidine therapy and based on adult studies, maximum demethylation occurs approximately 5-10 days after treatment with 5'azacitidine. As such combination of azacitidine and carboplatin is a rationale therapy for several pediatric brain tumours, particularly those with a hypermethylated phenotype.

Two phases of the study will be conducted. The Phase I will establish the maximum tolerated dose of carboplatin and 5'azacytidine in a rolling 6 design. 5'azacytidine will be administered on Days 1-7 followed by Carboplatin on Day 15. The initial dose level will be 5'Azacytidine 75mg/m2/day for 7 days with Carboplatin administered on Day 15 at AUC (Area under curve) 4. Carboplatin will be dose escalated to a maximum of AUC 6, or de-escalated to AUC 3. The Phase Ib will be an ependymoma specific expansion cohort at the established MTD (maximum tolerated dose), to determine the feasibility and initial efficacy of the combination of carboplatin and 5'azacytidine in patients with recurrent/refractory posterior fossa and supratentorial ependymoma.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Childhood CNS Tumor
  • Ependymoma, Recurrent Childhood
  • Childhood Solid Tumor
Intervention  ICMJE Drug: 5 Azacytidine
Dose escalation of carboplatin combined with 5'azacytidine
Other Name: Carboplatin
Study Arms  ICMJE
  • Experimental: Phase I Dose-escalation
    5'azacytidine will be administered on Days 1-7 at a dose of 75mg/m2/day, followed by escalating doses of Carboplatin on Day 14 in a rolling 6 design. Carboplatin will be dosed initially at AUC 4. Dose level -1 will reduce 5'azacytidine to 50mg/m2/day.
    Intervention: Drug: 5 Azacytidine
  • Experimental: Posterior Fossa Ependymoma Expansion Arm
    5'azacytidine will be administered on days 1-7 and carboplatin will be administered on day 14 at the maximum tolerated dose achieved in the Phase I dose escalation to 20 patients with recurrent/refractory posterior fossa ependymoma.
    Intervention: Drug: 5 Azacytidine
  • Experimental: Supratentorial Ependymoma Expansion Arm
    5'azacytidine will be administered on days 1-7 and carboplatin will be administered on day 14 at the maximum tolerated dose achieved in the Phase I dose escalation to 10 patients with recurrent/refractory supratentorial ependymoma.
    Intervention: Drug: 5 Azacytidine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 28, 2017)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 1, 2022
Estimated Primary Completion Date July 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Greater than the age of 1 year and under age 18 at the time of study enrolment
  2. Recurrent or refractory solid tumor (Phase I), or recurrent or refractory ependymoma (Phase Ib)
  3. Tissue from diagnosis or resection prior to registration must be available (either flash frozen tissue or an FFPE (formalin fixed paraffin embedded) block)
  4. Previous therapy with carboplatin will be permitted
  5. Failed first line treatment (surgery, radiation therapy or chemotherapy).
  6. Be at least 4 weeks from the completion of myelosuppressive chemotherapy and/or biologic agents before starting day 1 of this study treatment
  7. Be at least 3 months post hematopoetic stem cell rescue following myeloablative therapy before starting day 1 of this study treatment
  8. Must have visible disease on imaging. Resection of visible disease is permitted while on study after two cycles including achievement of a gross total resection. If a resection is performed while on study, fresh frozen tissue should be submitted for analysis.
  9. Concurrent medications will be limited to supportive medications including anti-emetics, steroids, analgesics and non-enzyme inducing anticonvulsants. Inducers of the P450 system will not be permitted. Other concurrent medications require approval of the study sponsor.
  10. Ability of the parent and/or child to understand and the willingness to sign a written informed consent document
  11. Karnofsky ≥ 50 for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I for the Karnofsky-Lansky Scores). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Patients with posterior fossa syndrome/cerebellar mutism demonstrating clear improvement post-surgically can be enrolled based on physician discretion.
  12. Adequate hepatic, renal, marrow and cardiac function as defined below within 14 days prior to cycle 1 day 1:

    • Serum creatinine within normal institutional limits or creatinine clearance greater than 60mL/min
    • Serum bilirubin <1.5 times upper limit of institutional normal. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis
    • AST, ALT and Alkaline Phosphatase <2.5 times upper limit of institutional normal. If liver metastases are present, then <5 times upper limit of normal is permitted.
    • Normal cardiac function with a normal QTc interval at screening ECG
    • Adequate marrow function defined below within 14 days prior to cycle 1 day 1:

      • Leukocytes greater than or equal to 3000 x10 to the power of 6/L
      • Absolute neutrophil count greater than or equal to 1 x10 to the power of 9/L
      • Platelets greater than or equal to 100 x10 to the power of 9/L
      • Hemoglobin greater than or equal to 10g/dL (may be transfused).

Exclusion Criteria:

  1. Female patient who is pregnant or breast feeding (Lactating females must agree not to breast feed while taking azacitidine) or with childbearing potential and not willing to use a double method of contraception up to 3 months after the end of study treatment. Male patient who is not willing to use a barrier method of contraception up to 6 months after the end of study treatment.
  2. Patients may not be receiving any other investigational agents within 30 days prior to day 1 of protocol treatment
  3. Prior therapy with a DNA demethylase inhibitor
  4. Evidence of cardiac toxicity (shortening fraction below 28%; shortening fraction measures and ratios the change in the diameter of the left ventricle between the contracted and relaxed states)
  5. Abnormal coagulation parameters (PT >15 seconds, PTT>40 seconds, and/or INR >1.5)
  6. Significant active cardiac disease within the previous 6 months including:

    • NYHA class 3 or 4 CHF
    • Unstable angina
    • Myocardial infarction
  7. Known or suspected hypersensitivity to azacitidine or mannitol carboplatin
  8. Previous carboplatin exposure is not an exclusion criteria but previous allergic reaction to carboplatin will exclude enrolment.
  9. Patient must not require use of enzyme inducing anticonvulsants; patients who are receiving an enzyme inducing anticonvulsant must be able to switch to a non-enzyme inducing anticonvulsant such as Levetiracetam, Clobazam, Lacosamide, Valproate or Topiramate at least 2 weeks prior to study enrolment.
  10. Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment)
  11. Active viral infection with HIV or hepatitis type B or C Patients with advanced malignant hepatic tumors
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Vijay Ramaswamy, MD PhD FRCPC 4168137654 ext 228973 vijay.ramaswamy@sickkids.ca
Listed Location Countries  ICMJE Australia,   Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03206021
Other Study ID Numbers  ICMJE OZM-077
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Vijay Ramaswamy, The Hospital for Sick Children
Study Sponsor  ICMJE The Hospital for Sick Children
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Vijay Ramaswamy, MD PhD FRCPC The Hospital for Sick Children
Principal Investigator: Peter Dirks, MD PhD FRCSC The Hospital for Sick Children
Principal Investigator: Eric Bouffet, MD The Hospital for Sick Children
Principal Investigator: Daniel Morgenstern, MD PhD The Hospital for Sick Children
PRS Account The Hospital for Sick Children
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP