COZMOS:Phase I/Ib Trial of Combined 5'Azacitidine and Carboplatin for Recurrent/Refractory Pediatric Brain/Solid Tumors

NCT03206021 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: OZM-077
• Study Type: interventional
• Target: 31
• Locations: 3 countries
• Sites: 17

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.

Conditions

Recurrent Childhood CNS Tumor; Ependymoma, Recurrent Childhood; Childhood Solid Tumor

Outcome Measures

Primary Outcomes (1)

• Establish maximum tolerated dose of carboplatin in combination with 5'azacytidine

  Number of participants with treatment-related adverse events as assessed by the CTCAE4.0

  1 year

Secondary Outcomes (3)

• Characterization of the pharmacodynamics of 5'-azacitidine in combination with carboplatin

  3 years

• Assessment of intratumoral DNA demethylation as a preliminary indication of biological efficacy of this combination.

  3 years

• Assessment of disease response as a preliminary indication of efficacy of this combination against recurrent, refractory pediatric brain and solid tumors

  3 years

Study Arms (3)

Phase I Dose-escalation

EXPERIMENTAL

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.

Drug: 5 Azacytidine

Posterior Fossa Ependymoma Expansion Arm

EXPERIMENTAL

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.

Drug: 5 Azacytidine

Recurrent Brain and Solid Tumour Expansion Arm

EXPERIMENTAL

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 up to 12 patients with recurrent/refractory brain and solid tumour.

Drug: 5 Azacytidine

Interventions

5 Azacytidine DRUG

Dose escalation of carboplatin combined with 5'azacytidine

Also known as: Carboplatin

Phase I Dose-escalation; Posterior Fossa Ependymoma Expansion Arm; Recurrent Brain and Solid Tumour Expansion Arm

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Greater than the age of 1 year and under age 18 at the time of study enrolment
• Recurrent or refractory brain or solid tumor, including recurrent or refractory ependymoma
• Tissue from diagnosis or resection prior to registration must be available (either flash frozen tissue or an FFPE block)
• Previous therapy with carboplatin will be permitted
• Failed first line treatment (surgery, radiation therapy or chemotherapy) and should not be eligible for treatment with curative potential.
• Be at least 4 weeks from the completion of myelosuppressive chemotherapy and/or biologic agents before starting day 1 of this study treatment
• Be at least 14 days from the completion of radiation therapy and MIBG before starting day 1 of this study treatment
• Be at least 3 months post hematopoetic stem cell rescue following myeloablative therapy before starting day 1 of this study treatment
• 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.
• Concurrent medications will be limited to supportive medications/agents including but not limited to anti-emetics, steroids, analgesics and non-enzyme inducing anticonvulsants. Strong inducers of the P450 system will not be permitted. Other concurrent medications require approval of the study Sponsor.
• Ability of the parent and/or child to understand and the willingness to sign a written informed consent document
• 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
• Adequate hepatic, renal, marrow and cardiac function as defined below within 28 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

You may not qualify if:

• 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.
• Patients may not be receiving any other investigational agents within 30 days prior to day 1 of protocol treatment
• Prior therapy with a DNA demethylase inhibitor
• 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)
• Abnormal coagulation parameters (PT \>15 seconds, PTT\>40 seconds, and/or INR \>1.5)
• Significant active cardiac disease within the previous 6 months including:
• NYHA class 3 or 4 CHF
• Unstable angina
• Myocardial infarction
• Known or suspected hypersensitivity to azacitidine or mannitol carboplatin
• 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.
• 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)
• Active viral infection with HIV or hepatitis type B or C Patients with advanced malignant hepatic tumors
• Patients with advanced malignant hepatic tumors

Sponsors & Collaborators

• The Hospital for Sick Children: lead

Study Sites (17)

Children's National Medical Center

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

Location

Royal Children's Hospital Melbourne

Melbourne, Victoria, Australia

Location

Women's and Children's Hospital

Adelaide, Australia

Location

Monash Children's Hospital

Clayton, Australia

Location

John Hunter Children's Hospital

Lambton, Australia

Location

Perth Children's Hospital

Perth, Australia

Location

Queensland Children's Hospital

South Brisbane, Australia

Location

Sydney Children's Hospital

Sydney, Australia

Location

Children's Hospital at Westmead

Westmead, Australia

Location

Alberta Children's Hospital

Calgary, Alberta, Canada

Location

BC Children's Hospital

Vancouver, British Columbia, Canada

Location

McMaster Children's Hospital

Hamilton, Ontario, Canada

Location

London Health Sciences Centre

London, Ontario, Canada

Location

Children's Hospital of Eastern Ontario

Ottawa, Ontario, Canada

Location

Hospital for Sick Children

Toronto, Ontario, M5G1X8, Canada

Location

Centre hospitalier universitaire Sainte-Justine

Montreal, PQ, Canada

Location

Montreal Children's Hospital

Montreal, PQ, Canada

Location

Related Publications (2)

• Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM, Wang X, Gallo M, Garzia L, Zayne K, Zhang X, Ramaswamy V, Jager N, Jones DT, Sill M, Pugh TJ, Ryzhova M, Wani KM, Shih DJ, Head R, Remke M, Bailey SD, Zichner T, Faria CC, Barszczyk M, Stark S, Seker-Cin H, Hutter S, Johann P, Bender S, Hovestadt V, Tzaridis T, Dubuc AM, Northcott PA, Peacock J, Bertrand KC, Agnihotri S, Cavalli FM, Clarke I, Nethery-Brokx K, Creasy CL, Verma SK, Koster J, Wu X, Yao Y, Milde T, Sin-Chan P, Zuccaro J, Lau L, Pereira S, Castelo-Branco P, Hirst M, Marra MA, Roberts SS, Fults D, Massimi L, Cho YJ, Van Meter T, Grajkowska W, Lach B, Kulozik AE, von Deimling A, Witt O, Scherer SW, Fan X, Muraszko KM, Kool M, Pomeroy SL, Gupta N, Phillips J, Huang A, Tabori U, Hawkins C, Malkin D, Kongkham PN, Weiss WA, Jabado N, Rutka JT, Bouffet E, Korbel JO, Lupien M, Aldape KD, Bader GD, Eils R, Lichter P, Dirks PB, Pfister SM, Korshunov A, Taylor MD. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014 Feb 27;506(7489):445-50. doi: 10.1038/nature13108. Epub 2014 Feb 19.

  PMID: 24553142 RESULT

• Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW, Jones DT, Luu B, Cavalli FM, Aldape K, Remke M, Mynarek M, Rutkowski S, Gururangan S, McLendon RE, Lipp ES, Dunham C, Hukin J, Eisenstat DD, Fulton D, van Landeghem FK, Santi M, van Veelen ML, Van Meir EG, Osuka S, Fan X, Muraszko KM, Tirapelli DP, Oba-Shinjo SM, Marie SK, Carlotti CG, Lee JY, Rao AA, Giannini C, Faria CC, Nunes S, Mora J, Hamilton RL, Hauser P, Jabado N, Petrecca K, Jung S, Massimi L, Zollo M, Cinalli G, Bognar L, Klekner A, Hortobagyi T, Leary S, Ermoian RP, Olson JM, Leonard JR, Gardner C, Grajkowska WA, Chambless LB, Cain J, Eberhart CG, Ahsan S, Massimino M, Giangaspero F, Buttarelli FR, Packer RJ, Emery L, Yong WH, Soto H, Liau LM, Everson R, Grossbach A, Shalaby T, Grotzer M, Karajannis MA, Zagzag D, Wheeler H, von Hoff K, Alonso MM, Tunon T, Schuller U, Zitterbart K, Sterba J, Chan JA, Guzman M, Elbabaa SK, Colman H, Dhall G, Fisher PG, Fouladi M, Gajjar A, Goldman S, Hwang E, Kool M, Ladha H, Vera-Bolanos E, Wani K, Lieberman F, Mikkelsen T, Omuro AM, Pollack IF, Prados M, Robins HI, Soffietti R, Wu J, Metellus P, Tabori U, Bartels U, Bouffet E, Hawkins CE, Rutka JT, Dirks P, Pfister SM, Merchant TE, Gilbert MR, Armstrong TS, Korshunov A, Ellison DW, Taylor MD. Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol. 2016 Jul 20;34(21):2468-77. doi: 10.1200/JCO.2015.65.7825. Epub 2016 Jun 6.

  PMID: 27269943 RESULT

MeSH Terms

Conditions

Central Nervous System Neoplasms; Ependymoma

Interventions

Azacitidine; Carboplatin

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Coordination Complexes

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Physician

Study Record Dates

• First Submitted: June 21, 2017
• First Posted: July 2, 2017
• Study Start: August 1, 2017
• Primary Completion: August 31, 2022
• Study Completion: March 1, 2024
• Last Updated: April 5, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (8); US (1); AU (8)