Recurrent Childhood CNS TumorPhase 1COZMOSNCT03206021
COZMOS:Phase I/Ib Trial of Combined 5'Azacitidine and Carboplatin for Recurrent/Refractory Pediatric Brain/Solid Tumors
A Phase 1 study testing 5 Azacytidine in people with Recurrent Childhood CNS Tumor and Ependymoma, Recurrent Childhood, run by The Hospital for Sick Children at 17 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 year to 18 years
- Conditions the study is for
- Recurrent Childhood CNS Tumor, Ependymoma, Recurrent Childhood, Childhood Solid Tumor
- What is being tested?
- 5 Azacytidine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 31 participants
- Where
- 17 sitesin 3 countries
- Study dates
- 1 Aug 2017to 1 Mar 2024
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
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- 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
- AST, ALT and Alkaline Phosphatase <3 times upper limit of institutional normal. If liver metastases are present, then <5 times upper limit of normal is permitted.
- Normal QTc interval at screening ECG (baseline echocardiogram is not required)
- Adequate marrow function defined below within 14 days prior to cycle 1 day 1:
- Leukocytes greater than or equal to 1000 x106/L
- Absolute neutrophil count greater than or equal to 0.75 x109/L
- Platelets greater than or equal to 75 x109/L
- Hemoglobin greater than or equal to 10g/dL (may be transfused).
Who cannot join
- 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:
Show all 15Show fewer
- NYHA class 3 or 4 CHF
- Unstable angina
- Myocardial infarction
- Known or suspected hypersensitivity to azacitidine or mannitol carboplatin
- Previous carboplatin exposure is not an exclusion criteria but previous allergic reaction to carboplatin will exclude enrolment.
- 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
Trial locations and contacts
17 sites in 3 countries.
17 sites in 3 countries
Australia8 sites
Women's and Children's Hospital
Adelaide
Monash Children's Hospital
Clayton
John Hunter Children's Hospital
Lambton
Royal Children's Hospital Melbourne
Melbourne, Victoria
Perth Children's Hospital
Perth
Queensland Children's Hospital
South Brisbane
Sydney Children's Hospital
Sydney
Children's Hospital at Westmead
Westmead
Canada8 sites
Alberta Children's Hospital
Calgary, Alberta
McMaster Children's Hospital
Hamilton, Ontario
London Health Sciences Centre
London, Ontario
Centre hospitalier universitaire Sainte-Justine
Montreal, PQ
Montreal Children's Hospital
Montreal, PQ
Children's Hospital of Eastern Ontario
Ottawa, Ontario
Hospital for Sick Children
Toronto, Ontario, M5G1X8
BC Children's Hospital
Vancouver, British Columbia
United States1 site
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
Official title: Phase I/Ib Trial of COmbined 5'aZacitidine and Carboplatin for Recurrent/Refractory Pediatric Brain and Solid Tumors
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.
Read the 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.
- Being tested
- 5 Azacytidine
- Medical subject headings
- Central Nervous System Neoplasms, Ependymoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
5 AzacytidineDrug
Also called Carboplatin
Dose escalation of carboplatin combined with 5'azacytidine
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: 5 Azacytidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 1 year
Secondary outcomes (3)
Characterization of the pharmacodynamics of 5'-azacitidine in combination with carboplatin
Plasma pharmacodynamics will be assessed using methylation profiling of whole blood collected before and after administration of 5'Azacytidine, and after administration of carboplatin.
Measured: 3 years
Assessment of intratumoral DNA demethylation as a preliminary indication of biological efficacy of this combination.
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.
Measured: 3 years
Assessment of disease response as a preliminary indication of efficacy of this combination against recurrent, refractory pediatric brain and solid tumors
Response to therapy, particularly in ependymoma will be evaluated to determine if a larger Phase II study is warranted.
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2017
- Study start1 Aug 2017
- Primary completion31 Aug 2022
- Study completion1 Mar 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Recurrent Childhood CNS TumorStudies of the same condition, open and under way.
- More trials run by The Hospital for Sick ChildrenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 31 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Hospital for Sick Children
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Vijay Ramaswamy, The Hospital for Sick Children
- Investigators
- Vijay Ramaswamy, MD PhD FRCPC, Principal investigator, The Hospital for Sick ChildrenPeter Dirks, MD PhD FRCSC, Principal investigator, The Hospital for Sick ChildrenEric Bouffet, MD, Principal investigator, The Hospital for Sick ChildrenDaniel Morgenstern, MD PhD, Principal investigator, The Hospital for Sick Children
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03206021
- Sponsor's protocol ID
- OZM-077
- Acronym
- COZMOS
- Status last verified
- Apr 2024
- First submitted
- 21 Jun 2017
- Last updated
- 5 Apr 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 24553142Ramaswamy 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.
PubMed 27269943
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/Ib Trial of COmbined 5'aZacitidine and Carboplatin for Recurrent/Refractory Pediatric Brain and Solid Tumors
- ClinicalTrials.gov ID
- NCT03206021
- Acronym / sponsor ID
- COZMOS / OZM-077
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 31 participants (actual)
- Lead sponsor
- The Hospital for Sick ChildrenUniversity, hospital or other
- Study start
- 1 Aug 2017 (actual)
- Primary completion
- 31 Aug 2022 (actual)
- Study completion
- 1 Mar 2024 (actual)
- First posted
- 2 Jul 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Phase I Dose-escalation | Experimental | Drug: 5 Azacytidine5'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. |
| Posterior Fossa Ependymoma Expansion Arm | Experimental | Drug: 5 Azacytidine5'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. |
| Recurrent Brain and Solid Tumour Expansion Arm | Experimental | Drug: 5 Azacytidine5'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. |
Who may qualify
- Ages
- 1 year to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (22 listed)
- 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.
Key exclusion criteria (15 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 5 AzacytidineAlso: CarboplatinDose escalation of carboplatin combined with 5'azacytidine | Drug | Phase I Dose-escalation, Posterior Fossa Ependymoma Expansion Arm, Recurrent Brain and Solid Tumour Expansion Arm |
Primary outcome
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
3 secondary outcomes
Characterization of the pharmacodynamics of 5'-azacitidine in combination with carboplatin
Time frame: 3 years
Assessment of intratumoral DNA demethylation as a preliminary indication of biological efficacy of this combination.
Time frame: 3 years
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2024.
- Results publication: PubMed 24553142Mack 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.
- Results publication: PubMed 27269943Ramaswamy 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.
- Individual participant dataSharing planned: No
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RecruitingPhase 1
Immunotherapy for Malignant Pediatric Brain Tumors Employing Adoptive Cellular Therapy (IMPACT)
Medulloblastoma, Childhood, Atypical Teratoid/Rhabdoid Tumor of CNS
RecruitingPhase 1
GPC2-CAR T Cell Therapy for Relapsed or Refractory Medulloblastoma in Children and Young Adults
Medulloblastoma, Central Nervous System Embryonal Tumor
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vijay Ramaswamy, MD PhD FRCPC principal investigator
The Hospital for Sick Children
Peter Dirks, MD PhD FRCSC principal investigator
The Hospital for Sick Children
Eric Bouffet, MD principal investigator
The Hospital for Sick Children
17 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing 5 Azacytidine in people with Recurrent Childhood CNS Tumor and Ependymoma, Recurrent Childhood, run by The Hospital for Sick Children at 17 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in Australia, Canada, United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Establish maximum tolerated dose of carboplatin in combination with 5'azacytidine (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03206021, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2024.