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

Childhood Solid Tumor Clinical Trial

— COZMOS  

Official title:

Phase I/Ib Trial of COmbined 5'aZacitidine and Carboplatin for Recurrent/Refractory Pediatric Brain and Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03206021
• Other study ID #: OZM-077
• Status: Completed
• Phase: Phase 1
• Start date: August 1, 2017
• Est. completion date: March 1, 2024

Study information

• Verified date: April 2024
• Source: The Hospital for Sick Children
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: March 1, 2024
• Est. primary completion date: August 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

Inclusion Criteria:

1. Greater than the age of 1 year and under age 18 at the time of study enrolment

2. Recurrent or refractory brain or solid tumor, including recurrent or refractory ependymoma

3. Tissue from diagnosis or resection prior to registration must be available (either flash frozen tissue or an FFPE block)

4. Previous therapy with carboplatin will be permitted

5. Failed first line treatment (surgery, radiation therapy or chemotherapy) and should not be eligible for treatment with curative potential.

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 14 days from the completion of radiation therapy and MIBG before starting day 1 of this study treatment

8. Be at least 3 months post hematopoetic stem cell rescue following myeloablative therapy before starting day 1 of this study treatment

9. 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.

10. 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.

11. Ability of the parent and/or child to understand and the willingness to sign a written informed consent document

12. 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

13. 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).

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

12. Patients with advanced malignant hepatic tumors

Related Conditions & MeSH terms

• Central Nervous System Neoplasms
• Childhood Solid Tumor
• Ependymoma
• Ependymoma, Recurrent Childhood
• Neoplasms
• Recurrence
• Recurrent Childhood CNS Tumor

Intervention

Drug:
• 5 Azacytidine
Dose escalation of carboplatin combined with 5'azacytidine

Locations

Country	Name	City	State
Australia	Women's and Children's Hospital	Adelaide
Australia	Monash Children's Hospital	Clayton
Australia	John Hunter Children's Hospital	Lambton
Australia	Royal Children's Hospital Melbourne	Melbourne	Victoria
Australia	Perth Children's Hospital	Perth
Australia	Queensland Children's Hospital	South Brisbane
Australia	Sydney Children's Hospital	Sydney
Australia	Children's Hospital at Westmead	Westmead
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Centre hospitalier universitaire Sainte-Justine	Montréal	PQ
Canada	Montreal Children's Hospital	Montréal	PQ
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	BC Children's Hospital	Vancouver	British Columbia
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
The Hospital for Sick Children

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

References & 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 — View Citation

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 Veele — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	3 years
Secondary	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.	3 years
Secondary	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.	3 years