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A Phase I/II study of Azacitidine (Vidaza®) in pediatric patients with relapsed high-grade pediatric MDS or JMML.


- candidate number8583
- NTR NumberNTR2578
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR25-okt-2010
- Secondary IDsITCC-015 Consortium Innovative Therapy for Children with Cancer
- Public TitleA Phase I/II study of Azacitidine (Vidaza®) in pediatric patients with relapsed high-grade pediatric MDS or JMML.
- Scientific TitleA Phase I/II study of Azacitidine (Vidaza®) in pediatric patients with relapsed high-grade pediatric MDS or JMML.
- ACRONYMVidaza study in pediatric MDS and JMML
- hypothesisThere is clear medical need in pediatric high-grade MDS and JMML to control disease pre-SCT without the disadvantages associated with intensive chemotherapy. So far no agents have been successfully applied in this window, or are specifically registered for use in these disease conditions.

Based on adult data in MDS using the hypomethylating agent azacitidine regarding efficacy, and the favorable safety profile, we feel that a study in pediatric MDS is warranted. There are unpublished data suggesting that hypermethylation is also an important mechanism of disease pathogenesis in JMML, which is a subentity of pediatric MDS.

There are available pediatric safety data using azacitidine dosages that are much higher than proposed in this study, therefore we decided not to dose-reduce azacitidine in this study but to use a similar dose as has been shown to be safe and effective in adult MDS. Apparently this dose results in adequate hypomethylation, whereas the leukemia studies in the past have focused on the use of azacitidine as a regular cytotoxic compound (hence MTD-based).

We aim at determining a recommended dose for pediatric MDS and JMML and provide preliminary efficacy data, as well as pharmacokinetics and dynamics.
- Healt Condition(s) or Problem(s) studiedJuvenile myelomonocytic leukemia (JMML), Pediatric myelodysplastic syndrome (MDS)
- Inclusion criteria1. Established diagnosis of advanced MDS or JMML according to EWOG-criteria, either newly diagnosed or relapsed/refractory disease after a prior stem cell transplantation;
2. 1 year to ≤ 18 years old;
3. Lansky play score > 60; or Karnofsky performance status > 60;
4. Life expectancy ≥ 3 months;
5. Normal renal function defined as less than or equal to NCI-CTCAE grade 1 (max 1.5 x ULN);
6. Normal liver function defined as less than or equal to NCI-CTCAE grade 1 (max 2.5 x ULN for transaminases and bilirubin);
7. No other chemotherapy within 3 weeks of start of study medication;
8. For JMML patients: no oxygen need due to pulmonary infiltration and saturation >92% without need for oxygen therapy;
9. For JMML patients: WBC > 20x109/l;
10. For relapsed patients: minimum 3 months following stem cell transplantation, and recovery of all acute toxic effects of prior chemotherapy/stem-cell transplantation;
11. Able to comply with scheduled follow-up and with management of toxicity;
12. For patients with childbearing potential, a negative pregnancy test should be available;
13. If applicable, both male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after stopping study treatment;
14. Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations.
- Exclusion criteria1. Other serious illnesses or medical conditions;
2. Noonan syndrome patients with stable or regressive disease;
3. Presence of genetic abnormalities indicative of AML according to WHO-criteria;
4. Isolated extramedullary disease or isolated CNS-localization;
5. Symptomatic CNS-involvement;
6. Current uncontrolled infection;
7. Evidence of cardiac toxicity (shortening fraction below 28%);
8. Concurrent treatment with any other anti-cancer therapy or investigational agents is not allowed;
9. Pregnant or lactating patients;
10. Patients who cannot be regularly followed up for psychological, social, familial or geographic reasons;
11. Patient with expected non compliance to toxicity management guidelines.
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- groupParallel
- Type2 or more arms, non-randomized
- Studytypeintervention
- planned startdate 1-jan-2011
- planned closingdate1-jan-2021
- Target number of participants24
- InterventionsVidaza will be given IV for 7 days with a 28-day interval.

In this study 4 subgroups of pediatric MDS and JMML patients are eligible, and will be enrolled in 4 different strata:
1. Stratum 1: Newly diagnosed patients with advanced MDS (RAEB or RAEB-t) in a ‘pre stem cell transplantation window’;
2. Stratum 2: Relapsed patients with advanced MDS in a ‘re-transplantation window’. At relapse azacitidine may also be continued when a 2nd transplant is not feasible, as long as the patient benefits from treatment;
3. Stratum 3: Newly diagnosed patients with JMML in a ‘pre stem cell transplantation window’;
4. Stratum 4: Relapsed patients with JMML in a ‘re-transplantation window’. Azacitidine may also be continued when a 2nd transplant is not feasible and as long as the patient benefits from treatment.
- Primary outcomeThe current study aims to establish the recommended dose, safety and preliminary efficacy of azacitidine administered IV in children with advanced newly diagnosed or relapsed/refractory MDS or JMML, in 4 different subgroups (strata) of patients. Recommended dose will be determined by:
1. Dose-limiting toxicities;
2. DLTs are AEs considered at least possibly drug-related and will be limited to the first course of azacitidine.
- Secondary outcome1. To determine the safety and tolerability of azacitidine per stratum;
2. To determine (preliminary) the hematological remission rate in these patients;
3. To describe the durability of response and long-term follow-up, including that of patients undergoing stem-cell transplant after treatment with azacitidine;
4. To determine the plasma pharmacokinetic parameters of azacitidine;
5. To study the pharmacodynamic effects of azacitidine in pediatric MDS and JMML.

Efficacy will be determined by response definitions:
1. For advanced MDS: Cheson et al, 2006;
2. For JMML :Chan et al, 2009.
- TimepointsResponse and safety will be evaluated at differen time-points according to the stratum the patient is included is. DLTs are limited to the 1st course of treatment.
- Trial web siteN/A
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESMD. PhD. C.M. Zwaan
- CONTACT for SCIENTIFIC QUERIESMD. PhD. C.M. Zwaan
- Sponsor/Initiator Erasmus Medical Center, Sophia Children's Hospital, Children Oncology Center Rotterdam (KOCR)
- Funding
(Source(s) of Monetary or Material Support)
Celgene corporation, Stichting Go4Children
- PublicationsN/A
- Brief summaryThis is an international, collaborative, prospective, open label, phase I/II trial to establish the recommended dose and preliminary efficacy of azacitidine in children with relapsed high-grade MDS or JMML. Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare malignant diseases of childhood. So far, stem cell transplantation is the only curative treatment option. No other agents are available to treat these diseases successfully, and HSCT results in approximately 50% survival only; hence there is clear unmet medical need. Over the past few years, we have increasing evidence that aberrant methylation contributes to the malignant phenotype of JMML and childhood advanced MDS. The demethylating agent azacitidine has been shown to improve survival in adults with MDS, but so far no studies are available in children with MDS or JMML. In the current study we want to establish the recommended dose and preliminary efficacy of azacitidine, in children with relapsed MDS or JMML in a pre-transplantation window. This study will provide a preliminary proof of concept whether a demethylating agent is able to induce responses in these diseases, and whether this agent indeed results in hypomethylation. Pharmacodynamic studies should provide this proof of concept. It needs to be mentioned that the HSCT procedure itself is not part of this protocol and should be performed under EWOG or institutional guidelines at the discretion of the principle investigator.

Two dose-levels will be studied:
1. Level 1: 75 mg/m2/day IV x 7 days with a 28-day interval;
2. Level 2: 100 mg/m2/day IV x 7 days with a 28-day interval.

In this study 2 subgroups of patients are eligible, which will be enrolled in 2 different strata:
1. Stratum 1: Relapsed patients with MDS in a ‘re-transplantation window’. At relapse azacitidine may also be continued when a 2nd transplant is not feasible, as long as the patient benefits from treatment;
2. Stratum 2: Relapsed patients with JMML in a ‘re-transplantation window’. Azacitidine may also be continued when a 2nd transplant is not feasible and as long as the patient benefits from treatment.

The patients in the two strata need to be analyzed separately as there may be marked differences in tolerability and response.

For the MDS arm, if there is at least one patient achieving response (defined as CR or PR) and there are no patients experiencing a dose-limiting toxicity among the three first patients in stage one, another three patients will be treated at the next higher dose level, if applicable. In case of 1 dose- limiting toxicity among the first three patients, the cohort will be expanded to 6 patients at the starting dose-level. If there is at least one out of six patients achieving response and no more than one patient experiences a dose-limiting toxicity in stage one, stage two shall open for enrolment. In case of no responses the arm shall be closed to enrollment. In case there is more than one dose- limiting toxicity in stage one, the dose is set to the previous level (if applicable), and stage 2 shall open for enrolment if at least one patient responded at that dose-level. Otherwise, the arm shall be closed to enrolment.

The dose will be increased only if <2 of the 6 evaluable patients (30%, across stage-one and stage- two) achieve a response, and/or there are ≤ two dose-limiting toxicities; otherwise the therapy will be deemed unpromising for further consideration.

For the JMML arm, the safety run-in will include 3 patients and the tolerability of the therapy will be considered using a classic 3+3 design. Should the therapy be considered tolerable, stage one shall enrol patients to a higher dose, or otherwise the patients in the safety run-in will be considered part of stage one. During stage-one, if ≥ 1 of the 3 evaluable patients for the primary endpoint achieve a response then stage two shall open to enrolment, or otherwise that arm shall be closed to enrolment. At the end of stage two, the therapy will be considered positive for possible further investigation if ≥ 2 of the 6 evaluable patients (30%, across stage-one and stage-two) achieve a response; or otherwise considered unpromising for further consideration.

We will recruit a maximum of 12 patients in each stratum, and hence 24 patients in total. Including screen failures or drop-outs or in case of DLTs we may need to recruit a maximum of 28 patients.

The study will last approximately 8 years from first patient first visit (FPFV) to last patient last visit (LPLV).
- Main changes (audit trail)14-10-2013:
- TARGET NUMBER OF PARTICIPANTS 60

Including approved amendment 1 and 2. Amendment 1:both IV and SC administration of azacitidine; Amendment 2: revised inclusion criteria, new stratum: stratum 5, newly diagnosed or relapsed secondary advanced MDS;

new inclusion criteria
1. Advanced primary or secondary MDS or JMML confirmed by the diagnostic criteria as specified in the EWOG-MDS 2006 protocol
2. 1 month to ≤ 18 years old;
3. Lansky play score > 60; or Karnofsky performance status > 60;
4. Life expectancy ≥ 3 months;
5. Normal renal function defined as less than or equal to NCI-CTCAE grade 1 (max 1.5 x ULN);
6. Normal liver function defined as less than or equal to NCI-CTCAE grade 1 (max 2.5 x ULN for transaminases and bilirubin);
7. No other chemotherapy within 3 weeks of start of study medication;For 6- MP or low-dose cytarabine in JMML patients 1 week wash-out time is sufficient
8. For JMML patients: saturation >92% without additional supply of oxygen
9. For JMML patients: peripheral blood monocyte count greater than 1.0x109/l
10. For relapsed patients following HSCT: recovery of all acute toxic effects of prior chemotherapy/stem-cell transplantation.
11. Able to comply with scheduled follow-up and with management of toxicity;
12.For patients with childbearing potential, a negative test for pregnancy is to be considered before entry on study. If applicable, use of an effective contraceptive method.
13. Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations.


new exlclusion criteria
1. Other serious illnesses or medical conditions; 2. Genetic abnormalities indicative of AML 3. JMML patients in whom a diagnosis of Noonan syndrome is suspected based on clinical history and/or presenting symptoms 4. Patients with secondary MDS with underlying bone-marrow failure syndromes or with familial MDS 5. Isolated extramedullary disease .6 Symptomatic CNS-involvement;7. Current uncontrolled infection;8. cardiac toxicity (shortening fraction below 28%); 9. Concurrent treatment with any other anti-cancer therapy or investigational agents is not allowed;10. Pregnant or lactating patients; 11. Patients who cannot be regularly followed up for psychological, social, familial or geographic reasons; 12. Patient with expected non compliance to toxicity management guidelines. 13 Prior treatment with a demethylating agent 14. Allergy to azicitidine or mannitol.

- INTERVENTIONS Vidaza will be given IV for 7 days with a 28-day interval. In this study 5 subgroups of pediatric MDS and JMML patients are eligible, and will be enrolled in 5 different strata: 1. Stratum 1: Newly diagnosed patients with advanced MDS (RAEB or RAEB-t) in a ‘pre stem cell transplantation window’; 2. Stratum 2: Relapsed patients with advanced MDS in a ‘re-transplantation window’. At relapse azacitidine may also be continued when a 2nd transplant is not feasible, as long as the patient benefits from treatment; 3. Stratum 3: Newly diagnosed patients with JMML in a ‘pre stem cell transplantation window’; 4. Stratum 4: Relapsed patients with JMML in a ‘re-transplantation window’. Azacitidine may also be continued when a 2nd transplant is not feasible and as long as the patient benefits from treatment. 5. Stratum 5: newly diagnosed or relapsed patients with secondary advanced MDS, occurring after chemotherapy, radiotherapy and or stem-cell transplantation, or secondary cases after prior treatment for aplastic anemia.


28-jul-2018 -IK:

INCLUSION CRITERIA:
1. Established diagnosis of advanced MDS or JMML according to EWOG-criteria, either newly diagnosed or relapsed/refractory disease after a prior stem cell transplantation;
2. 1 year to ≤ 18 years old;
3. Lansky play score > 60; or Karnofsky performance status > 60;
4. Life expectancy ≥ 3 months;
5. Normal renal function defined as less than or equal to NCI-CTCAE grade 1 (max 1.5 x ULN);
6. Normal liver function defined as less than or equal to NCI-CTCAE grade 1 (max 2.5 x ULN for transaminases and bilirubin);
7. No other chemotherapy within 3 weeks of start of study medication;
8. For JMML patients: no oxygen need due to pulmonary infiltration and saturation >92% without need for oxygen therapy;
9. For JMML patients: WBC > 20x109/l;
10. For relapsed patients: minimum 3 months following stem cell transplantation, and recovery of all acute toxic effects of prior chemotherapy/stem-cell transplantation;
11. Able to comply with scheduled follow-up and with management of toxicity;
12. For patients with childbearing potential, a negative pregnancy test should be available;
13. If applicable, both male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after stopping study treatment;
14. Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations.

replaced by

1. Established diagnosis of relapsed MDS or JMML according to EWOG-criteria, after a prior stem cell transplantation;
2. 1 month to ≤ 18 years old;
3. Lansky play score > 60; or Karnofsky performance status > 60;
4. Life expectancy ≥ 3 months;
5. Normal renal function defined as less than or equal to NCI-CTCAE grade 1 (max 1.5 x ULN);
6. Normal liver function defined as less than or equal to NCI-CTCAE grade 1 (max 2.5 x ULN for transaminases and bilirubin);
7. No other chemotherapy within 3 weeks of start of study medication; For 6-MP or low-dose cytarabine in JMML patients 1 week wash-out time is sufficient.
8. For JMML patients: no oxygen need due to pulmonary infiltration and saturation >92% without need for oxygen therapy;
9. For JMML patients: peripheral blood monocyte count > 1.0x109/l
10. For relapsed patients: minimum 3 months following stem cell transplantation, and recovery of all acute toxic effects of prior chemotherapy/stem-cell transplantation;
11. Able to comply with scheduled follow-up and with management of toxicity;
12. Reproductive Function
• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of child-bearing potential must agree to use an highly effective method of contraception approved by the investigator during the study and for 90 days after the last dose of azacitidine.
• Highly effective methods of contraception include (but not exclusively) the following contraceptive methodsFor patients with childbearing potential, a negative pregnancy test should be available;
13. Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations.



EXCLUSION CRITERIA:
1. Other serious illnesses or medical conditions;
2. Noonan syndrome patients with stable or regressive disease;
3. Presence of genetic abnormalities indicative of AML according to WHO-criteria;
4. Isolated extramedullary disease or isolated CNS-localization;
5. Symptomatic CNS-involvement;
6. Current uncontrolled infection;
7. Evidence of cardiac toxicity (shortening fraction below 28%);
8. Concurrent treatment with any other anti-cancer therapy or investigational agents is not allowed;
9. Pregnant or lactating patients;
10. Patients who cannot be regularly followed up for psychological, social, familial or geographic reasons;
11. Patient with expected non compliance to toxicity management guidelines.

replaced by

1. Prior or current history:
o Other serious illnesses or medical conditions
o Genetic abnormalities indicative of AML
2. JMML patients in whom a diagnosis of Noonan syndrome is suspected based on clinical history and/or presenting symptoms
3. Patients with secondary MDS with underlying bone-marrow failure syndromes or with familial MDS
4. Isolated extramedullary disease
5. Symptomatic CNS-involvement
6. Current uncontrolled infection
7. Cardiac toxicity (shortening fraction below 28%)
8. Concurrent treatment with any other anti-cancer therapy is not allowed
9. Pregnant or lactating patients
10. Patients who cannot be regularly followed up for psychological, social, familial or geographic reasons
11. Patient with expected non-compliance to toxicity management guidelines
12. Prior treatment with a demethylating agent
13. Allergy to azacitidine or mannitol.



INTERVENTIONS:
Vidaza will be given IV for 7 days with a 28-day interval.
In this study 4 subgroups of pediatric MDS and JMML patients are eligible, and will be enrolled in 4 different strata:
1. Stratum 1: Newly diagnosed patients with advanced MDS (RAEB or RAEB-t) in a ‘pre stem cell transplantation window’;
2. Stratum 2: Relapsed patients with advanced MDS in a ‘re-transplantation window’. At relapse azacitidine may also be continued when a 2nd transplant is not feasible, as long as the patient benefits from treatment;
3. Stratum 3: Newly diagnosed patients with JMML in a ‘pre stem cell transplantation window’;
4. Stratum 4: Relapsed patients with JMML in a ‘re-transplantation window’. Azacitidine may also be continued when a 2nd transplant is not feasible and as long as the patient benefits from treatment.

replaced by

Vidaza will be given IV for 7 days with a 28-day interval.
In this study 2 subgroups of pediatric MDS and JMML patients are eligible, and will be enrolled in 2 different strata:
1. Stratum 1: Relapsed patients with MDS in a ‘re-transplantation window’. At relapse azacitidine may also be continued when a 2nd transplant is not feasible, as long as the patient benefits from treatment;
2. Stratum 2: Relapsed patients with JMML in a ‘re-transplantation window’. Azacitidine may also be continued when a 2nd transplant is not feasible and as long as the patient benefits from treatment.


New protocol version 1.3, 13-02-2017
Major changes involving:
• IV administration and additional clarification on time-lines between dissolving and administration
• Removal of newly diagnosed and secondary MDS stratum as included in company sponsored studies by Celgene
• Revision of trial methodology (adding a formal design), and sample size calculation
• Adding language for highly effective methods of contraception. Male and female patients of child- bearing potential must agree to use an highly effective method of contraception approved by the investigator during the study and for 90 days after the last dose of azacitidine.
• Administrative changes, including adding a new statistician and institute change of one of the Coordinating Investigators
• Implementing information from recent IB releases
• Adapting study time-lines
• Relapse definitions for JMML and MDS were added
• Updated literature review
- RECORD25-okt-2010 - 28-jul-2018


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