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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-004830-28 | EudraCT Number |
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This study will evaluate the safety, efficacy and pharmacokinetics of midostaurin in combination with standard chemotherapy in pediatrics patients with newly diagnosed FLT3-mutated Acute Myeloid Leukemia. The study has two parts: Part 1 to define the Recommended Phase 2 Dose, and Part 2 to evaluate safety and tolerability and efficacy of midostaurin. Both parts will consist of 2 induction blocks, 3 consolidation blocks, 12 cycles of post-consolidation consisting of continuous therapy with midostaurin, and a follow-up phase.
This trial is an open label, multi center single arm study to evaluate twice daily oral midostaurin with standard induction, consolidation chemotherapy with sequential midostaurin therapy for 5 treatment blocks (2 induction blocks, 3 consolidation blocks, followed by single agent midostaurin post consolidation therapy for 12 cycles).
The total maximum planned duration on treatment is 17 cycles (5 blocks and 12 cycles). A block is defined as the time from start of study treatment to the time of hematopoietic recovery, at the latest at Day (D) 42, or determination of persistent disease, whichever occur first.
In both Part 1 and Part 2, patients will receive the first course of induction chemotherapy according to local standard and duration is from 8 to 12 days. Upon FLT3 mutation confirmation, patients will receive midostaurin for 14 days. After determination of remission and hematopoietic recovery, patients will receive Block 2.
In Part 1:
Patients in continuous remission with hematopoietic recovery will receive continuous post consolidation therapy of midostaurin, during 12 cycles (28 days per cycle).
In Part 1 of the study, patients in cohorts of 3 will receive sequential midostaurin administered at 30mg/m2bid. If the 30mg/m2 bid is well tolerated as measured by the Dose Limited Toxicity (DLT) rate during Bock 1, additional patients in cohort of 3 will be treated with sequential midostaurin at 60mg/m2 bid. When the recommended phase 2 dose (RP2D) is confirmed, subsequent patients will be treated in Part 2 of the study at the RP2D.
In Part 2:
Patients in continuous remission with hematopoietic recovery will receive continuous post consolidation therapy of midostaurin, during 12 cycles (28 days per cycle). Patients who relapse will discontinue further study treatment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Chemotherapy followed by Midostaurin | Experimental | In Part 1, midostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing fludarabine, cytarabine, daunorubicin/idarubicin) and consolidation (Block 3: cytarabine + mitoxantrone, Block 4: cytarabine + etoposide, Block 5: cytarabine) followed by single agent midostaurin post-consolidation therapy. In Part 2, midostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing cytarabine + mitoxantrone) and consolidation (Block 3: cytarabine + etoposide, Block 4: cytarabine + mitoxantrone, Block 5: cytarabine) followed by single agent midostaurin post-consolidation therapy. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Midostaurin | Drug | midostaurin 30mg/m2 bid |
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| Measure | Description | Time Frame |
|---|---|---|
| Part 1 of the study: Occurence of dose limiting toxicities (DLT) | Dose-limiting toxicity (DLT) is defined as any death due to toxicity related to study treatment (chemotherapy + midostaurin) and/or any CTCAE grade 4 non-hematological adverse event or abnormal laboratory value grade 4 related to study treatment unless the event improves sufficiently by day 42 and therefore does not further delay the next cycle of study treatment. | From the start of midostaurin treatment in Block 1 to the end of Block 2, from Day 1 to Day 84 |
| Part 2 of the study: To evaluate Safety of midostaurin (30mg/m2 bid or 1 mg/kg bid for participants <10 kg body weight) in sequential combination with chemotherapy followed by 12 cycles of midostaurin post-consolidation therapy. | Safety profile includes type, frequency and severity of adverse events during the induction, consolidation and post consolidation phase. AEs are also collected during post treatment follow-up phase | From the start of treatment up to 5 years follow-up of last patient |
| Part 2 of the study: To evaluate Tolerability of midostaurin (30mg/m2 bid or 1 mg/kg bid for participants <10 kg body weight) in sequential combination with chemotherapy followed by 12 cycles of midostaurin post-consolidation therapy. | Number of dose interruptions/reductions and discontinuations due to study drug | From the start of treatment up to 5 years follow-up of last patient |
| Measure | Description | Time Frame |
|---|---|---|
| Part 2 of the study: Percentage of participants with response (CR, CR/modified CRi and CR/CRi) | Percentage of participants with a response of CR, CRi or modified CRi at the end of Block 2 | From the start of treatment in Block 1 to the end of Block 2, from Day 1 up to Day 84 |
| Part 2 of the study: Time to response (TTR) and response duration |
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Inclusion Criteria:
Exclusion Criteria:
Other protocol-defined inclusion/exclusion criteria may apply
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Prague | 150 06 | Czechia | |||
| Novartis Investigative Site |
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
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| Fludarabine | Drug | 30mg/m2/day on D1-D5 of Block 2 FLADx |
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| Cytarabine | Drug | Part 1: 2000mg/m2/day D1 to D5 of Block 2 FLADx 1000mg/m2 every 12 hours D1 to D3 Block 3 HAM 3000mg/m2 every 12 hours D1 to D3 Block 4 HA3E 3000mg/m2 every 12 hours D1 to D3 Block 5 HIDAC Part 2: 1000mg/m2 every 12 hours D1 to D3 Block 2 HAM 3000mg/m2 every 12 hours D1 to D3 Block 3 HA3E 1000mg/m2 every 12 hours D1 to D3 Block 4 HAM 3000mg/m2 every 12 hours D1 to D3 Block 5 HIDAC |
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| Daunorubicin or idarubicin | Drug | daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx |
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| Mitoxantrone | Drug | 10mg/m2/day D3 and D4 |
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| Etoposide | Drug | 100mg/m2/day D1 to D5 |
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TTR is defined as the time between start of treatment to the date of first onset of response (CR, CRi or modified CRi). Response duration is defined as the time from CR, CRi or modified CRi to relapse or death due to any cause. |
| From the start of treatment up to 5 years follow-up of last patient |
| Part 2 of the study: Event Free Survival (EFS) | EFS is defined as the time from Day 1 of chemotherapy until an EFS event is observed. An EFS event is defined as a failure to obtain CR/Modified CRi within induction, relapse after CR/modified CRi, or death due to any cause, whichever occurs first. EFS will be measured after all participants completed at least 18 months of follow-up. | From the start of treatment to time when all patients have completed at least 18 months of follow up (~ 48 months) |
| Part 2 of the study: Overall Survival (OS) | OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause. | At each visit, every 3 months after last follow-up visit and up to 5 years after last patient first treatment |
| Part 2 of the study: Disease free survival (DFS) | DFS is defined as the time from CR/modified CRi in induction to relapse or death due to any cause | From the start of treatment up to 5 years follow-up of last patient |
| Part 2 of the study: Percentage of participants with MRD negative status during each study phase | Percentage of patient with MRD negative status by multiparameter flow cytometry | MRD is evaluated at Day 14 after end of chemotherapy induction Block 1, at Day 21 of Blocks 2, 3, 4 and 5, and Cycle 7 during post-consolidation phase (each block could last up to 42 days) |
| Part 2 of the study: Palatability of oral solution of midostaurin | Palatability is assessed through questionnaires- Palatability PRO and obsPRO | Day 14 after end of chemotherapy induction Block 1, Day 21 of Blocks 2, 3, 4 and 5 (each block can last up to 42 days), post-consolidation Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11 |
| Part 2 of the study: Percentage of blasts in bone marrow and peripheral blood | Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction Block 1 and Block 2 | Parameters are assessed 14 days after end of chemotherapy induction Block 1 and Day 14 induction Block 2 |
| Part 1 and Part 2 of the study: Plasma concentrations of midostaurin and its metabolites | Plasma concentration of midostaurin and its 2 metabolites | Days 1, 7 & 14 after end of local chemotherapy-induction in Block 1, Days 14 & 21 of Block 2, Day 21 of Blocks 3, 4 & 5 (each block can last up to 42 days), in-post consolidation Day 1 of Cycle (C)2, C3, C5, C7, C9 and C12 (each cycle = 28 days) |
| Berlin |
| 13353 |
| Germany |
| Novartis Investigative Site | Essen | 45147 | Germany |
| Novartis Investigative Site | Pavia | PV | 27100 | Italy |
| Novartis Investigative Site | Roma | RM | 00165 | Italy |
| Novartis Investigative Site | Torino | TO | 10126 | Italy |
| Novartis Investigative Site | Naples | 80122 | Italy |
| Novartis Investigative Site | Osaka | 5340021 | Japan |
| Novartis Investigative Site | Amman | 11941 | Jordan |
| Novartis Investigative Site | Krakow | 30-663 | Poland |
| Novartis Investigative Site | Moscow | 117198 | Russia |
| Novartis Investigative Site | Ljubljana | 1000 | Slovenia |
| Novartis Investigative Site | Seoul | 03080 | South Korea |
| Novartis Investigative Site | Seoul | 05505 | South Korea |
| Novartis Investigative Site | Adana | Adana | 1330 | Turkey (Türkiye) |
| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C059539 | midostaurin |
| C024352 | fludarabine |
| D003561 | Cytarabine |
| D003630 | Daunorubicin |
| D015255 | Idarubicin |
| D008942 | Mitoxantrone |
| D005047 | Etoposide |
| ID | Term |
|---|---|
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001087 | Arabinonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D000880 | Anthraquinones |
| D000095322 | Anthrones |
| D000873 | Anthracenes |
| D011809 | Quinones |
| D011034 | Podophyllotoxin |
| D013764 | Tetrahydronaphthalenes |
| D009281 | Naphthalenes |
| D005960 | Glucosides |
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