Description:
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.
Title
- Brief Title: A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML
- Official Title: A Phase II, Open-label, Single Arm Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Twice Daily Midostaurin (PKC412) Combined With Standard Chemotherapy and as a Single Agent Post-consolidation Therapy in Children With Untreated FLT3-mutated AML
Clinical Trial IDs
- ORG STUDY ID:
CPKC412A2218
- SECONDARY ID:
2017-004830-28
- NCT ID:
NCT03591510
Conditions
- FLT3-mutated Acute Myeloid Leukemia
Interventions
| Drug | Synonyms | Arms |
|---|
| Midostaurin | PKC412 | Chemotherapy followed by Midostaurin |
| Fludarabine | Part 1 Block 2 induction FLADx | Chemotherapy followed by Midostaurin |
| Cytarabine | Part 1:, Block 2 induction FLADx, Block 3 consolidation HAM, Block 4 consolidation HA3E, Block 5 consolidation HIDAC, Part 2:, Block 2 induction HAM, Block 3 consolidation HA3E, Block 4 consolidation HAM | Chemotherapy followed by Midostaurin |
| Daunorubicin or idarubicin | Part 1 Block 2 induction FLADx | Chemotherapy followed by Midostaurin |
| Mitoxantrone | Part 1:, Block 3 consolidation HAM, Part 2:, Block 2 induction HAM, Block 4 consolidation HAM | Chemotherapy followed by Midostaurin |
| Etoposide | Part 1:, Block 4 consolidation HA3E, Part 2:, Block 3 consolidation HA3E | Chemotherapy followed by Midostaurin |
Purpose
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.
Detailed Description
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:
- Block 2 FLADx treatment duration is D1 to D6, and midostaurin from D8 to D21. Patients
who achieve hematopoietic recovery at the latest at D42 from the first day of Block 2
will receive Block 3.
- Block 3 consolidation HAM treatment duration is D1 to D4, followed by midostaurin D8 to
D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day
of Block 3 will receive Block 4.
- Block 4 HA3E treatment duration is D1 to D5 followed by midostaurin D8 to D21. Patients
who achieve hematopoietic recovery at the latest at D42 from the first day of Block 4
will receive Block 5.
- Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. 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:
- Block 2 HAM treatment duration is D1 to D4 and midostaurin from D8 to D21. Patienta who
achieve hematopoietic recovery at the latest at D42 from the first day of Block 2 will
receive Block 3.
- Block 3 consolidation HA3E treatment duration is D1 to D5, followed by midostaurin D8 to
D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day
of Block 3 will receive Block 4.
- Block 4 HAM treatment duration is D1 to D4 followed by midostaurin D8 to D21. Patients
who achieve hematopoietic recovery at the latest at D42 from the first day of Block 4
will receive Block 5.
- Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. Patient
in continuous remission with hematopoietic recovery will receive continuous post
consolidation therapy of midostaurin, during 12 cycles (28 days per cycle).
Trial Arms
| Name | Type | Description | Interventions |
|---|
| 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. | - Midostaurin
- Fludarabine
- Cytarabine
- Daunorubicin or idarubicin
- Mitoxantrone
- Etoposide
|
Eligibility Criteria
Inclusion Criteria:
- Documented Diagnosis of previously untreated de novo AML according to WHO 2016
criteria
- Presence of a FLT3 mutation status with results available prior first dose of
Midostaurin
- Patients with Lansky or Karnofsky performance status equal or superior to 60
- Patient with the following laboratory value : AST and ALT ≤ 3times ULN
- Serum Total bilirubin ≤ 1.5times ULN
- Estimated creatinine clearance ≥30ml/min
Exclusion Criteria:
- Any concurrent malignancy, AML with Philadelphia Chromosome, AML-DS, JMML
- Symptomatic leukemic CNS involvement
- Isolated extramedullary leukemia, secondary AML and MDS
- Acute Promyelocytic Leukemia with the PML RARA rearrangement
- Patient who have received prior treatment with a FLT3 inhibitor.
Other protocol-defined inclusion/exclusion criteria may apply
| Maximum Eligible Age: | 17 Years |
| Minimum Eligible Age: | 3 Months |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Part 1 of the study: Occurence of dose limiting toxicities (DLT) |
| Time Frame: | From the start of midostaurin treatment in Block 1 to the end of Block 2, from Day 1 to Day 84 |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Percentage of participants with complete response (CR or modified CRi) |
| Time Frame: | From the start of treatment in Block 1 to the end of Block 2, from Day 1 up to Day 84 |
| Safety Issue: | |
| Description: | Percentage of participants with a complete response and modified CRi at the end of Block 2 |
| Measure: | Time to response (TTR) and response duration |
| Time Frame: | From the start of treatment up to 5 years follow-up of last patient |
| Safety Issue: | |
| Description: | TTR is defined as the time between start of treatment to the date of first onset of CRi or better response.
Response duration is defined as the time from CR/modified CRi to relapse or death due to AML. |
| Measure: | Event Free Survival (EFS) |
| Time Frame: | From the start of treatment to time when all patients have completed at least 18 months of follow up (~ 48 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Overall Survival (OS) |
| Time Frame: | At each visit, every 3 months after last follow-up visit and up to 5 years after last patient first treatment |
| Safety Issue: | |
| Description: | OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause. |
| Measure: | Disease free survival (DFS) |
| Time Frame: | From the start of treatment up to 5 years follow-up of last patient |
| Safety Issue: | |
| Description: | DFS is defined as the time from CR/modified CRi in induction to relapse or death due to any cause |
| Measure: | Percentage of participants with MRD negative status during each study phase |
| Time Frame: | 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) |
| Safety Issue: | |
| Description: | Percentage of patient with MRD negative status by multiparameter flow cytometry |
| Measure: | Palatability of oral solution of midostaurin |
| Time Frame: | Day 14 after end of chemotherapy induction Block 1, Day 21 of Blocks 2, 3, 4 and 5, Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11 post consolidation (each block could last up to 42 days) |
| Safety Issue: | |
| Description: | Palatability is assessed through questionnaires- Palatability PRO and obsPRO |
| Measure: | Percentage of blasts in bone marrow and peripheral blood |
| Time Frame: | Parameters are assessed 14 days after end of chemotherapy induction Block 1 and Day 14 induction Block 2 |
| Safety Issue: | |
| Description: | Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction Block 1 and Block 2 |
| Measure: | Plasma concentrations of midostaurin and its metabolites |
| Time Frame: | 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, Day 1 of Cycle (C)2, C3, C5, C7, C9 and C12 of post-consolidation (each block could last up to 42 days, each cycle = 28 days) |
| Safety Issue: | |
| Description: | Plasma concentration of midostaurin and its 2 metabolites |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Novartis Pharmaceuticals |
Trial Keywords
- PKC412
- Acute Myeloid Leukemia
- AML
- FLT3-mutated
- pediatric population
- midostaurin
- midostaurin combined with standard chemotherapy
- single agent post-consolidation therapy
- untreated FLT3-mutated AML
Last Updated
June 24, 2021
