A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML

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

Sponsors

Lead Sponsor: Novartis Pharmaceuticals

Source Novartis
Brief Summary

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).

Overall Status Recruiting
Start Date 2019-03-13
Completion Date 2029-02-15
Primary Completion Date 2025-08-18
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Part 1 of the study: Occurence of dose limiting toxicities (DLT) 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. 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. From the start of treatment up to 5 years follow-up of last patient
Secondary Outcome
Measure Time Frame
Percentage of participants with complete response (CR or modified CRi) From the start of treatment in Block 1 to the end of Block 2, from Day 1 up to Day 84
Time to response (TTR) and response duration From the start of treatment up to 5 years follow-up of last patient
Event Free Survival (EFS) From the start of treatment to time when all patients have completed at least 18 months of follow up (~ 48 months)
Overall Survival (OS) At each visit, every 3 months after last follow-up visit and up to 5 years after last patient first treatment
Disease free survival (DFS) From the start of treatment up to 5 years follow-up of last patient
Percentage of participants with MRD negative status during each study phase 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)
Palatability of oral solution of midostaurin 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)
Percentage of blasts in bone marrow and peripheral blood Parameters are assessed 14 days after end of chemotherapy induction Block 1 and Day 14 induction Block 2
Plasma concentrations of midostaurin and its 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, 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)
Enrollment 50
Condition
Intervention

Intervention Type: Drug

Intervention Name: Midostaurin

Description: midostaurin 30mg/m2 bid

Arm Group Label: Chemotherapy followed by Midostaurin

Other Name: PKC412

Intervention Type: Drug

Intervention Name: Fludarabine

Description: 30mg/m2/day on D1-D5 of Block 2 FLADx

Arm Group Label: Chemotherapy followed by Midostaurin

Other Name: Part 1 Block 2 induction FLADx

Intervention Type: Drug

Intervention Name: Cytarabine

Description: 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

Arm Group Label: Chemotherapy followed by Midostaurin

Intervention Type: Drug

Intervention Name: Daunorubicin or idarubicin

Description: daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx

Arm Group Label: Chemotherapy followed by Midostaurin

Other Name: Part 1 Block 2 induction FLADx

Intervention Type: Drug

Intervention Name: Mitoxantrone

Description: 10mg/m2/day D3 and D4

Arm Group Label: Chemotherapy followed by Midostaurin

Intervention Type: Drug

Intervention Name: Etoposide

Description: 100mg/m2/day D1 to D5

Arm Group Label: Chemotherapy followed by Midostaurin

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

Gender:

All

Minimum Age:

3 Months

Maximum Age:

17 Years

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Novartis Pharmaceuticals Study Director Novartis Pharmaceuticals
Overall Contact

Last Name: Novartis Pharmaceuticals

Phone: 1-888-669-6682

Email: [email protected]

Location
Facility: Status:
Childrens Hospital Colorado | Aurora, Colorado, 80045, United States Withdrawn
Miami Children s Hospital | Miami, Florida, 33155, United States Recruiting Jose Rodriguez-Alonso 305-668-5576 [email protected] Guillermo DeAngulo Principal Investigator
Novartis Investigative Site | Brno, 613 00, Czechia Recruiting
Novartis Investigative Site | Praha 5, 150 06, Czechia Recruiting
Novartis Investigative Site | Bologna, BO, 40138, Italy Recruiting
Novartis Investigative Site | Roma, RM, 00165, Italy Recruiting
Novartis Investigative Site | Napoli, 80100, Italy Recruiting
Novartis Investigative Site | Kobe-city, Hyogo, 650-0047, Japan Recruiting
Novartis Investigative Site | Setagaya-ku, Tokyo, 157-8535, Japan Recruiting
Novartis Investigative Site | Osaka, 534-0021, Japan Recruiting
Novartis Investigative Site | Saitama, 330 8777, Japan Recruiting
Novartis Investigative Site | Shizuoka, 420 8660, Japan Recruiting
Novartis Investigative Site | Amman, 11941, Jordan Recruiting
Novartis Investigative Site | Seoul, 03080, Korea, Republic of Recruiting
Novartis Investigative Site | Seoul, 05505, Korea, Republic of Recruiting
Novartis Investigative Site | Gdansk, 80 952, Poland Recruiting
Novartis Investigative Site | Krakow, Poland Recruiting
Novartis Investigative Site | Moscow, 117198, Russian Federation Recruiting
Novartis Investigative Site | Ljubljana, 1000, Slovenia Recruiting
Novartis Investigative Site | Antalya, 07070, Turkey Recruiting
Location Countries

Czechia

Italy

Japan

Jordan

Korea, Republic of

Poland

Russian Federation

Slovenia

Turkey

United States

Verification Date

2021-06-01

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Chemotherapy followed by Midostaurin

Type: Experimental

Description: 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.

Patient Data Yes
Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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