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

• ClinicalTrials.gov Identifier: NCT03591510
• Recruitment Status: Recruiting
• First Posted: July 19, 2018
• Last Update Posted: October 19, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
FLT3-mutated Acute Myeloid Leukemia	Drug: Midostaurin; Drug: Fludarabine; Drug: Cytarabine; Drug: Daunorubicin or idarubicin; Drug: Mitoxantrone; Drug: Etoposide	Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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 documented CR (and 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. Patients who relapse will discontinue further study treatment.
• 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 who relapse will discontinue further study treatment.

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. Patients who achieve documented CR (and 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. Patients who relapse will discontinue further study treatment.
• 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. Patients who relapse will discontinue further study treatment.

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 13, 2019
• Estimated Primary Completion Date: August 18, 2025
• Estimated Study Completion Date: February 15, 2029

Arms and Interventions

Arm

Intervention/treatment

Experimental: Chemotherapy followed by Midostaurin; 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.

Drug: Midostaurin; midostaurin 30mg/m2 bid; Other Name: PKC412; Drug: Fludarabine; 30mg/m2/day on D1-D5 of Block 2 FLADx; Other Name: Part 1 Block 2 induction FLADx; Drug: Cytarabine; 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; Other Names: 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; Drug: Daunorubicin or idarubicin; daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx; Other Name: Part 1 Block 2 induction FLADx; Drug: Mitoxantrone; 10mg/m2/day D3 and D4; Other Names: Part 1:; Block 3 consolidation HAM; Part 2:; Block 2 induction HAM; Block 4 consolidation HAM; Drug: Etoposide; 100mg/m2/day D1 to D5; Other Names: Part 1:; Block 4 consolidation HA3E; Part 2:; Block 3 consolidation HA3E

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   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.
2. 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. [ Time Frame: From the start of treatment up to 5 years follow-up of last patient ]
   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
3. 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. [ Time Frame: From the start of treatment up to 5 years follow-up of last patient ]
   Number of dose interruptions/reductions and discontinuations due to study drug

Secondary Outcome Measures :

1. Part 2 of the study: Percentage of participants with response (CR, CR/modified CRi and CR/CRi) [ Time Frame: From the start of treatment in Block 1 to the end of Block 2, from Day 1 up to Day 84 ]
   Percentage of participants with a response of CR, CRi or modified CRi at the end of Block 2
2. Part 2 of the study: Time to response (TTR) and response duration [ Time Frame: From the start of treatment up to 5 years follow-up of last patient ]

   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.

3. Part 2 of the study: 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) ]

   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.

4. Part 2 of the study: 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 ]
   OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause.
5. Part 2 of the study: Disease free survival (DFS) [ Time Frame: From the start of treatment up to 5 years follow-up of last patient ]
   DFS is defined as the time from CR/modified CRi in induction to relapse or death due to any cause
6. Part 2 of the study: 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) ]
   Percentage of patient with MRD negative status by multiparameter flow cytometry
7. Part 2 of the study: 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 (each block can last up to 42 days), post-consolidation Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11 ]
   Palatability is assessed through questionnaires- Palatability PRO and obsPRO
8. Part 2 of the study: 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 ]
   Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction Block 1 and Block 2
9. Part 1 and Part 2 of the study: 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 (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) ]
   Plasma concentration of midostaurin and its 2 metabolites

Eligibility Criteria

• Ages Eligible for Study: 3 Months to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Documented Diagnosis of previously untreated de novo AML according to WHO 2016 criteria
• Presence of a FLT3 mutation status as measured/confirmed by a designated lab 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. However, up to 1 week of FLT3 inhibitor (except midostaurin) exposure prior to study enrollment is permissible.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

Locations

United States, Colorado

Novartis Investigative Site; Withdrawn

Aurora, Colorado, United States, 80045

United States, Florida

Novartis Investigative Site; Withdrawn

Miami, Florida, United States, 33155

Austria

Novartis Investigative Site; Recruiting

Wien, Austria, A 1090

Czechia

Novartis Investigative Site; Recruiting

Brno, Czechia, 613 00

Novartis Investigative Site; Recruiting

Praha 5, Czechia, 150 06

Germany

Novartis Investigative Site; Recruiting

Regensburg, Bavaria, Germany, 93053

Novartis Investigative Site; Recruiting

Berlin, Germany, 13353

Novartis Investigative Site; Recruiting

Essen, Germany, 45147

Novartis Investigative Site; Recruiting

Freiburg, Germany, 79106

Novartis Investigative Site; Recruiting

Halle, Germany, 06120

Greece

Novartis Investigative Site; Withdrawn

Athens, Greece, 115 27

Italy

Novartis Investigative Site; Recruiting

Bologna, BO, Italy, 40138

Novartis Investigative Site; Recruiting

Genova, GE, Italy, 16147

Novartis Investigative Site; Recruiting

Monza, MB, Italy, 20900

Novartis Investigative Site; Recruiting

Padova, PD, Italy, 35128

Novartis Investigative Site; Recruiting

Pavia, PV, Italy, 27100

Novartis Investigative Site; Recruiting

Roma, RM, Italy, 00165

Novartis Investigative Site; Recruiting

Torino, TO, Italy, 10126

Novartis Investigative Site; Recruiting

Napoli, Italy, 80100

Japan

Novartis Investigative Site; Withdrawn

Kobe-city, Hyogo, Japan, 650-0047

Novartis Investigative Site; Withdrawn

Setagaya-ku, Tokyo, Japan, 157-8535

Novartis Investigative Site; Completed

Osaka, Japan, 534-0021

Novartis Investigative Site; Withdrawn

Saitama, Japan, 330 8777

Novartis Investigative Site; Recruiting

Shizuoka, Japan, 420 8660

Jordan

Novartis Investigative Site; Recruiting

Amman, Jordan, 11941

Korea, Republic of

Novartis Investigative Site; Recruiting

Seoul, Korea, Republic of, 03080

Novartis Investigative Site; Recruiting

Seoul, Korea, Republic of, 05505

Poland

Novartis Investigative Site; Recruiting

Gdansk, Poland, 80 952

Novartis Investigative Site; Recruiting

Krakow, Poland, 30-663

Russian Federation

Novartis Investigative Site; Withdrawn

Ekaterinburg, Russian Federation, 620149

Novartis Investigative Site; Active, not recruiting

Moscow, Russian Federation, 117198

Slovenia

Novartis Investigative Site; Recruiting

Ljubljana, Slovenia, 1000

Turkey

Novartis Investigative Site; Recruiting

Adana, Turkey, 1330

Novartis Investigative Site; Recruiting

Antalya, Turkey, 07070

Novartis Investigative Site; Recruiting

Istanbul, Turkey, 34093

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03591510
• Other Study ID Numbers: CPKC412A2218; 2017-004830-28 ( EudraCT Number )
• First Posted: July 19, 2018
• Last Update Posted: October 19, 2023
• Last Verified: October 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

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.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

PKC412; Acute Myeloid Leukemia; AML; FLT3-mutated; pediatric population; midostaurin; midostaurin combined with standard chemotherapy; single agent post-consolidation therapy; untreated FLT3-mutated AML

Additional relevant MeSH terms:

Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Neoplasms by Histologic Type; Neoplasms; Cytarabine; Fludarabine; Etoposide; Daunorubicin; Mitoxantrone; Idarubicin; Midostaurin; Antineoplastic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Antiviral Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Protein Kinase Inhibitors