Neoplasms

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Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Venetoclax

Azacitidine

Daunorubicin

Idarubicin

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Participants with relapsed/refractory AML harboring either NPM1 or KMT2A alterations will receive JNJ-75276617 in combination with either venetoclax (VEN) (Cohort A1: JNJ75276617+VEN) or azacitidine (AZA) (Cohort A2: JNJ-75276617+AZA) or VEN+AZA (Cohort A3: JNJ-75276617+VEN+AZA) to select the recommended phase 2 dose (RP2D) of JNJ-75276617 in combination with VEN, AZA or VEN+AZA (dose selection). In dose expansion portion of the study, participants will receive JNJ-75276617 in combination with AML directed therapies at the RP2D(s).

Participants will receive JNJ-75276617 in combination with VEN+AZA as frontline chemo therapy for newly diagnosed AML participants harboring either KMT2A or NPM1 alterations who are greater than or equal to (\>=)18 years of age to less than (\<) 75 years of age with comorbidities that preclude the use of intensive induction chemotherapy.

Participants will receive combination of JNJ-75276617 with cytarabine+daunorubicin or idarubicin chemotherapy as frontline treatment regimen for participants \>=18 to \<75 years of age with AML harboring either NPM1 or KMT2A alterations and eligible for intensive chemotherapy.

JNJ-75276617

Venetoclax (VEN)

Azacitidine (AZA)

Participants will receive daunorubicin or idarubicin

Daunorubicin or Idarubicin

Study Contact

Janssen Research & Development, LLC Clinical Trial

The purpose of this study is to determine the recommended Phase 2 dose (RP2D) candidate(s) of JNJ-75276617 in combination with AML directed therapies (dose selection) and further to evaluate safety and tolerability of JNJ-75276617 in combination with AML directed therapies at the RP2D(s) (dose expansion).

AML is a heterogenous disease characterized by uncontrolled clonal expansion of hematopoietic progenitor cells (myeloid blasts) in the peripheral blood, bone marrow and other tissues and is the most common type of acute leukemia in adults. JNJ-75276617 is an orally bioavailable, potent, and selective protein-protein interaction inhibitor of the binding between histone-lysine N-methyltransferase 2A (\[KMT2A\], also called mixed-lineage leukemia 1 \[MLL1\]; wild-type and fusion) and menin, with activity in leukemic cell lines and primary leukemia patient or patient-derived samples with either KMT2A alterations including gene rearrangements (KMT2A-r), duplications, and amplification, or nucleophosmin 1 gene (NPM1) alterations. The aim of this study is to determine the RP2D(s), safety, pharmacokinetic, pharmacodynamic and preliminary clinical activity of JNJ-75276617 in combination with AML directed therapies for adult participants with relapsed/refractory or newly diagnosed AML with NPM1 or KMT2A gene alterations and will include dose selection and subsequent combination specific dose expansion. The total study duration will be up to 2 years. Safety evaluations include adverse events (AE) monitoring, clinical laboratory tests, electrocardiograms (ECGs), vital sign measurements, physical examination findings, and eastern cooperative oncology group (ECOG) performance status score.

A Study of JNJ-75276617 in Combination With Acute Myeloid Leukemia (AML) Directed Therapies

A Phase 1b Study of JNJ-75276617 in Combination With AML-Directed Therapies for Participants With Acute Myeloid Leukemia Harboring KMT2A or NPM1 Alterations

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson \& Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.

Number of Participants with AEs by severity will be reported. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event.

Number of participants with DLT will be reported. The DLTs are specific adverse events and are defined per protocol as any of the following: non-hematologic toxicity, or hematologic toxicity.

Plasma samples will be analyzed to determine concentrations of JNJ-75276617 using a validated, specific, and sensitive method.

Number of participants with depletion of leukemic blasts will be reported.

Number of participants with differentiation of leukemic blasts will be reported.

Changes in expression of menin-KMT2A target genes will be reported.

Percentage of participants who achieve complete Remission (CR) will be reported. CR is defined as Bone marrow blasts less than (\<) 5 percent (%); Absence of circulating blasts and blasts with Auer rods; Absence of extramedullary disease; Absolute neutrophil count (ANC) greater than or equal to (\>=) 1.0 x 109/Liter (1,000/microliter \[μL\] ); Platelet count \>= 100 x 109/L (100,000/μL).

Percentage of participants who achieve complete remission with partial hematologic recovery (CRh) will be reported. CRh is defined as All criteria of CR with both ANC \>0.5 x 109/L (500/μL) and platelet count \>50 x 109/L (50,000/μL).

Percentage of participants who achieve complete remission with incomplete hematologic recovery (CRi) will be reported. CRi is defined as All CR criteria except for residual neutropenia (\<1.0 x 109/L \[1,000/μL\]) or thrombocytopenia (\<100 x 109/L \[100,000/μL\]).

Percentage of participants who achieve overall response will be reported. Overall response rate (ORR) is defined as the percentage of participants achieving CR, CRh, or CRi.

Duration of response is defined as time from achieving first response of CR, CRh, CRi or overall response to hematologic relapse or death of any cause.

Time to response is defined as time from first dose to achieving the first response of CR, CRh, CRi or overall response.

Janssen Research & Development, LLC

Analgesics

Etoposide

Mitoxantrone

Fludarabine

Fludarabine phosphate

Etoposide phosphate

Midostaurin

Protein Kinase Inhibitors

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.

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

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

Daunorubicin or idarubicin

Novartis Pharmaceuticals

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:

* 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.

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

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.

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.

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

Number of dose interruptions/reductions and discontinuations due to study drug

Percentage of participants with a response of CR, CRi or modified CRi at the end of Block 2

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.

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.

OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause.

DFS is defined as the time from CR/modified CRi in induction to relapse or death due to any cause

Percentage of patient with MRD negative status by multiparameter flow cytometry

Palatability is assessed through questionnaires- Palatability PRO and obsPRO

Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction Block 1 and Block 2

Plasma concentration of midostaurin and its 2 metabolites

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of JNJ-75276617 in Combination With Acute Myeloid Leukemia (AML) Directed Therapies	NCT05453903	Leukemia, Myelo...	JNJ-75276617 Venetoclax (VEN... Azacitidine (AZ... Cytarabine Daunorubicin or...	18 Years -	Janssen Research & Development, LLC
A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML	NCT03591510	FLT3-mutated Ac...	Midostaurin Fludarabine Cytarabine Daunorubicin or... Mitoxantrone Etoposide	3 Months - 17 Years	Novartis
A Study of JNJ-75276617 in Combination With Acute Myeloid Leukemia (AML) Directed Therapies	NCT05453903	Leukemia, Myelo...	JNJ-75276617 Venetoclax (VEN... Azacitidine (AZ... Cytarabine Daunorubicin or...	18 Years -	Janssen Research & Development, LLC
A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML	NCT03591510	FLT3-mutated Ac...	Midostaurin Fludarabine Cytarabine Daunorubicin or... Mitoxantrone Etoposide	3 Months - 17 Years	Novartis

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