Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Acute Disease

Neoplasms by Histologic Type

Hematologic Diseases

Disease Attributes

Acute Graft Versus Host Disease

Patients with poor risk active acute leukemia and who have 2 matched sibling donors can be included. Patients' conditioning may be myeloablative or non-myeloablative. Both matched donors will be mobilized with G-CSF and their peripheral blood stem cells will be collected on day 0.Equal numbers of CD34+ cells from both donors will be transfused to the patient.

Patients will be followed for engraftment kinetics, chimerism, GVHD rate, severity and response to treatment, relapse rates, DFS and OS.

Double matched sibling transplantation

Moshe Yeshurun, MD

Ron Ram, MD

Patients with active acute leukemia have dismal prognoses even with allogeneic transplantation.Thus,new measures to enhance graft versus leukemia effect and reduce relapse rates are needed.

Relapse risk after double umbilical cord transplantations have been shown to be significantly lower compared to matched sibling and matched unrelated donor transplantations due to better graft versus leukemia effect.

The investigators hypothesize, that concomitant transplantation from 2 matched siblings may improve GVL effect and reduce relapse rate in patients with high risk acute leukemias and other high risk hematological malignancies.

Pilot Study of Hematopoietic Stem Cell Transplantation From Two Matched Sibling Donors in Treating Patients With Poor Prognosis Acute Leukemia and Advanced Lymphoproliferative Malignancies

Rabin Medical Center

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasm, Residual

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Daunorubicin

Idarubicin

Midostaurin

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.

Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation

Midostaurin was provided as 25 mg capsules 8PC, was supplied as double-blind in blister packs and taken orally.

Placebo was provided as 25 mg soft gelatin capsules 8PC, was supplied as double-blind in blister packs and taken orally.

Placebo

Along with the study drug/placebo, chemotherapy was given as well: either Daunorubicin or Idarubicin and Cytarabine - all taken by i.v.

Chemotherapy

Novartis Pharmaceuticals

The purpose of this study was to confirm the preliminary evidence from early clinical trials that midostaurin may provide clinical benefit not only to AML patients with the FLT3-mutations but also in FLT3-MN (SR\<0.05) AML (FLT3 mutant to wild type signal ratio below the 0.05 clinical cut-off).

This study evaluated the efficacy and safety of midostaurin in combination with daunorubicin or idarubicin and cytarabine for induction and intermediate-dose cytarabine for consolidation, and midostaurin single agent post-consolidation therapy in newly diagnosed patients with FLT3-MN (SR\<0.05) AML.

This was a multi-center, multinational, randomized, double-blind Phase III study using a group sequential design. Subjects were stratified according to age (\<60 vs. ≥ 60 years). Subjects within each stratum were randomized in a 1:1 ratio into one of two treatment arms: Midostaurin + chemotherapy 'or' Placebo + chemotherapy.

The study consisted of the following phases:

Screening/randomization phase: Subjects had to sign informed consent form before screening for enrollment. Subjects started chemotherapy at day 1 and were randomized at day 8.

Induction phase: All subjects received at least one cycle (28 days) of induction therapy with continuous infusion cytarabine (D1 - D7) and daunorubicin or idarubicin (D1 - D3) (induction 1). Subjects who did not achieve CR or CRi with adequate blood count recovery after Induction 1 received a second cycle with intermediate-dose cytarabine (D1 - D3) and daunorubicin or idarubicin (D1 - D3) (induction 2). Subjects who did not achieve CR or CRi with adequate blood recovery after induction 2 discontinued study treatment and were followed for survival.

Consolidation phase: Subjects who achieved CR or CRi with adequate blood count recovery after induction with one or two cycles of induction proceeded to consolidation therapy with either 3 or 4 cycles respectively of intermediate-dose cytarabine (D1 - D3), or to Hematopoietic Stem Cells Transplantation (HSCT) with or without preceding consolidation cycles.

Post-consolidation phase: Subjects who maintained CR or CRi with adequate blood count recovery at the end of the consolidation phase received 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice daily at 50 mg. Subjects who underwent HSCT after achieving CR or CRi with adequate blood count recovery received midostaurin or placebo twice daily 50 mg post-transplant therapy, continuously, for up to 12 cycles (28 days/cycle). Post HSCT post-consolidation therapy began \>30 days but not later than 100 days following HSCT.

Follow-up phase: All enrolled subjects were followed through the treatment period and until relapse/treatment failure, thereafter for start of new line of therapy and survival.

A Global Study of the Efficacy and Safety of Midostaurin + Chemotherapy in Newly Diagnosed Patients With FLT3 Mutation Negative (FLT3-MN) Acute Myeloid Leukemia (AML)

A Phase III, Randomized, Double-blind Study of Chemotherapy With Daunorubicin or Idarubicin and Cytarabine for Induction and Intermediate Dose Cytarabine for Consolidation Plus Midostaurin (PKC412) or Chemotherapy Plus Placebo in Newly Diagnosed Patients With FLT-3 Mutation Negative Acute Myeloid Leukemia (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.

EFS was defined as the time from randomization to failure to obtain a complete remission (CR) or Complete remission with incomplete hematologic recovery (CRi) with adequate blood count recovery in induction, relapse after CR or CRi with adequate blood count recovery or death due to any cause, whichever occurred first as assessed by the investigator.

OS was defined as the time from randomization to date of death due to any cause. Patients entered the survival follow-up phase once they completed the safety follow up period (30 days after the last dose of midostaurin/placebo) in case of induction failure or if they had relapsed during post-treatment follow-up. Patients were then contacted by telephone every 3 months +/- 2 weeks or had a visit to follow up on their survival status, per Kaplan-Meier estimates.

Assessment was based on the International Working Group (IWG) criteria for AML as per investigator assessment.

CR: Bone marrow: \< 5% blasts no blasts with Auer rods; Peripheral blood: neutrophils ≥ 1.0 x 109/L platelets ≥ 100 x 109/L, no blasts; No evidence of extramedullary disease (such as central nervous system (CNS) or soft tissue involvement); Transfusion independent.

CRi with adequate blood count recovery is defined as the following:

Bone marrow \< 5% blasts no blasts with Auer rods Peripheral blood Neutrophils \>= 1.0 x 109/L and 50 x 109/L \<=platelets \< 100 x 109/L no blasts No evidence of extramedullary disease (such as CNS or soft tissue involvement).

MRD- rate was defined as the rate of participants reaching MRD at any timepoint. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP).

MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.

MRD- rate was defined as the rate of participants reaching MRD at any timepoint during Post-consolidation phase. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP).

MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.

Time to MRD- is defined as time from randomization to first occurrence of MRD-. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP).

MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.

DFS as measured from the date of first CR or CRi with adequate blood count recovery to relapse or death due to any cause, whichever occurred first. Participants who did not relapse nor die were censored at the last adequate response assessment. Assessment was based on the IWG criteria for AML as per investigator assessment

Cumulative Incidence of Relapse (CIR) was defined for participants with CR or CRi with adequate blood count recovery and was the time from achieving the CR or CRi with adequate blood count recovery until the onset of relapse from CR or CRi with adequate blood recovery. Participants without relapse were censored at the last adequate response assessment. Participants who died without relapse were counted as a competing cause of failure.

Cumulative Incidence of Death (CID) was defined for all participants achieving CR or CRi with adequate blood count recovery measured from the date of achievement of CR or CRi until the date of death due to any reason. Participants not known to have died were censored on the last contact date. Participants who experienced relapse were counted as a competing cause of failure.

Time to CR or CRi with adequate blood count recovery was defined as the time from randomization to CR or CRi with adequate blood count recovery whichever occurred first

The time to neutrophil recovery was assessed for the following criteria: Partial neutrophil recovery: Number of days from start of treatment to the first day neutrophils ≥0.5 x 10\^9/L.

Full neutrophil recovery: Number of days from start of treatment to the first day neutrophils ≥1.0 x 10\^9/L

Time to platelet recovery was assessed for the following criteria: Partial platelet recovery: Number of days from start of treatment to the first day platelets ≥50 x 10\^9/L.

Full platelet recovery: Number of days from start of treatment to the first day platelets ≥100 x 10\^9/L.

Serial pharmacokinetics (PK) samples were collected in Non-poor metabolizer participants to assess the plasma concentrations of midostaurin, CGP52421 and CGP62221.

The AUC from time zero to a measurable concentration sampling time (t) (mass x time x volume-1). Note: as the last sampling time was at 12 h, AUC0-12h was determined after the first dose, reported at Cycle 1, Day 8

The AUC from time zero to the last measurable concentration sampling time after the first dose reported at Cycle 1, Day 8

The maximum (peak) observed plasma drug concentration after the first dose administration reported at Cycle 1, Day 8

The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration reported at Cycle 1, Day 8

The total FACT-Leu score consists of 44 items with total scores ranging from 0 to 176. Higher scores indicate better health-related quality of life ( HRQoL). Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL.

The EQ5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient is asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a Visual Analogue Scale (VAS), where the patient is asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state.

Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Deaths in the post-treatment survival follow-up are not considered Adverse Events. The total number at risk in the post-treatment survival includes patients that entered the post-treatment survival follow-up period.

AEs during on-treatment period (up to 30 days post-treatment)

Midostaurin + Chemotherapy (On-treatment)

Placebo + Chemotherapy (On-treatment)

Deaths collected in the post- treatment survival follow-up phase (starting from day 31 post- treatment). No AEs were collected during this period

Midostaurin + Chemotherapy (Post-treatment Survival Follow-up)

Placebo + Chemotherapy (Post-treatment Survival Follow-up)

Midostaurin + Chemotherapy

Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.

Placebo + Chemotherapy

Total

Age, Continuous

Sex: Female, Male

White

Black or African American

Asian

Multiple

Missing

Race/Ethnicity, Customized

0 (Asymptomatic)

1 (Symptomatic, fully ambulatory)

2 (Symptomatic, in bed <50% of the day)

3 (Symptomatic, in bed >50% of the day)

ECOG performance status determines the ability of a patient to tolerate therapies in serious illness, specifically for chemotherapy.

ECOG performance status

Full analysis set (FAS) comprised all participants to whom study drug was assigned by randomization.

Study Director

Full analysis set comprised all participants to whom study drug was assigned by randomization.

Event Free Survival (EFS)

Overall Survival (OS) (Key Secondary)

Percentage of Participants With Complete Remission (CR) and Complete Remission With Incomplete Hematological Recovery (CRi) But With Adequate Blood Count Recovery Rate.

Percentage of Participants With Minimal Residual Disease (MRD) Negative Status

Full analysis in post-consolidation phase comprised of participants who entered post-consolidation phase

Percentage of Participants With Minimal Residual Disease (MRD) Negative Status During Post-consolidation Phase

Analysis set comprised all participants to whom study drug was assigned by randomization.

Time to Measurable Residual Disease (MRD) Negativity by Flow Cytometry

Full analysis set comprised all participants to whom study drug was assigned by randomization. DFW was derived only for participants who reached CR or CRi with adequate blood count recovery in induction (during first 93 days).

Disease-free Survival (DFS)

Full analysis set comprised all participants to whom study drug was assigned by randomization. CIR was only for participants who achieved CR or CRi with adequate blood count recovery.

Cumulative Incidence of Relapse (CIR)

Full analysis set comprised all participants to whom study drug was assigned by randomization. CID was only for participants who achieved CR or CRi with adequate blood count recovery.

Cumulative Incidence of Death (CID)

Time to CR or CRi With Adequate Blood Count Recovery

Partial neutrophil recovery

Full neutrophil recovery

Time to Partial and Full Neutrophil Recovery

Partial platelet recovery

Full platelet recovery

Time to Partial and Full Platelet Recovery

IND C1D8 0hr (Predose) (n = 34, 34, 34)

IND C1D8 1hr (n= 6, 6, 6)

IND C1D8 3hr (n = 108, 104, 108)

IND C1D8 6hr ( n= 7, 7, 7)

IND C1D8 12hr (n= 7, 7, 7)

IND C1D11 0hr (Predose) (n = 33, 33, 33)

IND C1D11 3hr (n = 92, 92, 92)

IND C1D11 12hr (n = 57, 57, 57)

IND C1D15 0hr (Predose) (n = 25, 25, 25)

IND C1D15 12hr (n = 63, 63, 63)

IND C1D18 0hr (Predose) (n = 19, 19, 19)

IND C1D18 12hr (n = 50, 50, 50)

IND C1D21 0hr (Predose) (n = 26, 26, 26)

IND C1D21 3hr (n = 89, 89, 89)

IND C1D21 12hr (n = 61, 61, 61)

CONS C1D4 0hr (predose) (n = 16, 15, 16)

CONS C1D4 3hr (n = 49, 44, 49)

CONS C1D4 12hr (n = 2, 2, 2)

CONS C1D17 0hr (predose) (n = 14, 14, 14)

CONS C1D17 3hr (n = 48, 47, 48)

CONS C1D17 12hr (n = 29, 29, 29)

CONS C3D4 0hr (predose) ( n = 9, 9, 9)

CONS C3D4 3hr (n = 25, 24, 25)

CONS C3D4 12hr (n = 2, 2, 2)

CONS C3D17 0hr (predose) (n = 9, 9, 9)

CONS C3D17 3hr ( n = 24, 24, 24)

CONS C3D17 12hr (n = 17, 17, 17)

POSTCONS C1PRE 0hr (predose) (n = 2, 2, 2)

POSTCONS C1PRE 12hr (n = 1, 1, 1)

POSTCONS C4D1 0hr (predose) (n= 4, 4, 4)

POSTCONS C4D1 3hr (n = 4, 3, 4)

POSTCONS C4D1 12hr (n = 2, 2, 2)

POSTCONS C7D1 0hr (predose) (n = 1, 1, 1)

POSTCONS C7D1 12hr (n = 3, 3, 3)

POSTCONS C10D1 0hr (predose) (n = 1, 1, 1)

CGP52421

CGP62221

Pharmacokinetic analysis set-all (PAS-all) included all participants in the safety set who provided at least one evaluable PK concentration for Non-poor metabolizers. PK samples were not collected in all timepoints of all patients and reported for Non-poor metabolizers only.

Plasma Concentrations for Midostaurin and Its Metabolites: CGP52421 and CGP62221 for Non-poor Metabolizers

Pharmacokinetic analysis set-all (PAS-all) included all participants in the safety set who provided at least one evaluable PK concentration.

AUC0-t: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8

AUClast: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8

GCP62221

Cmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8

GCP52421

Tmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8

Baseline (n = 225, 223)

Induction Phase (n = 137, 147)

Induction I (n = 105, 90)

Induction ll (n = 32, 57)

Consolidation (prior) (n = 210, 196)

Post- consolidation (n = 169, 114)

Follow-up (n = 74, 111)

Total Score for Each Time Point for the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)

Baseline ( n= 225, 220)

Induction Phase (n = 135, 146)

Induction l (n = 104, 89)

Induction ll (n = 31, 57)

Consolidation (prior) (n = 207, 197)

Post-consolidation (n = 167, 113)

Follow-up ( n- 74, 112)

Scores for Each Time Point for the EQ5D-5L (a Visual Analogue Scale (VAS))

Total Deaths

Randomized but not treated deaths

Deaths on-treatment (n = 245, 249)

Post-treatment survival follow-up deaths

On-treatment deaths were collected from start of treatment (FPFT) up to 30 days after study drug discontinuation, for a maximum duration of approx. 18 months.

Randomized but not treated deaths were collected after randomization but before treatment with study drug.

Post-treatment survival follow-up deaths were collected after the on-treatment period up to approx. 18 months. Participants who did not die during the on-treatment period and had not stopped study participation at the time of data cut-off (when study was terminated) were censored.

Clinical Database Population: all enrolled participants

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pilot Study of Hematopoietic Stem Cell Transplantation From Two Matched Sibling Donors in Treating Patients With Poor Prognosis Acute Leukemia and Advanced Lymphoproliferative Malignancies	NCT01385072	Relapsed and Re...	Double matched ...	18 Years -	Rabin Medical Center
A Global Study of the Efficacy and Safety of Midostaurin + Chemotherapy in Newly Diagnosed Patients With FLT3 Mutation Negative (FLT3-MN) Acute Myeloid Leukemia (AML)	NCT03512197	Acute Myeloid L...	Midostaurin Placebo Chemotherapy	18 Years -	Novartis

Spots Global Cancer Trial Database for induction failure