AMLSG16-10/CPKC412ADE02T

Universitätsklinikum Ulm

Albert-Einstein-Allee 23, Ulm, Germany, 89081

Hartmut Doehner, University Hospital Ulm, +49 73150045501, daniela.weber@uniklinik-ulm.de

Hartmut Doehner, University Hospital Ulm, 3150045980 73150045501, daniela.weber@uniklinik-ulm.de

No

No

No

Final

01 Feb 2021

Yes

26 Feb 2020

Yes

26 Feb 2020

No

Primary Efficacy Objective To evaluate the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on event-free survival (EFS) in adult patients with AML exhibiting a FLT3- ITD. Key-Secondary Efficacy Objective • To evaluate the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on OS in adult patients with AML exhibiting a FLT3-ITD. To perform two predefined subgroup analyses in the age-groups 18-60 years and 61-70 years evaluating the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on EFS and OS and in adult patients with AML exhibiting a FLT3-ITD.

In this study, safety was assessed by evaluating the following: reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, chest X-ray, echo scan, physical examination findings, monitoring of concomitant therapy. For each safety parameter, all findings (whether normal or abnormal) were recorded in the CRF.

05 Jun 2012

No

Yes

Austria: 39

Germany: 401

440

440

0

0

0

0

0

0

373

67

0

Overall trial period (overall period)

Non-randomised - controlled

Midostaurin

PKC412

Capsule

Oral use

Midostaurin was administered orally in a dose of 50mg twice daily starting on day 8 during the induction chemotherapy cycles and on day 6 during the consolidation chemotherapy cycles, thereafter with continuous dosing until 48h before start of subsequent chemotherapy cycle. After allogeneic HSCT or after high-dose Cytarabine consolidation therapy, a maintenance therapy with Midostaurin was administered orally in a dose of 50mg twice daily for 365 days.

Cytarabine

Concentrate for concentrate for solution for infusion

Intravenous use

During induction chemotherapy, Cytarabine was administered by continuous intravenous infusion in a dose of 200 mg/m2 from day 1 up to day 7 for up to two cycles. During consolidation therapy four cycles high-dose Cytarabine was intended. Cytarabine was administered by intravenous infusion in a dose of 3 g/m2 twice a day on days 1, 3 and 5. For patients > 65 years of age, dose of Cytarabine was restrained to 1 g/m2.

Daunorubicin

Powder for concentrate and solution for solution for infusion

Intravenous use

Daunorubicin was administered by 1-hour intravenous infusion in a dose of 60 mg/m2 on days 1 up to day 3 during induction chemotherapy for up to two cycles.

AMLSG 16-10 study population

Historical control

• Historical control population served as a control group comprised of all AML cases with FLT3-ITD (excluding patients older than 70 years, or exhibiting translocation t(15;17)), or low cytogenetic risk profile according to ELN2010) from 5 previous AMLSG trials o AMLHD93 (R F Schlenk et al. 2003), o AMLHD98A (Richard F Schlenk et al. 2010), o HD98B (Richard F Schlenk et al. 2009), o AMLSG 06-04 (Tassara et al. 2014), o AMLSG 07-04 (Richard F Schlenk et al. 2016). The above-mentioned trials were actively recruiting between 1993 and 2008 at the same centers also involved in the AMLSG 16-10 trial. Treatment in all patients consisted of induction therapy with idarubicin, cytarabine, etoposide, and up to 3 cycles of high- dose cytarabine-based consolidation therapy. Allogeneic HSCT in first CR was performed on investigators discretion. The historical population included 415 intensively treated patients exhibiting a FLT3-ITD.

AMLSG 16-10 study population

Historical control

• Historical control population served as a control group comprised of all AML cases with FLT3-ITD (excluding patients older than 70 years, or exhibiting translocation t(15;17)), or low cytogenetic risk profile according to ELN2010) from 5 previous AMLSG trials o AMLHD93 (R F Schlenk et al. 2003), o AMLHD98A (Richard F Schlenk et al. 2010), o HD98B (Richard F Schlenk et al. 2009), o AMLSG 06-04 (Tassara et al. 2014), o AMLSG 07-04 (Richard F Schlenk et al. 2016). The above-mentioned trials were actively recruiting between 1993 and 2008 at the same centers also involved in the AMLSG 16-10 trial. Treatment in all patients consisted of induction therapy with idarubicin, cytarabine, etoposide, and up to 3 cycles of high- dose cytarabine-based consolidation therapy. Allogeneic HSCT in first CR was performed on investigators discretion. The historical population included 415 intensively treated patients exhibiting a FLT3-ITD.

The primary endpoint of the AMLSG 16-10 trial was event-free survival (EFS), defined as the time from enrolment to induction failure (failure of achieving CR or CR with incomplete recovery (CRi)), death or relapse, whichever occurs first, based on response assessed by the investigator.

Primary

after 24 months

AMLSG 16-10 study population v Historical control

855

Pre-specified

0.55

2-sided

Standard deviation

0.08

Subgroup analysis of patients <= 60 years of age (n=312 patients from the AMLSG 16-10 population and n=352 patients from the historical population)

AMLSG 16-10 study population v Historical control

855

Pre-specified

0.59

2-sided

Standard deviation

0.1

Subgroup analysis of patients > 60 years of age (n=128 patients from the AMLSG 16-10 population and n=63 patients from the historical population)

AMLSG 16-10 study population v Historical control

855

Pre-specified

0.42

2-sided

Standard deviation

0.17

The key secondary endpoint of the AMLSG 16-10 trial was overall survival (OS), defined as the time from enrolment to death from any cause in months.

Secondary

after 24 months

AMLSG 16-10 study population v Historical control

855

Pre-specified

0.57

2-sided

Standard deviation

0.09

Subgroup analysis of patients <= 60 years of age (n=312 patients from the AMLSG 16-10 population and n=352 patients from the historical population)

AMLSG 16-10 study population v Historical control

855

Pre-specified

0.59

2-sided

Standard deviation

0.11

Subgroup analysis of patients > 60 years of age (n=128 patients from the AMLSG 16-10 population and n=63 patients from the historical population)

AMLSG 16-10 study population v Historical control

855

Pre-specified

0.48

2-sided

Standard deviation

0.18

A patient was said to have achieved CR/CRi in two cases: (a) when a patient’s response after one cycle of induction was CR or CRi (b) when a patient’s response after one cycle of induction was partial remission then he/she might have received a second cycle and thereby achieved CR/CRi during the second cycle.

Secondary

after one or two induction cycles (within maximal 2 months)

AMLSG 16-10 study population v Historical control

855

Pre-specified

1.7

2-sided

Standard deviation

0.16

Relapse-free survival (RFS) was defined as the time from first CR/CRi until relapse or death, whichever came first. RFS was defined only for patients achieving CR/CRi as a response to induction therapy.

Secondary

after 24 months

AMLSG 16-10 study population v Historical control

596

Pre-specified

0.5

2-sided

Standard deviation

0.11

CIR was measured from the date of first CR/CRi until the date of relapse; patients not known to have relapsed were censored on the date they were last examined. Patients who died without relapse were counted as a competing cause of failure.

Secondary

after 24 months

AMLSG 16-10 study population v Historical control

596

Pre-specified

0.37

2-sided

Standard deviation

0.13

CID was measured from the date of first CR/CRi until the date of death. Patients not known to have died were censored on the date they were last examined; patients who relapsed were counted as a competing cause of failure.

Secondary

after 24 months

AMLSG 16-10 study population v Historical control

596

Pre-specified

1.1

2-sided

Standard deviation

0.21

The analyses investigate the potential effect of an allogeneic HSCT in first CR/CRi on the event-free survival of the patients. Since the decision process for or against conducting alloHSCT in the historical cohort was inconsistent, this analysis is restricted to patients of the 16-10 trial. In a first step, EFS was compared between patients having been transplanted versus patients without transplantation, irrespective of the type of donor. In a second step, transplanted patients were differentiated between those receiving stem cells from a matched related donor and those being transplanted with stem cells from an unrelated donor. Both multivariate models revealed alloHSCT as favorable prognostic factor for EFS 0.49 (P<.001). The favorable impact of HSCT was higher in patients with a family donor (HR 0.39, P<.001) compared to patients with donor stem cells from an unrelated donor (HR 0.51, P<.001).

Secondary

within the first 6 months of treatment

Quality of Life data was collected using the EORTC Quality of Life Core Questionnaire (QLQ-C30) at 5 timepoints throughout the AMLSG 16-10 study: before treatment starts, in first CR, after one year, 3 and 5 years after initial diagnosis. The scores of the questionnaire were computed according to the EORTC scoring manual transforming the raw scores into standardized scores ranging from 0 to 100. A higher score represents a higher (“better”) level of functioning or a higher (“worse”) level of symptoms. At diagnosis, median global health status was 41.7 (IQR: 16.7-62.5), at timepoint of first CR 50.0 (IQR: 41.7-66.7), after one year 58.3 (IQR: 50.0-70.8), after 3 years 66.7 (IQR:50.0-83.3) and after 5 years 50.0 (IQR:54.2-83.3).

Other pre-specified

at baseline, in first CR, after one year, 3 years and 5 years after initial diagnosis

The adverse event reporting period began upon signing of informed consent and ended 28 days after the last treatment administration or until all drug-related toxicities were resolved, or until the Investigators assessed AEs as chronic or stable.

22.1

Overall treatment period