Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication RYDAPT is a kinase inhibitor indicated for the treatment of adult patients with: Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. ( 1.1 ) Limitations of Use: RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML. FDA label
Also known as PKC412, Midostaurin (PKC412), N-benzoyl-staurosporine, CGP41251, CGP41231
Midostaurin · 12 trials · 19 indications
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.
Safety of Midostaurin was represented by various types of AEs, SAEs \& death up to M24. AE: the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient's signed informed consent has been obtained. AE grades to characterize the severity of AEs were based on the Common Terminology Criteria for AEs ver. 4.03 with Grade (Gr) 1: mild; Gr 2: moderate; Gr 3: severe; Gr 4: life-threatening; Gr 5: death related to AE. AEs not related to hematological toxicities were generally of grade 1 or 2 severity. SAE: 1 of the following: is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, i.e. an event that jeopardizes the patient or may require medical or surgical intervention to prevent 1 of the outcomes listed above, requires inpatient hospitalization or prolongation of existing hospitalization with a few exceptions.
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 event-free survival (EFS) in adult patients with AML exhibiting a FLT3-ITD.
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 Safety Events, defined as death or serious adverse event leading to treatment discontinuation that occurs on or before Day 21 of the first Consolidation cycle. This was determined by the Independent Safety Committee (ISC) to be definitely or probably related to midostaurin. Percentage was calculated based on the percentage of subjects with safety event out of 3 evaluable subjects in Part 1.
Event Free survival is defined as the time from the date of randomization until an EFS event is observed. An EFS event is defined as a failure to obtain a complete remission (CR) within an induction 2, relapse after CR, or death due to any cause, whichever occurs first. The objective was to evaluate the efficacy based on EFS of midostaurin versus placebo in combination with daunorubicin/cytarabine induction, with high-dose cytarabine consolidation, and with midostaurin single agent continuation therapy in newly diagnosed patients with FLT3-mutated AML.
Relapse-free survival assesses the clinical benefit of remaining in remission free from relapse or death due to the disease. It was defined as the time from transplant to relapse or death due to the disease. Relapse following complete response was defined as reappearance of leukemic blasts in the peripheral blood or finding more than 5% blasts in the bone marrow.
Overall Response Rate (ORR) was defined as the percentage of participants who classified as confirmed responders (Major Response (MR) or Partial Response (PR)) by the adjudication of the SSC and based on a Modified Valent Criteria. A major responder had complete resolution of at least one C-Finding and no progression in other C-Findings. A partial responder showed a measurable improvement in one or more C-Finding(s) without confirmed progression in other C-Findings. A C-Finding was a Clinical Finding, which was considered by the investigator and corroborated by the Study Steering Committee (SSC) Chairperson or designee, attributable to the mast cell disease component and not the associated hematological clonal non-mast cell lineage disease (AHNMD) component or any other cause.
Clinical Response \[PR + CR\] will be assessed after 2 cycles of treatment, with each cycle being 28 days (4 weeks) in length. Except as otherwise noted, the minimum criteria for PR is improvement by at least 50% from the baseline value towards the indicated value for one or more of the criteria below: BONE MARROW \& BLOOD * ANC \<1000/uL * Hb \<10 g/dL * Platelets \>100,000/uL LIVER * If hepatomegaly with ascites, decrease in frequency of paracenteses by 50% * Elevated enzyme levels \> upper limit of normal (ULN) * Hypoalbuminemia \< ULN * Portal hypertension \> ULN SPLEEN * If palpable splenomegaly with hypersplenism/thrombocytopenia, hypersplenism markers improved GI TRACT * If malabsorption with hypoalbuminemia and/or weight loss, albumin improved BONES * If huge osteolyses or/and severe osteoporosis with pathologic fractures, partial resolution of osteolyses Subjects with PR or greater continue, those without response discontinue.
In subjects with Child Pugh A, Child Pugh B (and matching healthy volunteers) Cmax will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and matching healthy volunteers) Cmax will be measured at Day 1
Maximum tolerated dose of bortezomib and midostaurin in combination with MEC(mitoxantrone, etoposide,cytarabine)salvage chemotherapy. Specific toxicities and Dose-limiting toxicity of midostaurin and bortezomib in combination with intensive chemotherapy in relapsed/refractory AML.
cycle = between 28 days and 42 days in duration
Best clinical response was defined as complete response (CR) or partial response (PR), according to NCI definitions for AML and the guidelines for defining responses in MDS.
Overall clinical response was defined as CR, PR, minor response (MR) or blast response (BR). CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.
Blood samples were collected for pharmacokinetic (PK) analysis.
Blood samples were collected for pharmacokinetic (PK) analysis.
Blood samples were collected for PK analysis.
Blood samples were collected for PK analysis.
Blood samples were collected for PK analysis.
Blood samples were collected for pharmacokinetic (PK) analysis.
Blood samples were collected for pharmacokinetic (PK) analysis.
Blood samples were collected for PK analysis.
Blood samples were collected for PK analysis.
Blood samples were collected for PK analysis.
Blood samples were collected for pharmacokinetic (PK) analysis.
Blood samples were collected for pharmacokinetic (PK) analysis.
Blood samples were collected for PK analysis.
Blood samples were collected for PK analysis.
Blood samples were collected for analysis.
Blood samples were collected for analysis.
Blood samples were collected for analysis.
| Arm | Type | Description |
|---|---|---|
| Midostaurin + chemotherapy | EXPERIMENTAL | 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. |
| Placebo + chemotherapy | PLACEBO_COMPARATOR | 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 | EXPERIMENTAL | Patients went through 3 phases: Induction phase - Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase - D1 to D28 up to 12 cycles |
| Chemotherapy followed by Midostaurin | EXPERIMENTAL | 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. |
| Placebo | PLACEBO_COMPARATOR | Patients took placebo on day 8-21 during induction and consolidation phase; then on days 1-28 for 12 cycles in the continuation (post consolidation) phase. |
| Standard of Care with Midostaurin | EXPERIMENTAL | Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles). |
| Standard of Care | ACTIVE_COMPARATOR | Patients received standard of care alone in the post SCT setting |
| Midostaurin (PKC412) | EXPERIMENTAL | Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first. |
| Normal hepatic function - group 1 | EXPERIMENTAL | Matched control for group 2 and 3 - healthy volunteers matched with respect to age, body weight, BMI and gender to subjects in mild and moderate hepatic function groups. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. |
| Mild hepatic impairment - group 2 | EXPERIMENTAL | Subjects with mild impaired hepatic function - Child Pugh A classification score 5-6. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. |
| Moderate hepatic impairment - group 3 | EXPERIMENTAL | Subjects with moderate hepatic function - Child Pugh B classification score 7-9. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. |
| Severe hepatic impairment - group 4 | EXPERIMENTAL | Subjects with severe hepatic impairment function - Child Pugh C classification score 10-15. Subjects will be treated with a single dose of midostaurin of 50mg on day 1. |
| Normal hepatic function - group 5 | EXPERIMENTAL | Matched control for group 4 - healthy volunteers matched with respect to age, body weight, BMI and gender to subjects in severe hepatic function group. Subjects will be treated with a single dose of midostaurin of 50mg on day 1. |
| GROUP I (Dose levels 1-2): | EXPERIMENTAL | Patients receive midostaurin orally (PO) twice daily on days 1-14 and bortezomib intravenously (IV) on days 1, 4, 8, and 11. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. |
| GROUP II (Dose levels 3-6) | EXPERIMENTAL | Patients receive mitoxantrone hydrochloride IV over 10 minutes, etoposide IV over 1 hour, and cytarabine IV over 6 hours on days 1-6. Patients also receive midostaurin PO twice daily on days 8-21 and bortezomib IV on days 8, 11, 15, and 18. Treatment continues in the absence of disease progression or unacceptable toxicity. |
| PKC412 administered sequentially | EXPERIMENTAL | twice daily oral dosing of PKC412 administered sequentially |
| PKC412 administered concomitantly | EXPERIMENTAL | PKC412 administered concomitantly with standard induction daunorubicin and cytarabine therapy followed by high-dose consolidation therapy with cytarabine |
| PKC412 (Core) | EXPERIMENTAL | Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. |
| FLT3 mutated PKC412 100 mg/day (E1) | EXPERIMENTAL | Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. |
| FLT3 mutated PKC412 200 mg/day (E1) | EXPERIMENTAL | Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. |
| FLT3 wild type PKC412 100 mg/day (E1) | EXPERIMENTAL | Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. |
| FLT3 wild type PKC412 200 mg/day (E1) | EXPERIMENTAL | Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. |
| FLT3 mutated PKC412 dose escalation | EXPERIMENTAL | Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity. |
| FLT3 mutated PKC+Itraconazole (E2) | EXPERIMENTAL | Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent. |
| FLT3 wild type PKC412 dose escalation (E2) | EXPERIMENTAL | Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity. |
| FLT3 wild type PKC+Itraconazole (E2) | EXPERIMENTAL | Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent. |
| Name | Type | Description |
|---|---|---|
| Midostaurin | DRUG | Midostaurin was provided as 25 mg capsules 8PC, was supplied as double-blind in blister packs and taken orally. |
| Placebo | DRUG | Placebo was provided as 25 mg soft gelatin capsules 8PC, was supplied as double-blind in blister packs and taken orally. |
| Chemotherapy | DRUG | Along with the study drug/placebo, chemotherapy was given as well: either Daunorubicin or Idarubicin and Cytarabine - all taken by i.v. |
| Cytarabine | DRUG | Induction Phase (standard dose) (7 + 3 arm): 100-200 mg/m2/day by Continuous intravenous infusion (CIVI) days 1-7 (168 hours infusion); Induction Phase (5 + 2 arm): 100 mg/m2/day by CIVI days 1-5; Consolidation Phase: 1-3 g/m2 infusion over 3 hours every 12 h on days 1, 3 and 5, up to 4 cycles based on age and per investigator discretion |
| anthracycline ((daunorubicin or idarubicin): Induction Phase only | DRUG | daunorubicin (7 + 3 arm): 60-90 mg/m2/day by IV push on days 1-3 (with standard-dose cytarabine); daunorubicin (5 + 2 arm): 60 mg/m2/day by IV push on days 1-2; idarubicin (7 + 3 arm): 12 mg/m2/day by IV push on days 1-3 (with standard-dose cytarabine); idarubicin (5 + 2 arm): 12 mg/m2/day by IV push on days 1-2 |
| Daunorubicin | DRUG | Induction therapy: 60 mg/m², by 1-hour i.v. infusion, day 1-3 (total dose 180 mg/m²) |
| Fludarabine | DRUG | 30mg/m2/day on D1-D5 of Block 2 FLADx |
| Daunorubicin or idarubicin | DRUG | daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx |
| Mitoxantrone | DRUG | 10mg/m2/day D3 and D4 |
| Etoposide | DRUG | 100mg/m2/day D1 to D5 |
| Standard of Care | OTHER | Standard of Care was not defined per protocol. The investigator prescribed based on the commonly used medications given in the post SCT setting. |
| Midostaurin (PKC412) | DRUG | Midostaurin was provided as 25 mg soft gelatin capsules for oral administration. |
| Bortezomib | DRUG | Bortezomib given IV on days 1, 4, 8, and 11 |
| mitoxantrone hydrochloride | DRUG | Patients receive mitoxantrone hydrochloride IV over 10 minutes |
| daunorubicin hydrochloride | DRUG | - |
| Itraconazole | DRUG | Itraconazole was commercially available. |
| PKC412 | DRUG | PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. |
Inclusion Criteria: 1. Diagnosis of AML (≥20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL with PML-RARA are not eligible. 2. Suitability for intensive induction chemotherapy in the judgment of the investigator 3. Documented absence of an ITD and TKD activating mut...
Midostaurin is used to treat FLT3-mutated acute myeloid leukemia (AML) and aggressive systemic mastocytosis (ASM). It is also being studied in other forms of leukemia and in patients with hepatic impairment. It is a small molecule kinase inhibitor developed for oncology indications.
Midostaurin targets FLT3, KDR, PDGFRB, PDGFRA, PRKD3, and PRKCI. It is a multi-kinase inhibitor that blocks these enzymes, which are involved in cancer cell growth and survival. Its activity against FLT3 is particularly relevant in FLT3-mutated acute myeloid leukemia.
Midostaurin is developed by Novartis AG, which trades under the ticker NVS. Novartis is the sponsor of the clinical trials evaluating the drug in acute myeloid leukemia and other conditions.
Midostaurin is in Phase 3 clinical development. It has been studied in multiple Phase 3 trials, including NCT03512197 and NCT03379727, which have been completed. One trial, NCT03591510, is currently active but not recruiting.
Midostaurin has been evaluated in several clinical trials, including NCT03591510 (Phase 2 in pediatric FLT3-mutated AML), NCT03512197 (Phase 3 in FLT3 mutation negative AML), NCT03379727 (Phase 3 in FLT3-mutated AML), and NCT03280030 (Phase 2 in FLT3-mutated AML). These trials have enrolled a total of 1,637 patients.
Yes, Midostaurin is also known as PKC412. Both names refer to the same investigational drug. The alternative name PKC412 is sometimes used in scientific literature and clinical trial titles.