Evaluation of Midostaurin and Gemtuzumab Ozogamicin in Combination with Standard Induction Chemotherapy for Adult Acute Myeloid Leukemia
- Trial ID
- 2024-514014-13-00
- Protocol
- TUD-MOSAIC-075
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the study is to evaluate the **tolerability** and efficacy of a combination therapy consisting of **midostaurin** and **gemtuzumab ozogamicin** in conjunction with standard induction chemotherapy for the treatment of acute myeloid leukemia (AML) in adult patients. This objective is clinically relevant as it aims to assess the potential benefits and safety of integrating these agents into first-line therapy, which could improve treatment outcomes for patients with AML.
Participants
The clinical trial involves **adult patients** diagnosed with **acute myeloid leukemia** (AML), including both **female and male** participants. The study population comprises individuals aged 18 to 75 years for the Phase I Trial (MODULE) and 18 to 70 years for the Phase II Trials (MAGMA and MAGNOLIA). Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Score of 0-2, indicating a relatively stable general health status. The trial does not include a vulnerable population. The selection criteria emphasize adequate hepatic and renal function, with specific laboratory thresholds for ALAT/ASAT, bilirubin, and creatinine levels. Additionally, participants must have a white blood cell count of less than 30 × 10^9/L, with allowances for emergency stabilization using hydroxyurea or cytarabine. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the **tolerability** and efficacy of a combination therapy involving **midostaurin** and **gemtuzumab ozogamicin** in conjunction with standard induction chemotherapy for patients with newly diagnosed acute myeloid leukemia (AML). This trial is structured as a randomized, double-blind, controlled study, encompassing both Phase I and Phase II components. The estimated duration of the trial is from September 2020 to September 2029, allowing for comprehensive data collection and analysis over this period.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, **ECOG** score, and adequate hepatic and renal function. Following successful screening, participants will be randomized into treatment groups. The trial includes multiple follow-up visits to monitor the participants' response to the treatment, assess any adverse effects, and ensure compliance with the study protocol. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the primary and secondary endpoints.
The expected length of participant involvement varies depending on individual response and the occurrence of any adverse events. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or any medical condition that contraindicates continued participation. The primary endpoints focus on determining the maximum tolerated dose of the combination therapy and evaluating event-free survival, defined as the time until primary treatment failure, relapse, or death. The trial aims to provide valuable insights into the potential benefits of this combination therapy for AML patients.
Treatment
The clinical trial involves the administration of **Rydapt** 25 mg soft capsules, which contain the active substance **midostaurin**. This medication is formulated as soft capsules and is administered orally. The dosage and frequency of administration are determined based on the trial protocol, with the primary aim of evaluating its efficacy and tolerability in combination with other treatments for **acute myeloid leukemia** (AML). The capsules are labeled for clinical trial use only, as per the regulatory requirements.
Another experimental medication used in the trial is **MYLOTARG** 5 mg powder for concentrate for solution for infusion, containing the active substance **gemtuzumab ozogamicin**. This medication is an immunoconjugate and is administered via intravenous infusion. The preparation involves reconstituting the powder to form a solution suitable for infusion, with dosing schedules specified in the trial protocol to ensure optimal therapeutic outcomes.
In addition to the experimental treatments, the trial includes the use of **DAUNORUBICIN HYDROCHLORIDE**, which is provided as a powder for solution for injection or infusion. This anthracycline antibiotic is administered intravenously, and its role in the trial is to serve as part of the standard induction chemotherapy regimen for AML. The dosing and administration are conducted according to established clinical guidelines to ensure safety and efficacy.
**CYTARABINE** is also utilized in the trial as a non-experimental treatment. It is a cytostatic drug from the series of antimetabolites, provided as a solution for injection or infusion. The administration is performed intravenously, with dosing schedules aligned with standard AML treatment protocols. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence and to evaluate the treatment's impact on the disease.
Efficacy
The efficacy of the clinical trial titled "MidOStaurin + Gemtuzumab OzogAmIcin Combination in First-line Standard Therapy for Acute Myeloid Leukemia (MOSAIC)" will be assessed using specific primary endpoints. In the dose escalation part of Phase I (MODULE), the primary endpoint is the determination of the Maximum Tolerated Dose (MTD) of **midostaurin** and gemtuzumab ozogamicin (GO) in combination. For the expansion part in Phase II, the primary endpoint for patients with Core Binding Factor Acute Myeloid Leukemia (CBF AML) in the MAGNOLIA trial and for patients with FLT3 mutation-positive Acute Myeloid Leukemia (FLT3mut AML) in the MAGMA trial is event-free survival. An event is defined as either primary treatment failure, relapse, or death, whichever occurs first.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent
- Newly diagnosed AML according to the criteria of the World Health Organisation plus the following molecular or cytogenetic specifications: Phase I Trial - MODULE: o ITD or TKD activating mutation at codons D835 and I836 in the FLT3 gene or o t(8;21)/RUNX1-RUNX1T1 or o inv(16) or o t(16;16)/CBFB-MYH11; Phase II Trial - MAGNOLIA: o t(8;21)/RUNX1-RUNX1T1 or o inv(16) or o t(16;16)/CBFB-MYH11; Phase II Trial - MAGMA: o ITD or TKD activating mutation at codons D835 and I836 in the FLT3 gene (FLT3- ITD or FLT3-TKD), o Absence of mutations in the core-binding factor genes (i.e. t(8;21)/RUNX1-RUNX1T1 or inv(16) or t(16;16)/CBFB-MYH11)
- Male and female patients aged: • 18 - ≤ 75 years in Phase I Trial - MODULE • 18 - ≤ 70 years in Phase II Trials - MAGMA and MAGNOLIA
- Eastern Cooperative Oncology Group (ECOG) Score of 0-2
- Life expectancy > 14 days
- Adequate hepatic and renal function: o ALAT/ASAT ≤ 2.5 x ULN o Bilirubin < 2 x ULN unless in case of hyperbilirubinemia due to an isolated Gilbert syndrome o Creatinine < 1.5 x ULN or Creatinine clearance > 40 ml/min,
- White blood cell count < 30 × 109/L. Note: Hydroxyurea and/or a dose of 100-200 mg/m2 cytarabine per day for up to 3 days (for emergency use for clinical stabilization) is permitted to meet this criterion
Exclusion Criteria
- Exclusion Criteria (all study parts): Previous antineoplastic treatment for AML other than hydroxyurea and/or cytarabine for emergency use (100-200 mg/m2 per day on maximal 3 days)
- Previous treatment with anthracyclines
- CNS involvement
- Isolated extramedullary AML
- Uncontrolled infection
- AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
- Any investigational agent within 30 days or 5 half-lives, whichever is greater, prior to day 1. An investigational agent is defined as an agent with no approved medical use in adults or in pediatric patients
- Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
- Strong CYP3A4/5 enzyme inducing drugs (see 6.4) unless they can be discontinued or replaced prior to enrollment
- Any other known disease or concurrent severe and/or uncontrolled medical condition (e.g., cardiovascular disease including congestive heart failure or active uncontrolled infection) that could compromise participation in the study
- Impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin
- Confirmed diagnosis of HIV infection
- Active viral hepatitis unless serology demonstrates clearance of infection. Occult or prior hepatitis B virus (HBV) infection, defined as negative hepatitis B surface antigen and positive total hepatitis core antibodies, may be included if HBV DNA is undetectable, provided that patients are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody after vaccination or prior cured hepatitis B are eligible. Patients for hepatitis C virus (HCV) antibody are eligible provided PCR is negative for HCV RNA
- Cardiovascular abnormalities, including any of the following: o History of myocardial infarction, angina pectoris, Coronary Artery Bypass Grafting within 6 months prior to starting study treatment, o Clinically uncontrolled cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block), o Uncontrolled congestive heart failure, o Left ventricular ejection fraction of < 50%, o Poorly controlled arterial hypertension
- Pregnant or nursing (lactating) women
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfill at least one of the following criteria: o Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml), o Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy o Women of childbearing potential must have a negative serum pregnancy test performed within 7 days before the first dose of study drug, o Continuous and correct application of a contraception method with a Pearl Index of < 1% (e.g. implants, depots, oral contraceptives, intrauterine device) from initial study drug administration until at least 7 months after the last dose of gemtuzumab ozogamicin and at least 4 months after the last dose of midostaurin, whichever period is longer. A hormonal contraception method must always be combined with a barrier method (e.g. condom) o Sexual abstinence, o Vasectomy of the sexual partner
- Sexually active males unless they use a condom during intercourse while taking the drug during treatment, and for at least 4 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen
- Unwillingness or inability to comply with the protocol
- Known hypersensitivity to midostaurin, GO, cytarabine or daunorubicin or to any of the excipients of midostaurin, GO, cytarabine or daunorubicin
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 02 Sept 2020 | 214 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Rydapt 25 mg soft capsules | Test | SOFT CAPSULES | ORAL USE | — | — | PRD5414155 |
CYTARABINE | Other | — | INTRAVENOUS INFUSION | — | — | SUB06880MIG |
Rydapt 25 mg soft capsules | Test | SOFT CAPSULES | ORAL USE | — | — | PRD5589815 |
MYLOTARG 5 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD6503068 |
DAUNORUBICIN HYDROCHLORIDE | Other | — | INTRAVENOUS | — | — | SUB01556MIG |