International proof of concept therapeutic Stratification trial of Molecular Anomalies in Relapsed or Refractory HEMatological malignancies in children - Sub-protocol D
- Trial ID
- 2022-501869-41-00
- Protocol
- HEM-iSMART sub-D
Trial statistics
Objectives
The primary objective of this study is to assess the **safety** and tolerability of investigational agents in pediatric patients with relapsed or refractory hematological malignancies, specifically focusing on defining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) during Phase I. This is clinically relevant as it ensures the safe administration of new therapeutic agents, minimizing adverse effects while maximizing potential therapeutic benefits. Additionally, in Phase II, the study aims to evaluate the activity of new drugs in patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) who harbor specific genetic alterations that are linked to the mechanism of action of these drugs. This is crucial for understanding the efficacy of targeted therapies in these specific patient populations, potentially leading to more personalized and effective treatment strategies.
Participants
The clinical trial involves a total of **5 participants** diagnosed with **Acute Lymphoblastic Leukemia** in relapse or lymphoblastic lymphoma, either recurrent or refractory. The study population comprises both male and female children aged between 1 and 18 years at the time of first diagnosis, with inclusion extending to those under 21 years at the time of trial enrollment. Participants must be able to swallow tablets and meet specific weight requirements based on age. The trial population was selected based on the presence of RAS pathway activating mutations, as identified through molecular profiling. Participants are required to have a performance status of at least 50% on the Karnofsky or Lansky scale, depending on age, and must demonstrate adequate renal, hepatic, and cardiac function. The study includes a vulnerable population, and informed consent is mandatory. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the safety, tolerability, and efficacy of investigational agents in pediatric patients with relapsed or refractory hematological malignancies, specifically **Acute Lymphoblastic Leukemia** and lymphoblastic lymphoma. The trial is structured in two phases: Phase I aims to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of the investigational agents, while Phase II focuses on assessing the activity of these agents in patients with specific genetic alterations. The trial is expected to run from July 2023 to July 2030, with participant involvement lasting until the end of the study or until early termination criteria are met.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, performance status, and molecular profiling of the disease. Follow-up visits will be scheduled to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. The expected length of participant involvement is contingent upon the individual's response to treatment and the absence of any conditions that may necessitate early withdrawal, such as significant adverse events or disease progression.
Key elements of the research methodology include the use of **oral** formulations of trametinib, such as Spexotras and Mekinist, in combination with other agents. The primary endpoints are the determination of MTD in Phase I and the best overall response rate (ORR) in Phase II. Secondary endpoints include overall survival, event-free survival, cumulative incidence of relapse, and quality of life assessments. Participants will be closely monitored for dose-limiting toxicities and other safety parameters throughout the trial. The study is conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of **trametinib**, a chemical compound, in various pharmaceutical forms. One of the experimental medications used in the study is Spexotras, which is provided as a 0.05 mg/ml powder for oral solution. This formulation is intended for oral administration. The frequency and specific dosing schedule are determined based on the study protocol, ensuring adherence to the trial's objectives. The product is manufactured by Novartis Europharm Limited and is authorized under the marketing authorization number EU/1/23/1781/001. The product is not a pediatric formulation and is not classified as an orphan drug.
Another formulation of **trametinib** used in the trial is Mekinist, available as film-coated tablets in two different dosages: 0.5 mg and 2 mg. These tablets are also administered orally. The Mekinist tablets are produced by Novartis Europharm Limited and hold the marketing authorization numbers EU/1/14/931/002 and EU/1/14/931/006, respectively. Similar to Spexotras, Mekinist is not a pediatric formulation and does not have orphan drug status. The administration and dosing of Mekinist are conducted in accordance with the trial's protocol to ensure participant safety and compliance.
Throughout the trial, participant compliance with the dosing schedule is monitored to ensure the integrity of the study data. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus remains on evaluating the safety, tolerability, and efficacy of the investigational agents in the context of the study's objectives.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include determining the maximum tolerated dose (MTD) in Phase I and evaluating the Best Overall Response Rate (ORR) in Phase II. Secondary endpoints encompass a range of measures, including Overall Survival (OS), Event-Free Survival (EFS), Cumulative Incidence of Relapse (CIR), and the number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy. Additionally, the trial will assess the Cumulative Overall Response Rate (ORR), the rate of dose-limiting toxicities (DLTs), and the peak plasma concentration (Cmax) of **trametinib**. Quality of Life (QoL) will also be evaluated using the PedsQL™ Cancer Module at baseline, after cycle 1, and at the end of treatment.
The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial. The trial is designed to provide a comprehensive evaluation of the investigational agents' activity in patients with T-ALL/T-LBL harboring specific genetic alterations. The data collected will be analyzed to determine the therapeutic potential and safety profile of the investigational drugs, contributing to the understanding of their efficacy in treating relapsed or refractory hematological malignancies in children.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Children between 1 year (≥ 12 months) and 18 years of age at the time of first diagnosis and less than 21 years at the time of inclusion and able to swallow tablets. Patients under 6 years old must weigh at least ≥ 26 kg at the time of enrollment. Patients over 6 years old must weigh at least ≥ 33 kg at the time of enrollment.
- Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 50%
- Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study specific screening procedures are conducted, according to local, regional or national guidelines.
- Patients must have had molecular profiling and flow-cytometric analysis of their recurrent or refractory disease at a time-point before the first inclusion into this trial (see section 9.1 of this protocol for detailed description of the molecular diagnostics required). Drug response profiling and methylation is highly recommended but not mandatory. Patients with molecular profiling at first diagnosis lacking molecular diagnostics at relapse or refractory disease may be allowed to be included after discussion with the sponsor.
- Patients whose tumor present RAS pathway activating mutations including but not limited to KRAS, NRAS, HRAS, FLT3, PTPN11, MAP2K1, MP2K1 hotspot mutations, cCBL; NF1 del, as detected by molecular profiling.
- Adequate organ function: -RENAL AND HEPATIC FUNCTION (Assessed within 48 hours prior to C1D1) : o Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age or calculated creatinine clearance as per the Schwartz formula or radioisotope glomerular filtration rate ≥ 60 mL/min/1.73 m2. o Direct bilirubin ≤ 2 x ULN (≤ 3.0 × ULN for patients with Gilbert’s syndrome). o Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 5 x ULN. Note: Patients with hepatic disfunction related to the underling disease can be eligible even if they do not fulfill the aforementioned values for hepatic transaminases. In these cases, patients need to be discussed with the sponsor to confirm the eligibility. -CARDIAC FUNCTION: o Shortening fraction (SF) >29% (>35% for children < 3 years) and/or left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography or MUGA. o Absence of QTcF prolongation (QTc prolongation is defined as >450 msec on baseline ECG, using the Fridericia correction), or other clinically significant ventricular or atrial arrhythmia.
Exclusion Criteria
- Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1.
- Sexually active participants not willing to use highly effective contraceptive method (pearl index <1) as defined in CTFG HMA 2020 (Appendix II) during trial participation and until 6 months after end of antileukemic therapy.
- Breast feeding.
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome) in case of oral IMPs.
- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drugs, or drugs chemically related to study treatment or excipients that contraindicate their participation, including conventional chemotherapeutics (i.e. cytarabine and cyclophosphamide, intrathecal agents) and corticoids.
- Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
- Severe concomitant disease that does not allow treatment according to the protocol at the investigator’s discretion.
- Subjects unwilling or unable to comply with the study procedures.
- Previous treatment with trametinib
- Current use of a prohibited medication or herbal preparation or requires any of these medications during the study. See Section 7 and Appendix III for details. Drugs inducing QTc changes (prolongation of the QT interval or inducing Torsade de Points) are not permitted.
- Unresolved toxicity greater than NCI CTCAE v 5.0 ≥ grade 2 from previous anti-cancer therapy, including major surgery, except those that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profile of the study treatment (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy) (Common Terminology Criteria for Adverse Events (CTCAE) (cancer.gov).
- Active acute graft versus host disease (GvHD) of any grade or chronic GvHD of grade 2 or higher. Patients receiving any agent to treat or prevent GvHD post bone marrow transplant are not eligible for this trial.
- Received immunosuppression post allogenic HSCT within one moth of study entry.
- History or current evidence of retina vein occlusion (RVO) or central serous retinopathy are excluded.
- Wash-out periods of prior medication: a. CHEMOTHERAPY: At least 7 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea, 6-mercaptopurine, oral methotrexate and steroids which are permitted up until 48 hours prior to initiating protocol therapy. Patients may have received intrathecal therapy (IT) at any time prior to study entry. b. RADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first dose of drug. Palliative radiation in past 21 days is allowed. c. HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT): a. Autologous HSCT within 2 months prior to the first study drug dose. b. Allogeneic HSCT within 3 months prior to the first study drug dose. d. IMMUNOTHERAPY: At least 42 days must have elapsed after the completion of any type of immunotherapy other than monoclonal antibodies (e.g. inotuzumab) e. MONOCLONAL ANTIBODIES AND INVESTIGATIONAL DRUGS: At least 21 days or 5 times the half-life (whichever is shorter) from prior treatment with monoclonal antibodies or any investigational drug under investigation must have elapsed before the first study drug. f. SURGERY: Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 01 Jul 2023 | 1 |
 Belgium | Recruiting | 01 Jul 2023 | 1 |
 Denmark | Recruiting | 01 Jul 2023 | 1 |
 Finland | Not Yet Recruiting | 01 Jul 2023 | 1 |
 France | Not Yet Recruiting | 01 Jul 2023 | 3 |
 Germany | Recruiting | 01 Jul 2023 | 3 |
 Italy | Not Yet Recruiting | 01 Jul 2023 | 3 |
 The Netherlands | Recruiting | 01 Jul 2023 | — |
 Norway | Recruiting | 01 Jul 2023 | 1 |
 Spain | Recruiting | 01 Jul 2023 | 2 |
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 |
|---|---|---|---|---|---|---|
Mekinist 0.5 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD3853378 |
Spexotras 0.05 mg/ml powder for oral solution | Test | POWDER FOR ORAL SOLUTION | ORAL | — | — | PRD11036111 |
Spexotras 0.05 mg/ml powder for oral solution | Test | POWDER FOR ORAL SOLUTION | ORAL | — | — | PRD11036112 |
Mekinist 2 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD3853382 |
Spexotras 0.05 mg/ml powder for oral solution | Test | POWDER FOR ORAL SOLUTION | ORAL | — | — | PRD11036109 |
Spexotras 0.05 mg/ml powder for oral solution | Test | POWDER FOR ORAL SOLUTION | ORAL | — | — | PRD11036110 |