| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Molecularly profiled r/r ALL/LBL whose tumor harbors an actionable event that can be targeted by the investigational agents. In this subprotocol, patients must present alterations in the RAS signaling pathway. |
| Moleculaire geprofileerde r/r/ ALL/LBL waarvan de tumor een target heeft voor de onderzoeksmedicatie. In dit sub-protocol moet de tumor een verandering hebben in de RAS signaal transductie route. |
|
| E.1.1.1 | Medical condition in easily understood language |
| relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) with activating mutations of the RAS signaling pathway |
| recidief of refractaire acute lymfatische leukemie (ALL) of lymfoblastisch lymfoom(LL) met activerende mutaties van het RAS-signaalpad. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I: To assess the safety and tolerability of the investigational agents and define the MTD/RP2D(s);
Phase II: To evaluate the activity of new drugs in T-ALL/T-LBL patients harboring specific alterations linked to mechanism of action of these drugs. In case of subprotocol D this is trametinib. |
Fase I: De veiligheid en verdraagzaamheid van de onderzoeksmedicatie vaststellen en om de MTD/RP2D te bepalen.
Fase II: de activiteit van de nieuwe onderzoeksmedicatie evalueren in de T-ALL/T-LBL patienten die een specifieke verandering hebben in het werkingsmechanisme van deze medicatie. In het geval van subprotocol D gaat het om Trametinib. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate long term OS, EFS, incidence of relapse (CIR) and rate of transition to hematopoietic stem cell transplantation (HSCT).
- PK of the targeted agents.
- Quality of life (QoL). |
- het evalueren van de lange termijn effecten op OS, EFS, mate van relapse (CIR) en mate van overgang naar hematopoëtische stamceltransplantatie (HSCT)
- Farmacokintetiek van de targeted agents.
- Kwaliteit van leven vragenlijsten (QoL). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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. Patients under 6 years old must weigh at least 7 kg at the time of enrollment. Patients over 6 years old must weigh at least 10 kg at the time of enrollment.
2. Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 50% (Appendix I).
3. 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.
4. 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.
5. 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.
6. 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.
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|
| E.4 | Principal exclusion criteria |
7. Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1.
8. 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.
9. Breast feeding.
10. 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.
11. 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.
12. Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
13. Severe concomitant disease that does not allow treatment according to the protocol at the investigator’s discretion.
14. Subjects unwilling or unable to comply with the study procedures.
15. Previous treatment with trametinib.
16. 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.
17. 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).
18. 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.
19. Received immunosuppression post allogenic HSCT within one moth of study entry.
20. History or current evidence of retina vein occlusion (RVO) or central serous retinopathy are excluded.
21. 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):
i. Autologous HSCT within 2 months prior to the first study drug dose.
ii. 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. CAR-T therapy)
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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- The MTD will be defined as the dose associated with or closest to 25% of dose limiting toxicities (DLTs) in cycle (C)1. The RP2D of the combinations will be defined as the adult (adjusted for weight or BSA)/children recommended dose if toxicity (based on the occurrence of DLT during 1st cycle) is similar in children and in adults, or a higher dose, providing it is below or equal to the MTD. PK profiling will also be considered for the definition of RP2D.
- Overall Response Rate (ORR): Complete response (CR) and minimal residual disease (MRD) negativity rates after 1 cycle of treatment. Response in LBL patients is defined as CR, partial response and minor response (MR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- To estimate the OS, EFS, CIR from C1D1 until death, first event, relapse; rate of transition to HSCT is calculated by the number of patients who receive stem cell infusion divided by the total number of patients enrolled.
- PK parameters (C1D14), include plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, clearance, half-life time.
- QoL will be assessed at baseline and after cycle 1 and at the end of treatment using the PedsQL™ Cancer Module |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose finding combination therapy |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| Switzerland |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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