International proof of concept therapeutic Stratification trial of Molecular Anomalies in Relapsed or Refractory HEMatological malignancies in children. Sub-Protocol D: Trametinib + Dexamethasone
+ Cyclophosphamide and Cytarabine in pediatric patients with relapsed or refractory hematological malignancies

Patients must have any of the conditions (Group A to E) depicted below for
being eligible for the trial. Patients need to fulfill all inclusion and
exclusion criteria depicted in sections 5.1 and 5.2. T-ALL and T-LBL Cohort:
Group A: T-ALL in first or greater relapse/refractory to at least one prior
regimen defined as: - >= 5% blasts in the marrow after first line induction and
consolidaton blocks or any re-induction therapy for 1st or subsequent
relapse(s)/refractoriness OR - Be in complete morphological remission (< 5%
blasts in the marrow) but having o MRD >=1 x 10-3 after first line induction and
consolidaton blocks, or o >=1 x 10-4 after any re-induction therapy for 1st or
subsequent relapse(s)/refractoriness. Group B: T-LBL (histology proven or
diagnosed applying flow cytometry and/or cytomorphology of bone marrow (bone
marrow blast count >= 5% but < 25 %), peripheral blood and effusions) in
first or greater relapse/refractoriness to at least one prior induction regimen
defined as: - Evidence of measurable disease by radiological criteria after
first line induction and consolidaton blocks or any re-induction therapy for
1st or subsequent relapse(s)/refractoriness AND/OR - >= 5% blasts in the marrow
after first line induction and consolidaton blocks or any re-induction therapy
for 1st or subsequent relapse(s)/refractoriness OR - Be in complete
morphological remission (< 5% blasts in the marrow and no extra-medullary
disease) but having MRD >= 1 x 10-3 after first line induction and consolidaton
blocks or >=1 x 10-4 after any re-induction therapy for 1st or subsequent
relapse(s)/refractoriness. Group C: - Patients with either T-ALL or T-LBL who
are in complete morphological remission (< 5% blasts in the marrow and no
extra-medullary disease) but who have experienced a molecular reappearance
defined as *reconversion after minimal residual disease (MRD) negativity* to
reproducible MRD positivity (>=1 x 10-4). MRD positivity MUST be confirmed in
two different samples in the bone marrow two weeks apart before the enrolment
of these patients into the trial or by two independent methods (f.ex. PCR and
flow-cytometry) at one measurement. BCP-ALL and B-LL Cohort: These patients can
ONLY be enrolled into the dose finding phase (Phase I) of the sub-protocols at
the moment. Group D: BCP-ALL in second or greater relapse or refractory to 2
prior regimens defined as: - >= 5% blasts in the marrow after any re-induction
therapy for 2nd or subsequent relapse(s)/refractoriness OR - Be in complete
morphological remission (< 5% blasts in the marrow) but having MRD >= 1 x
10-4 after any re-induction therapy for 2nd or subsequent
relapse(s)/refractoriness NOTE: Patients with BCP-ALL MUST have received and
failed hematopoietic stem cell transplantation (HSCT) and/or CAR-T therapy.
Exceptions to this are: absence of a suitable donor, failure of manufacturing
CAR-T, impossibility to access a CAR-T-program, patients not candidates to
CAR-T-therapy due to clinical reasons. These patients need to be discussed with
the sponsor on a single case basis. Group E: B-LBL (histology proven or
diagnosed applying flow cytometry and/or cytomorphology of bone marrow (bone
marrow blast count >= 5% but < 25 %), peripheral blood and effusions) in
first or greater relapse/refractory to at least one prior induction regimen
defined as: - Evidence of measurable disease by radiological criteria after
first line induction and consolidaton blocks or any re-induction therapy for
1st or subsequent relapse(s)/refractoriness AND/OR - >= 5% blasts in the marrow
after first line induction and consolidaton blocks or any re-induction therapy
for 1st or subsequent relapse(s)/refractoriness OR - Be in complete
morphological remission (< 5% blasts in the marrow and no extra-medullary
disease) but having MRD >= 1 x 10-3 after first line induction and consolidaton
blocks or >=1 x 10-4 after any re-induction therapy for 1st or subsequent
relapse(s)/refractoriness Patients with isolated extramedullary disease (IEM)
are not eligible. IEM is defined as biopsy proven extramedullary disease after
documented CR following initial therapy. Standardized response criteria for IEM
are lacking which impairs analysis of the primary endpoint. In addition these
patients might need to undergo local therapy (radiation and/or surgery) which
is standardized exclusively for isolated CNS and testicular relapse and might
confound outcome analysis if it is based on physician*s choice in particular
for *other* IEM [57]. Patients with combined extramedullary and bone marrow
disease fulfilling the above mentionned conditions group A-E with MRD >= 10-3
are eligible since standardized bone marrow assessment is available. These
patients will undergo centralized review of bone marrow and of IEM response. 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 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. 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.

1. Pregnancy or positive pregnancy test (urine or serum) in females of
childbearing potential. Pregnancy test must be performed within 7 days prior to
C1D1. 2. 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. 3. Breast feeding. 4. 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. 5. 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. 6. Known active viral
hepatitis or known human immunodeficiency virus (HIV) infection or any other
uncontrolled infection. 7. Severe concomitant disease that does not allow
treatment according to the protocol at the investigator*s discretion. 8.
Subjects unwilling or unable to comply with the study procedures. 9. Previous
treatment with trametinib. 10. 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. 11. 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). 12. 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. 13. Received immunosuppression post allogenic HSCT
within one moth of study entry. 14. History or current evidence of retina vein
occlusion (RVO) or central serous retinopathy are excluded. 15. 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.
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.