Phase I/II Study of Ruxolitinib and Venetoclax in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma with IL-7R/JAK-STAT Mutations
- Trial ID
- 2022-501867-42-01
- Protocol
- HEM-iSMART sub C
Trial statistics
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of the investigational agents, **ruxolitinib** and **venetoclax**, in pediatric patients with relapsed or refractory leukemia or lymphoma. This includes defining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in Phase I. In Phase II, the study aims to assess the activity of these new drugs in patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) who harbor specific genetic alterations linked to the mechanism of action of these drugs. The clinical relevance of this study lies in its potential to provide targeted therapeutic options for children with these challenging hematological malignancies, particularly those with mutations in the IL-7R/JAK-STAT signaling pathway.
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 year (≥ 12 months) and 18 years at the time of first diagnosis, with inclusion extending to those under 21 years at the time of trial entry. Participants are required to have a performance status of at least 50% on the Karnofsky or Lansky Play score, depending on age. The trial population was selected based on specific molecular alterations in the IL-7R and JAK-STAT signaling pathways, among other criteria. Participants must demonstrate adequate renal, hepatic, and cardiac function, with allowances for certain conditions related to the underlying disease. The study includes a vulnerable population, emphasizing the need for informed consent from parents or legal representatives, as well as age-appropriate assent from the participants themselves. 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 to evaluate the safety, tolerability, and efficacy of **venetoclax** and **ruxolitinib** in pediatric patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. This is a Phase I/II trial, structured as a randomized, double-blind, controlled study. The trial is expected to commence recruitment in October 2024 and conclude by October 2031. Participants will be involved in the study for a duration that varies depending on their response to treatment and the occurrence of any adverse events.
The trial will begin with a screening visit to assess eligibility based on specific inclusion criteria, such as age, performance status, and molecular profiling of the disease. Following successful screening, participants will undergo a series of study visits, including baseline assessments and regular follow-up visits to monitor safety and efficacy. The primary endpoints include determining the maximum tolerated dose in Phase I and assessing the best overall response rate in Phase II. Secondary endpoints encompass overall survival, event-free survival, and the rate of dose-limiting toxicities, among others.
Participants will be required to attend scheduled visits throughout the study, including an end-of-study visit to evaluate the final outcomes and any long-term effects of the treatment. The expected length of participant involvement will depend on individual response and the study phase they are enrolled in. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to comply with study procedures. The trial aims to provide valuable insights into the treatment of pediatric hematological malignancies with specific genetic alterations.
Treatment
The clinical trial involves the administration of **Venetoclax**, an anti-neoplastic agent, in two pharmaceutical forms: oral suspension and film-coated tablet. The oral suspension form of Venetoclax is produced by ABBVIE DEUTSCHLAND GMBH & CO. KG and is identified by the sponsor product code ABT-199. The active substance, **venetoclax**, is of chemical origin. The oral suspension is administered orally, with the frequency and dosage determined by the study protocol. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
In addition to the oral suspension, Venetoclax is also provided in a film-coated tablet form. This formulation is similarly produced by ABBVIE DEUTSCHLAND GMBH & CO. KG, with the same sponsor product code, ABT-199. The film-coated tablet is also administered orally, and the dosing schedule is aligned with the study's requirements. Compliance monitoring is conducted to ensure participants adhere to the prescribed regimen.
The trial also includes the administration of **Ruxolitinib**, marketed as Jakavi, in tablet form. Jakavi is available in various dosages, including 5 mg, 10 mg, 15 mg, and 20 mg tablets, all produced by NOVARTIS EUROPHARM LIMITED. The active substance, **ruxolitinib**, is of chemical origin and is administered orally. The dosing frequency and schedule are specified in the trial protocol, and participant adherence is monitored to ensure compliance with the treatment regimen.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided. The focus of the trial is on evaluating the safety, tolerability, and activity of the investigational agents in patients with relapsed or refractory hematological malignancies.
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 cumulative overall response rate (ORR) will be assessed, defined as the rates of complete remission (CR), complete remission with partial hematologic recovery (CRp), complete remission with incomplete hematologic recovery (CRi), and minimal residual disease (MRD) negativity after more than one cycle of treatment.
The trial will also evaluate the rate of dose-limiting toxicities (DLTs) and pharmacokinetic (PK) parameters, including plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, clearance, and half-life time. Quality of life (QoL) will be assessed at baseline, after cycle 1, and at the end of treatment using the PedsQL™ Cancer Module. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the investigational agents' impact on patients with relapsed or refractory hematological malignancies.
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.
- 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 advanced 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 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 presents alterations in the IL-7R and/or JAK-STAT signaling pathways including but not limited to the following are eligible: CRLF2: Rearrangements and mutations leading to CRLF2 overexpression (P2RY8-CRLF2, IGH-CRLF2, and CRLF2 F232C), CRFL2 overexpression; EPOR: Truncating rearrangements or mutations in exon 8, EPOR fusions; JAK1/2/3: Recurrent or novel missense and in-frame indel mutations in or flanking the pseudokinase and kinase domains, JAK fusion; IL-7R: Recurrent or novel missense or in-frame indel mutations in the transmembrane domain; SH2B3: Copy number deletions, or mutations that result in frameshifts or premature termination; JAK2: In frame fusions retaining the tyrosine kinase domain; USP9X truncating mutation or USP9X-DDX3X fusion; STAT5B and DNM2 mutations; PTPN2 deletion described as involved in IL7R/JAK/STAT pathway activation; IL7R mutations
- 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 dysfunction 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 Friedericia 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 anti-leukemic 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.
- Patients whose tumor present known mutations conferring resistance to JAK inhibitors: JAK1 Phe958 and Pro960 mutations and JAK2 Y931C mutations.
- Patients whose tumor present known mutations conferring resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations).
- 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 when applicable, 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 ruxolitinib and venetoclax in combination (Patients who have previously received any of these two drugs separately can be eligible for this sub-protocol).
- Current use of a prohibited medication or herbal preparation or requires any of these medications during the study. See Section 7, Appendix III and IV for details. In general, CYP3A4 inhibitors/Pgp inhibitors, moderate or strong inducers of CYP3A4 or drugs inducing QTc changes (prolongation of the QT interval or inducing Torsade de Points) are not permitted. Among others and not exclusively that relates to antiviral, antifungal, antibiotic, antimalarial, antipsychotic and anti-depressive drugs.
- Patients who have consumed grapefruit, grapefruit products, Seville oranges (Including marmalade containing Seville oranges) or starfruit within 72 hours prior to the first dose of study drug.
- 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 month of study entry.
- History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis.
- History of progressive multifocal leuko-encephalopathy (PML).
- History of endocrine or kidney related growth retardation prior to the underlying diagnosis.
- Evidence of clinically active tuberculosis (clinical diagnosis per local practice).
- 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 Oct 2024 | 1 |
 Belgium | Recruiting | 01 Oct 2024 | 1 |
 Denmark | Recruiting | 01 Oct 2024 | 1 |
 Finland | Not Yet Recruiting | 01 Oct 2024 | 1 |
 France | Not Yet Recruiting | 01 Oct 2024 | 3 |
 Germany | Recruiting | 01 Oct 2024 | 3 |
 Italy | Not Yet Recruiting | 01 Oct 2024 | 3 |
 The Netherlands | Recruiting | 01 Oct 2024 | — |
 Norway | Recruiting | 01 Oct 2024 | 1 |
 Spain | Recruiting | 01 Oct 2024 | 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 |
|---|---|---|---|---|---|---|
Jakavi 5 mg tablets | Test | TABLETS | OPHTHALMIC USE | — | — | PRD3949639 |
Venetoclax | Test | FILM-COATED TABLET | ORAL | — | — | PRD2186235 |
Jakavi 20 mg tablets | Test | TABLETS | ORAL | — | — | PRD3949631 |
Venetoclax | Test | FILM-COATED TABLET | ORAL | — | — | PRD2186234 |
Jakavi 10 mg tablets | Test | TABLETS | ORAL | — | — | PRD3949611 |
Venetoclax | Test | ORAL SUSPENSION | ORAL | — | — | PRD11264661 |
Venetoclax | Test | ORAL SUSPENSION | ORAL | — | — | PRD11264660 |
Venetoclax | Test | FILM-COATED TABLET | ORAL | — | — | PRD2186236 |
Venetoclax | Test | ORAL SUSPENSION | ORAL | — | — | PRD11264659 |
Jakavi 15 mg tablets | Test | TABLETS | ORAL | — | — | PRD3949623 |