​ Trials

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Study Description

Researchers are looking for new ways to treat children with hepatoblastoma or rhabdomyosarcoma (RMS) that has relapsed or is refractory:

• Hepatoblastoma is a common liver cancer in babies and very young children
• RMS is a cancer that starts in muscle cells, often in a child's head and neck, bladder, arms, or legs
• Relapsed means the cancer came back after treatment
• Refractory means the cancer did not respond (get smaller or go away) to treatment

The study treatment HER3-DXd (also known as MK-1022 or patritumab deruxtecan) is an antibody-drug conjugate (ADC). An ADC attaches to a protein on cancer cells and delivers treatment to destroy those cells. The goals of this study are to learn:

• About the safety of HER3-DXd in children and if they tolerate it
• What happens to HER3-DXd in children's bodies over time
• If children who receive HER3-DXd have the cancer get smaller or go away

This study will have 2 parts: a safety lead-in to demonstrate a tolerable safety profile and confirm a preliminary recommended phase 2 dose (RP2D) (Part 1) followed by an efficacy evaluation (Part 2).

Inclusion Criteria

• Has one of the following histologically confirmed advanced or metastatic solid tumors: Rhabdomyosarcoma (RMS), or Hepatoblastoma
• Has progressed after at least 1 prior systemic treatment for RMS or hepatoblastoma and who has no satisfactory alternative treatment option (ie, is ineligible for other standard treatment regimens)
• Participants who have adverse events (AEs) due to previous anticancer therapies must have recovered to Grade ≤1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have Grade ≤2 neuropathy are eligible
• Hepatitis B surface antigen (HBsAg) positive participants are eligible if they have received hepatitis B virus (HBV) antiviral therapy and have undetectable HBV viral load
• Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable

Exclusion Criteria

• Has a history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids or has current ILD/pneumonitis, and/or suspected ILD/pneumonitis that cannot be ruled out by standard diagnostic assessments
• Has clinically severe respiratory compromise resulting from intercurrent pulmonary illness
• Has a history of solid organ transplant
• Has a history of allogeneic stem cell transplant
• Has clinically significant corneal disease
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis/leptomeningeal disease; participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks
• Has uncontrolled or significant cardiovascular disorder
• Has a history of clinically significant congenital cardiac syndrome
• Has a history of human immunodeficiency virus (HIV) infection
• Has a known additional malignancy that is progressing or has required active treatment within the past 1 year
• Has an active infection requiring systemic therapy
• Has concurrent active hepatitis B (HBsAg positive and/or detectable HBV deoxyribonucleic acid [DNA]) and HCV defined as anti-HCV antibody (Ab) positive and detectable HCV ribonucleic acid [RNA]) infection
• Has not adequately recovered from major surgery or have ongoing surgical complications

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

The phase I portion of this study is designed for children or adolescents and young adults (AYA) with a diagnosis of a solid tumor that has recurred (come back after treatment) or is refractory (never completely went away). The trial will test 2 combinations of therapy and participants will be randomly assigned to either Arm A or Arm B. The purpose of the phase I study is to determine the highest tolerable doses of the combinations of treatment given in each Arm.

In Arm A, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and talazoparib. Onivyde works by damaging the DNA of the cancer cell and talazoparib works by blocking the repair of the DNA once the cancer cell is damaged. By damaging the tumor DNA and blocking the repair, the cancer cells may die. In Arm B, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and temozolomide. Both of these medications work by damaging the DNA of the cancer call which may cause the tumor(s) to die.

Once the highest doses are reached in Arm A and Arm B, then "expansion Arms" will open. An expansion arm treats more children and AYAs with recurrent or refractory solid tumors at the highest doses achieved in the phase I study. The goal of the expansion arms is to see if the tumors go away in children and AYAs with recurrent or refractory solid tumors. There will be 3 "expansion Arms". In Arm A1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and talazoparib. In Arm A2, children and AYAs with recurrent or refractory solid tumors, whose tumors have a problem with repairing DNA (identified by their doctor), will receive Onivyde and talazoparib. In Arm B1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and temozolomide.

Once the highest doses of medications used in Arm A and Arm B are determined, then a phase II study will open for children or young adults with Ewing sarcoma that has recurred or is refractory following treatment received after the initial diagnosis. The trial will test the same 2 combinations of therapy in Arm A and Arm B. In the phase II, a participant with Ewing sarcoma will be randomly assigned to receive the treatment given on either Arm A or Arm B.

Inclusion Criteria

• Age: Patients must be > 12 months and < 30 years at the time of enrollment on study.
• Diagnosis:
  • Phase I (Only expansion cohort open)
    • Patients with refractory or recurrent non-central nervous system (CNS) solid tumors not amenable to curative treatment are eligible. Patients must have had histologic verification of malignancy at original diagnosis or at the time of relapse. Patients eligible for the expansion cohort, A2, will include non-ES patients with refractory or recurrent non-CNS solid tumors with a deleterious alteration in germline or somatic genes involved in HR repair and DSBs signaling, germline or somatic assessed by prior comprehensive sequencing performed in a CLIA-approved (or equivalent) facility.
  • Phase II (Open)
    • Patients with refractory or recurrent Ewing sarcoma (during or after completion of first-line therapy). Refractory disease is defined as progression during first line treatment or within 12 weeks of completion of first line treatment. Recurrent disease includes patients who received first line treatment and experienced disease progression at any time point >12 weeks from the completion of first line therapy.
    • Patients must have a histologic diagnosis of Ewing sarcoma with EWSR1- FLI1 translocation or other EWS rearrangement at the time of initial diagnosis. Repeat biopsy at the time of disease recurrence is strongly encouraged but it is not required/mandated for enrollment.
• Disease status
  • Patients must have either measurable or evaluable disease (see Section 7.0 for definitions). Measurable disease includes soft tissue disease evaluable by cross-sectional imaging (RECIST). Patients with bone disease without a measurable soft tissue component or bone marrow disease only are eligible for the phase 1 and phase 2 study but will not be included in the OR endpoint.
• Performance level: Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients < 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior therapy
  • Phase I: Patients who have received prior therapy with an irinotecan-based or temozolomide-based regimen are eligible. Patients who have received prior therapy with a PARP inhibitor other than talazoparib are eligible.
  • Phase II: Patients should have received first line therapy and developed either refractory or recurrent disease (first relapse).
• Organ function: Must have adequate organ and bone marrow function as defined by the following parameters:
  • Patients with solid tumors not metastatic to bone marrow:
    • Peripheral absolute neutrophil count (ANC) >1,000/mm3 (1x109/L)
    • Platelet count > 75,000/mm3 (75x109/L) (no transfusion within 7 days of enrollment)
    • Hemoglobin > 9 g/dL (with or without support)
  • In the phase I study, patients with solid tumors metastatic to bone marrow or with bone marrow hypocellularity defined as <30% cellularity in at least one bone marrow site will be eligible for study, but they will not be evaluable for hematologic toxicity. These patients must not be refractory to red cell or platelet transfusions. At least 2 of every cohort of 3 patients (in the phase I study) must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed at any dose level, all subsequent patients enrolled at that dose level must be evaluable for hematologic toxicity.
  • Adequate renal function defined as: Creatinine clearance or radioisotope GFR > 60ml/min/1.73m2 or a serum creatinine maximum based on age/sex: age 6months to <1 year, creatinine 0.4; 1 to < 2 years, creatinine 0.6; 2 < 6 years, creatinine 0.8; 6 < 10 years, creatinine 1; 10 to <13 years, creatinine 1.2; 13 to < 16 years creatinine 1.5 (males) or 1.4 (females); > 16 years, creatinine 1.7 (males) 1.4 (females)
  • Adequate liver function defined as: normal liver function as defined by SGPT (ALT) concentration <5x the institutional ULN, a total bilirubin concentration <2x the institutional ULN for age, and serum albumin > 2g/dL.
  • Adequate pulmonary function defined as no evidence of dyspnea at rest and a pulse oximetry > 94% if there is a clinical indication for determination. Pulmonary function tests are not required.
• Patients must have fully recovered from the acute toxic effects of chemotherapy, immunotherapy, surgery, or radiotherapy prior to entering this study:
  • Myelosuppressive chemotherapy: Patient has not received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (8 weeks if received prior myeloablative therapy).
  • Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim.
  • Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur.
  • Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody or 28 days have elapsed since last dose of the monoclonal antibody with complete resolution of symptoms related to treatment.
  • Radiotherapy: At least 2 weeks must have elapsed since any irradiation; at least 6 weeks must have elapsed since craniospinal RT, 131I-mIBG therapy or substantial bone marrow irradiation (e.g., >50% pelvis irradiation).
• Female participant who is post-menarchal must have a negative urine or serum pregnancy test and must be willing to have additional serum and urine pregnancy tests during the study.
• Female or male participant of reproductive potential must agree to use effective contraceptive methods at screening and throughout duration of study treatment.
• Written informed consent/assent from the patient and/or parent/legal guardian

Exclusion Criteria

Pregnant or breastfeeding

• Pregnant or breast-feeding women will not be entered on this study. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control: a medically accepted barrier of contraceptive method (e.g., male or female condom) and a second method of birth control during protocol therapy. Two highly effective methods of contraception are required for female patients during treatment and for at least 7 months after completing therapy. Male patients with female partners of reproductive potential and/or pregnant partners are advised to use two highly effective methods of contraception during treatment and for at least 4 months after the final dose.
• Male and female participants must agree not to donate sperm or eggs, respectively, after the first dose of study drug through 105 days and 45 days after the last dose of study drug. Females considered not of childbearing potential include those who are surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy).

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This international multi-centre phase 2 pilot trial aims to explore the efficacy of Opdualag, a fixed dose combination of nivolumab and relatlimab, across two cohorts of children, adolescent, and young adult (CAYA) patients, ≥ 12 years of age, with relapsed/refractory extra-cranial solid and CNS tumours. The main study cohort will enrol CAYA patients with relapsed/refractory extra cranial solid and CNS tumours, characterised by high immune infiltration as indicated by their high CD8+ T cell infiltration, M1M2 macrophage ratios and/or Immune Paediatric Signature Score (IPASS), established using whole transcriptome sequencing of RNA extracted from tumour samples and subsequent comparison to other paediatric cancers. A second exploratory cohort includes CAYA patients with deficient (RRD) tumours that have progressed on, or recurred following PD(L)-1 blockade treatment.

The efficacy assessment of both cohorts will be complemented by safety data (AEs), alongside further exploratory data on patient- and parent/proxy-reported outcomes, focusing on symptoms experienced during treatment with Opdualag and its impact on patient quality of life. Biological samples will be collected to explore the correlation between quantitative circulating tumour DNA and disease response, as well as other genomic, transcriptomic, proteomic, and immunological biomarkers. These analyses will offer a detailed understanding of the tumour immune microenvironment and enhance our ability to predict responses to Opdualag for paediatric, adolescent, and young adult patients in the future.

Inclusion Criteria

Patients must meet all the study eligibility criteria outlined in BOTH the Master Protocol, in addition to Arm’s C specific inclusion criteria as listed below: 

Arm C Inclusion Criteria

Specific criteria for Cohort C1 only:

• Age: Patients should be ≥ 12 years of age at the time of entry into screening.
• Tumour characterised by high immune infiltration: Patients must be diagnosed with a relapsed or refractory extracranial or CNS solid tumour that is characterised by high immune infiltration as outlined in lab manual and as evidenced by any two immune scores, including a CD8+ T cell score, M1M2 score or IPASS score that are ≥80th percentile relative to a pre-defined comparator cohort of paediatric, adolescent, and young adult cancer patients

Specific criteria for Cohort C2 only:

• Age: Patients should be ≥ 12 years of age at the time of entry into screening.
• Diagnosis: CAYA patients RRD relapsed or refractory extracranial or CNS solid tumour, with evidence of replication repair deficiency that has been established using tumour immunohistochemistry and/or a validated functional assay (e.g. genomic MSI burden using low-pass WGS/LOGIC) showing high MMRDness >0) or based on prior germline testing confirming congenital mismatch repair deficiency (CMMRD), Lynch syndrome or Polymerase-proofreading associated polyposis (PPAP) (Chung et al., 2022)
• Disease trajectory: They have objective evidence of disease progression at any time following (or during) previous PD(L)1 therapy.
• Ineligible for Cohort C1: They do not meet the criteria for high immune infiltration criteria as stipulated for Cohort C1, either because the immune score thresholds are not reached or because data relating to immune scores is not available).

All participants: 

• All patients should have measurable disease, except for patients with neuroblastoma who will also be eligible if they have metastatic disease evaluable only by mIBG scintigraphy
• Adequate organ function as per Master Protocol, with the following specific requirements of Arm C, including: 
  • Cardiac Function: 
    • Shortening fraction of ≥27% by echocardiogram, OR Ejection fraction of ≥50% by echocardiogram
    • QTC <480 msec by the Fridericia formula
  • Endocrine function:
    • TSH within institutional normal limits for age. Patients on treatment for thyroid dysfunction can be included if their TSH is within normal limits on therapy at the time of inclusion. 
• Patients with CNS lesions are eligible if all the following criteria are met: 
  • No evidence of uncal herniation or mass effect leading to severe midline shift.
  • Lesion <6 cm in single maximal dimension.
  • A lesion that in the opinion of the investigator does not show significant mass effect.
  • No history of clinically significant intracranial haemorrhage or spinal cord haemorrhage.
  • No ongoing requirement for corticosteroids as therapy for CNS disease.
• ≥14 days after last immunosuppressive dose of corticosteroids (>2mg/kg/day prednisone equivalent) or other systemic immunosuppressive medications azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor [anti-TNF] agents prior to Cycle 1, Day 1. Note: Concurrent use of corticosteroids for physiological replacement is permitted. Use of topical, intra-articular, ocular, intranasal or inhaled corticosteroids is permitted.
• Female patients of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods, as defined in the Master Protocol, for the duration of treatment with Opdualag plus 5 months after the last dose of Opdualag.
• Male patients must agree to remain abstinent (refrain from heterosexual intercourse with a female partner of childbearing potential or who is pregnant) or use contraceptive measures,as defined in the Master Protocol, and agree to refrain from donating sperm for the entire duration of treatment with Opdualag.

Master Protocol Inclusion Criteria

• Patients must be diagnosed with a solid tumour, CNS tumour or lymphoma that has progressed despite standard therapy, or for which no effective standard therapy exists.
• Age <21 years at inclusion; patients 21 years and older may be included after approval by the Study Chair if they have a paediatric type recurrent/refractory malignancy.
• Patients must be enrolled on a precision medicine study (i.e. PROFYLE, ZERO or equivalent as agreed with Study Chair (or their delegate)).
  • Tumour profiling should be performed as close to the time of study enrolment as possible; at a minimum profiling should have been performed on a sample obtained 
    within 12 months prior to enrolment, or had confirmation that the targeted molecular aberration is still present from a tumour sample collected within the 12 months prior to 
    enrolment. Patients for whom tumour profiling has been performed outside this window may only be enrolled after approval by the Study Chair.
  • Patients are eligible to enroll using existing sequencing results or other criteria such as immunohistochemistry (provided a report from a CLIA-approved or equivalent 
    laboratory is provided), but concurrent enrolment on a precision medicine study is still required.
• Patients enrolled in a Phase I cohort must have either evaluable or measurable disease*.
• Patients enrolled in a Phase II cohort must have measurable disease*.
  • *Evaluable and measurable disease are defined by standard imaging criteria for the patient’s
    tumour type (RECIST V1.1 for solid tumours, RAPNO or RANO criteria for patients with CNS 
    tumours, INRC criteria for patients with neuroblastoma, RECIL for lymphoma). Refer to Section 8.
• Disease evaluations, laboratory tests, and other clinical assessments that are considered standard of care may be undertaken at the patient’s local oncology treatment centre with results 
  transferred to study site for evaluation. 
• Performance status: Karnofsky performance status (for patients >16 years of age) or Lansky Play score (for patients ≤16 years of age) ≥50%. Patients who are unable to walk because of paralysis 
  or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Life expectancy ≥6 weeks
• Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer-directed therapy prior to 
  enrolment to an arm.
  • Cytotoxic chemotherapy or other anticancer agents known to be myelosuppressive: ≥21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days 
    if prior nitrosourea, e.g. lomustine). 
  • Anticancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or neutrophil counts): ≥7 days after the last dose of agent.
  • Antibodies: ≥21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to Grade ≤1.
  • Corticosteroids: If used to modify immune adverse events related to prior therapy, ≥14 days must have elapsed since last dose of corticosteroid.
  • Haematopoietic growth factors: ≥14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor
  • Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): ≥21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors) 
  • Stem cell Infusions (with or without TBI): 
    • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including DLI or boost infusion: ≥84 days after infusion and no evidence of GVHD.
    • Autologous stem cell infusion including boost infusion: ≥42 days
  • Cellular Therapy: ≥42 days after the completion of any type of cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
  • XRT/External Beam Irradiation including Protons: ≥14 days after local XRT; ≥150 days after TBI, craniospinal XRT or if radiation to ≥50% of the pelvis; ≥42 days if other substantial BM radiation. Note: target lesions being used to follow response to study 
    arm treatment that have been irradiated must show progression following radiotherapy to be considered evaluable for response
  • Radiopharmaceutical therapy (e.g. radiolabelled antibody, 131I-MIBG): ≥42 days after systemically administered radiopharmaceutical therapy. 
  • Palliative radiotherapy of up to 2 pre-existing, non-target bone metastases will be permitted without being considered progressive disease and may be administered concurrently with study therapy provided DLT evaluation period has been completed.
• Adequate organ function:
  • Haematologic criteria:
    • Peripheral absolute neutrophil count (ANC) ≥1.0 x 109/L (unsupported) (i.e. at least 7 days post filgrastim; at least 14 days post PEG-filgrastim (if administered)).
    • Platelet count ≥75 x 109/L (unsupported; defined as no platelet transfusions within prior 7 days).
    • Haemoglobin ≥80 g/L (transfusion is allowed).
  • Renal and hepatic function:
    • Serum creatinine ≤1.5 x upper limit of normal (ULN) for age.
    • Total bilirubin ≤1.5 x ULN.
    • Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤5 x ULN except in patients with documented tumour involvement of the liver who 
      must have AST and ALT ≤10 x ULN.
• Able to comply with scheduled follow-up and with management of toxicity.
• Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment and agree to use adequate contraception during the study 
  and following completion of treatment as per the treatment arm guidelines. 
• Fertile males must agree to use adequate contraception during the study and following completion of treatment as per the treatment arm guidelines. 
• Provide a signed and dated informed consent form or has a legally acceptable representative capable of understanding the informed consent document, and providing consent on the 
  participant’s behalf.

Exclusion Criteria

Patients must meet all the study eligibility criteria outlined in BOTH the Master Protocol, in addition to Arm’s C specific exclusion criteria as listed below: 

Arm C Exclusion Criteria

• For Cohort C1 only: A solid or CNS tumour patient with only lymph node derived tumour samples for assessing CD8+ T cell / M1M2 / IPASS high immune infiltration score (as such lymph node derived tumour samples were excluded during the development of the RICO container).
• An anticipated requirement for systemic immunosuppressive medications while receiving treatment with Opdualag.  
• A diagnosis of a haematolymphoid malignancies, including Hodgkin and non-Hodgkin lymphoma, will not be eligible (as may be eligible for RELATIVITY-069, NCT05255601). 
• An active autoimmune disease at any point within the last 2 years prior to enrolment including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Note: patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone, controlled Type I diabetes mellitus on a stable dose of insulin regimen or an autoimmune condition that is not expected to recur in the absence of an external trigger may be permitted to enrol. Asymptomatic laboratory abnormalities (e.g. ANA, rheumatoid factor) will not render a patient ineligible in the absence of a diagnosis of an autoimmune disorder
• Patients with eczema, psoriasis, lichen simplex chronicus, vitiligo with dermatologic manifestations only, or other chronic skin conditions are not eligible if any of the following apply:
  • Rash covers more than 10% of body surface area (BSA)
  • Disease is not well controlled at baseline, requiring more than low potency topical steroids
  • Patient has experienced acute exacerbation within previous 12 months requiring treatment with PUVA, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency/oral steroids
• Patients with severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents (such as immune checkpoint inhibitors).
• Patients with a history of myocarditis. 
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Prior solid organ or allogeneic stem cell transplant.
• Previous treatment with relatlimab. Note that prior therapy with PD(L)1 and/or CTLA-4 inhibitor is not an exclusion.
• Active tuberculosis.
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during Opdualag treatment.
• Patients who are breastfeeding. 

Master Protocol Exclusion Criteria

• Patients with symptomatic central nervous system (CNS) primary or metastatic tumours who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed 
  therapy to control their CNS disease. Patients on stable doses of corticosteroids for at least 7 days prior to receiving study drug may be included.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, 
  or malabsorption syndrome) – only for arms that include orally administered therapeutic agents
• Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality), unstable 
  ischemia, congestive heart failure within 12 months of screening.
• Known active viral hepatitis or human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
• Major surgery within 21 days of the first dose of investigational drug. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumour biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48-hour interval must be maintained before the first dose of the investigational drug is administered.
• Known hypersensitivity to any study drug or component of the formulation.
• Pregnant or nursing (lactating) females.
• Any other concomitant serious medical condition or organ dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the investigational drug(s).
   

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Study Description

The Phase I part of the study aims to evaluate the safety, efficacy, and tolerability of subcutaneous (SC) blinatumomab for treatment of Relapsed or Refractory B cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL), to determine the maximum tolerated dose (MTD), and recommended phase 2 dose(s) (RP2D) of SC administered blinatumomab.

The Phase II part of the study will evaluate the safety, efficacy, and tolerability of SC blinatumomab for treatment of R/R B-ALL and Minimum Residual Disease Positive (MRD+) B-ALL in participants 12 years old and greater. It will also conduct a clinical pharmacokinetic (PK) evaluation of SC1 and SC2 blinatumomab formulations.

Inclusion Criteria

• Age: 
  • Ph-IIRb and Ph-IIMb: Age ≥ 12 years and < 17 years at time of informed consent.
  • Ph-IIRa and Ph-IIMa: Aged ≥ 17 years at time of informed consent.
  • Ph-IIC, Dose Escalation and Dose Expansion: Aged 18 years or older
• Diagnosis:
  • Ph-IIR, Ph-IIC, Dose escalation, Dose Expansion: Participants with R/R B-precursor ALL.
  • Relapsed or Refractory B-precursor ALL at any time after first salvage therapy.
  • Relapsed B-precursor ALL at any time after allogenic hematopoietic stem cell transplant (HSCT).
• Bone Marrow:
  • Ph-IIR, Ph-IIC, Dose escalation, Dose expansion: Greater than or equal to 5% blasts in the Bone Marrow per local assessment.
  • Ph-IIM: B-precursor ALL and bone marrow blasts (BMB) ≥ 0.01% and < 5% per local assessment.
  • Ph-IIM: Availability of an appropriate archival BM specimen from initial or relapse diagnosis and the screening BM sample.
• Participants aged ≥ 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2.
• Participants aged 16 to < 18 years old: Karnofsky Performance Score ≥ 50%.
• Participants aged < 16 years old: Lansky Performance Score ≥ 50%.
• Any Ph+ participant intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are eligible.
• Ph-IIM: BM function as follows:
  • Absolute Neutrophil Count (ANC) ≥ 500/μL
  • Platelet count ≥ 50 000/μL (transfusion permitted)
  • Hemoglobin level ≥ 9 g/dL (transfusion permitted)

The above is a summary, other inclusion criteria details may apply.

Exclusion Criteria

• Active ALL in the central nervous system (CNS). Presence of greater than 5 white blood cells per cubic millimeter in cerebrospinal fluid (CSF) with lymphoblasts present and/or clinical signs of CNS leukemia. If CSF leukemia is present subjects will have to receive intrathecal therapy and have documented negative CSF prior to enrolling.
• History or presence of clinically relevant CNS pathology (excluding headache) such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis or severe (≥ grade 3) CNS events including immune effector cell-associated neurotoxicity syndrome (ICANS) from prior chimeric antigen receptor T-cell (CAR T) or other T cell engager therapies.
• Isolated Extramedullary (EM) Disease.
• For Ph-IIM only: Current EM disease or presence of circulating leukemia blasts.
• Current autoimmune disease or history of autoimmune disease with potential CNS involvement.
• Active acute or chronic graft versus host disease requiring systemic treatment with immunosuppressive medication.
• Symptoms and/or signs that indicate an acute or uncontrolled chronic infection, any other disease or condition that could be exacerbated by the treatment or would complicate protocol compliance.
• Testicular leukemia.
• History of malignancy (with certain exceptions) other than ALL within 3 years prior to start of protocol-specified therapy.
• Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy.
• Cancer chemotherapy within 2 weeks before the start of protocol-specified therapy (with certain exceptions).
• Immunotherapy within 4 weeks before start of protocol-specified therapy.
• Prior failed cluster of differentiation (CD19) directed therapy such as prior blinatumomab or CD19 CAR T cells will be allowed (with demonstrated continued CD19+ expression), if treatment ended more than 4 weeks prior to start of protocol therapy and no prior CNS complications.
• Currently receiving treatment in or less than 30 days or 5 half-lives since ending treatment on another investigational study(ies).
• Abnormal screening laboratory parameters.
• Female participant: Pregnant or breastfeeding or planning to become pregnant or donate eggs, or expected to breastfeed during treatment and for 96 hours after the last dose of investigational product (SC blinatumomab).

The above is a summary, other exclusion criteria details may apply.

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Study Description

Brief Summary:

Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1), or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the Pediatric Recommended Phase 2 Dose (RP2D).- PHASE 1 IS NOW CLOSED

Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric subjects with advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.

Detailed Description:

Enrollment of subjects into Phase 1 will proceed concurrently by age as follows:

• Subjects <12 years old will initially be enrolled in the Phase 1 part to determine the pediatric RP2D for this age group; once the pediatric RP2D is determined, subjects age <12 years old may be enrolled into the Phase 2 part of the study.
• Subjects 12 to 25 years old will be directly enrolled into the Phase 2 part concurrent with Phase 1 enrollment.

Phase 1:

Approximately 12 pediatric subjects with locally advanced or metastatic solid tumors, including a primary central nervous system (CNS) tumor, or anaplastic large cell lymphoma (ALCL), with disease progression or who are non-responsive or intolerant to available therapies and for which no standard or available curative therapy exists.

Phase 2:

Subjects will be enrolled in one of 3 cohorts as follows:

Cohort 1: approximately 10-20 subjects with solid tumors characterized by NTRK fusion, TRK tyrosine kinase inhibitor (TKI)-naïve, and centrally confirmed measurable disease at baseline.

Cohort 2: approximately 23 subjects with solid tumors characterized by NTRK fusion, TRK TKI-pretreated, and centrally confirmed measurable disease at baseline.

Cohort 3 (NOW CLOSED): approximately 20 subjects with solid tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease not otherwise eligible for Cohort 1 or 2. 

Inclusion Criteria

Key Inclusion Criteria:

1. Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion, amplification) as identified by local testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) is required.
2. Age <12 years.
3. Prior cytotoxic chemotherapy is allowed.
4. Prior immunotherapy is allowed.
5. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1.
6. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology Criteria (RANO) criteria at time of enrollment.
7. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 14 days prior to enrollment.
8. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least 50.
9. Life expectancy greater than or equal to 12 weeks.
10. Adequate hematologic, renal and hepatic function.

Phase 2 Inclusion Criteria:

1. Age 12 to <25 years

2. Cohort Specific Inclusion Criteria:

   • Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors (including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI naïve;
   • Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS tumors), that are TRK TKI pre-treated;
   • Cohort 3: subjects with tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease or not otherwise eligible for Cohort 1 or 2.
3. Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by BICR prior to enrollment.

Exclusion Criteria

1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only.
2. Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery.
3. Known active infections (bacterial, fungal, viral including HIV positivity).
4. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.

5. Any of the following cardiac criteria:

   • Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value
   • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec)
   • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval
6. Peripheral neuropathy of CTCAE ≥grade 2.
7. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.

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Study Description

This is a phase 1/2, open label, interventional clinical trial that will study the response rate of newly diagnosed pediatric low-grade glioma (PLGG) to oral administration of mirdametinib in combination with weekly vinblastine. Patients meeting all inclusion criteria for a given study group will receive mirdametinib twice daily (continuous) at a fixed dose (2 mg/m2 po BID up to 4 mg BID) for a total of 13 cycles (28 days cycle). Weekly intravenous vinblastine at MTD will be given for a total of 17 cycles.

The lead-in feasibility phase will be conducted to establish the maximum tolerated/recommended phase 2 dose (MTD/RP2D) of vinblastine in combination with mirdametinib combination using a modified Rolling-6 design. The established RP2D for mirdametinib (2 mg/m2 po BID up to 4 mg BID) will be used on this study. Mirdametinib will be administered on a continuous dosing schedule and de-escalated as necessary to an intermittent (3 weeks on, 1 week off) dosing schedule. Vinblastine will be escalated (or de-escalated) as necessary. Since these classes of agents do not have overlapping toxicities, the starting dose (i.e., Dose Level 0) for vinblastine is 4 mg/m2/week, which is 20% lower than the recommended single agent dose of vinblastine of 5 mg/m2/week. Dose Level 1 for vinblastine is 5 mg/m2/week and Dose Level -1 for vinblastine is 3 mg/m2/week.

Following the end of treatment, patients will be scheduled for a follow-up visit every 6 months for 36 months to evaluate PFS, TTP and OS. A total of 50 patients will be recruited as part of this clinical study.

Patients aged between 2 and 25 years old will be eligible, in order to include a maximum of patients affected by glioma. This study includes PLGG patients with neurofibromatosis type 1 (NF1) with a KIAA1549-BRAF fusion and patients with activation of the MAPK pathway with the exception of patients with a BRAFV600E mutation.

Response to treatment will be evaluated using the modified Response Assessment in Pediatric Neuro-Oncology (RAPNO), Response Assessment in Pediatric Neuro-Oncology (RANO) 1. Evaluation of quality of life will be measured using the Pediatric Quality of Life inventory (PedsQL) (Generic/Brain tumor modules).

This study will explore the genetic and epigenetic landscape of PLGG. Our biological study may include SNP array, nanoString studies, methylation array and RNAseq.

Inclusion Criteria

• Signed written informed consent prior to study participation.
• Study activities compliance: must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by contrast enhanced MRI.
• Aged ≥ 2 years to ≤ 25 years when starting mirdametinib.
• BSA ≥ 0.40m2
• Diagnosis:
  • Participants must have PLGG with NF1 gene mutation (based on clinical NIH criteria, germline NF1 mutation or molecular analysis of the tumor) or PLGG with KIAA1549-BRAF fusion (based on molecular analysis of the tumor) or PLGG with evidence of MAPK pathway alteration with the exception of patients with BRAF V600E mutation (based on molecular analysis of the tumor).
• Tumor tissue is required (at minimum, paraffin-embedded tissue block and additionally fresh frozen tissue [if available]). Patients with NF1 and Low Grade Glioma (LGG) can still be enrolled without tissue if no surgery or biopsy was conducted.
• Baseline MRI.
• Life expectancy greater than 6 months.
• Lansky/Karnofsky score ≥ 50.
• Normal organ and marrow function (see study protocol for specifics).
• Female and male patients of fertile age must agree to use highly effective contraceptive measures.
• Must be able to ingest by mouth and retain entirely the administered medication. Mirdametinib can not be administered via nasogastric tube or gastrostomy tube.

Other inclusion and exclusion criteria may apply and will be discussed with you by the study team. 

Exclusion Criteria

• Patients who are receiving other investigational agents.
• Cardiac: QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 49%.
• Patients who have any other malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Tumor with BRAF V600E mutation.
• Patients who received previous systemic or radiotherapy treatment.
• Other severe and uncontrollable medical disease
• Blood pressure higher than 95th percentile for patient's age, height and gender.
• Increased risk of serious retinopathy and retinal vein occlusion.
• Known diagnosis of human immunodeficiency virus infection, hepatitis B or C.
• Previous major surgery within 2 weeks.
• History of allergic reactions to compounds of similar chemical or biological composition to mirdametinib.
• Pregnant or breastfeeding.

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Study Description

Difluoromethylornithine (DFMO) will be used in an open label, single agent, multicenter, study for patients with neuroblastoma in remission. In this study subjects will receive 730 Days of oral difluoromethylornithine (DFMO) at a dose of 500 to 1000 mg/m2 BID on each day of study. This study will focus on the use of DFMO in high risk neuroblastoma patients that are in remission as a strategy to prevent recurrence.

Inclusion Criteria

• All patients must have a pathologically confirmed diagnosis of neuroblastoma, < 30.99 years of age and classified as high risk at the time of diagnosis. Exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible.

• All patients must be in complete remission (CR):

  1. No evidence of residual disease on scan
  2. No evidence of disease metastatic to bone marrow.
• Specific Criteria by Stratum:

Stratum 1: All patients must have completed standard upfront therapy that replicates treatment which patients who were enrolled on ANBL0032 received, including:

intensive induction chemotherapy and (if feasible) resection of primary tumor, followed by: consolidation with high-dose chemotherapy with stem cell transplant and radiotherapy, followed by: immunotherapy with Ch14.18/IL-2/GM-CSF (dinutuximab) and retinoic acid;.

All subjects on Stratum 1 must have also met the following criteria:

• A pre-transplant disease status evaluation that met International Neuroblastoma Response Criteria (INRC) for CR (complete response), VGPR (very good partial response), or PR (partial response) for primary site, soft tissue metastases and bone metastases. Patients who meet those criteria must also meet the protocol-specified criteria for bone marrow response prior to transplant as outlined below: No more than 10% tumor involvement (based on total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy.

Stratum 2: Neuroblastoma that is in first complete remission following standard upfront therapy different from that described for Stratum 1.

Stratum 3: Neuroblastoma that failed to have a response of at least PR following induction chemotherapy and surgical resection of the primary tumor, but that has achieved CR following additional therapy.

Stratum 4: Patients who have achieved a second or subsequent CR following relapse(s).

• Pre-enrollment tumor survey: Prior to enrollment on this study, a determination of mandatory disease staging must be performed:

  • Tumor imaging studies including
  • Bilateral bone marrow aspirates and biopsy
  • This disease assessment is required for eligibility and preferably should be done within 2 weeks prior to enrollment, but must be done within a maximum of 4 weeks before enrollment.
• Timing from prior therapy:

Stratum 1: Enrollment no later than 60 days after completion of upfront therapy, (last dose of cis-retinoic acid) with a maximum of 6 cycles of cis-retinoic acid maintenance therapy.

Stratum 2, 3 and 4: Enrollment no later than 60 days from last dose of the most recent therapy.

• Patients must have a Lansky or Karnofsky Performance Scale score of > 50% and patients must have a life expectancy of ≥ 2 months.
• All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated below.

• Patients must have adequate organ functions at the time of registration:

  • Hematological: Total absolute phagocyte count ≥1000/μL
  • Liver: Subjects must have adequate liver function
  • Renal: Adequate renal function
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA (food and drug administration) guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria

• BSA (Body Surface Area) of <0.25 m2.
• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from hematological and bone marrow suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion.

The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies.

The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201.

Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.

Inclusion Criteria

Cohort A (B cell lymphoma):

• Participants in the cohort A must be 18 years of age or older of age at time of informed consent.
• Participants must provide written informed consent. The investigator is responsible for obtaining written informed assent/consent for the subject after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• Participants must have a relapsed or refractory B cell lymphoma, including one of the following:
  • diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS)
  • high grade B cell lymphoma NOS
  • grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
  • primary mediastinal large B-cell lymphoma (PMBCL)
  • aggressive B cell lymphoma transformed from an indolent lymphoma
  • mantle cell lymphoma (MCL)
• Participants must have refractory or relapsed disease, defined as one of the following:
  • Relapse or refractory disease after at least 2 lines of therapy, OR
  • Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
  • Any relapse after CAR-T cell therapy
• Participants must have adequate organ function at enrolment, defined as:
  • Left ventricular ejection fraction (LVEF) ≥40%,
  • Creatinine clearance using Cockcroft-Gault of > 30 mL/min, AND
  • ALP/ALT < 5X upper limit of normal (ULN), conjugated bilirubin < 2X ULN, and no evidence or history of liver cirrhosis.
• Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 or Karnofsky Score ≥50%.
• Females of child-bearing potential and sexually active males must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• Participants with accessible disease, willingness to undergo a tumour biopsy at enrolment. For participants with a recent (within 3 months) tumor biopsy, access to the archival biopsy is acceptable.

Cohort B (B-ALL):

• Participants in the cohort B must be between 1-21 years of age at the time of consent.
• Parent or legal guardian of the participant signed the informed consent and the participant's assent/consent is obtained (if applicable). The investigator is responsible for obtaining written informed assent/consent for the subject or legally acceptable representative (e.g. parent, legal guardian) after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• Participants must have a relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL)
• Participants must have refractory or relapsed disease, defined as one of the following:
  • Relapse or refractory disease after at least 2 lines of therapy, OR
  • Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
  • Any relapse after CAR-T cell therapy.
• Participants in cohort B and/or those who have received CD22 targeted therapy must have documentation of CD22 tumour expression within the 6 months prior to study screening, and after any prior CD22 directed therapy (if applicable).
• Participants must have adequate organ function at enrolment, defined as:
  • Left ventricular ejection fraction (LVEF) ≥45%,
  • Creatinine clearance using Cockcroft-Gault or Schwartz equation of > 30 mL/min, AND
  • ALP/ALT < 5X upper limit of normal (ULN), conjugated bilirubin < 2X ULN, and no evidence or history of liver cirrhosis.
• Participants must have a Karnofsky or Lansky Score ≥50%.
• Participants in reproductive age must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• Participants willingness to undergo a bone marrow biopsy at enrolment.

Publications

Both Cohorts A and B

• Any uncontrolled or serious active infection at the time of enrolment.
• Active autoimmune disease requiring immunosuppressive therapy within 4 weeks of enrolment.
• Live vaccine ≤6 weeks prior to enrolment
• Active Graft Versus Host Disease (GVHD) requiring systemic immunosuppressive therapy within 4 weeks of enrolment.
• Treatment with any of the following in the specified time period before leukapheresis:
  • Allogeneic HCT within 3 months,
  • Autologous HCT within 3 months,
  • CD19 CAR-T cell infusion within 3 months,
  • Donor lymphocyte infusion (DLI) within 3 months,
  • Bendamustine within the last 6 months,
  • Any investigational agent within 30 days or 5 half-lives (whichever is shorter),
  • Systemic administration of therapeutic dose corticosteroids (>20 mg/day prednisone or equivalent for adults and ≥ 12 mg/m2/day for paediatric participants) within 7 days prior to leukapheresis.
  • Immunosuppressive therapies (i.e., calcineurin inhibitors, methotrexate, mycophenolate, rapamycin) within 4 weeks.
  • Oral chemotherapy agents (i.e., venetoclax) within 5 half-lives. An exception to this is that bruton tyrosine kinase (BTK) inhibitors like ibrutinib can be continued in participants with mantle cell lymphoma throughout the trial period.
• Other concurrent malignancy or a prior malignancy treated within the past 2 years, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
• Concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure or immunodeficiency syndrome.
• Active (confirmed by PCR) hepatitis B or hepatitis C at time of screening confirmed by PCR.
• Any Human Immunodeficiency Virus (HIV) infection at time of screening.
• Hypersensitivity to fludarabine or cyclophosphamide.
• Any allergy to gentamycin or its derivatives
• Pregnant or nursing participants.