​ Trials

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Study Description

The main goal of this study is to test a new medicine, Risvutatug Rezetecan also called Ris-Rez. We want to see if this medicine can help people with certain types of cancer, whether its safe to use, how well people tolerate it, and how their bodies handle the drug (how its absorbed and broken down). This research is for adolescents and adults who have either: Osteosarcoma, which is a type of bone cancer, or Soft Tissue Sarcoma, which is a type of cancer that starts in soft body tissues (like muscle, fat, or nerves). In both cancer types the cancer must have already been treated, but has come back or spread, and cant be removed by surgery

Inclusion Criteria

• Participants must be ≥ 12 years of age.
• Has histologically confirmed unresectable advanced or metastatic R/R OSA (Cohort 1) or unresectable advanced or metastatic STS (Cohort 2) that has progressed to at least one prior line of systemic therapy.
• Has documented disease progression on the last line of systemic treatment as confirmed by radiological imaging
• Has an ECOG performance status of 0 or 1, or Lansky PS/Karnofsky PS ≥ 70% for adolescent participants, with no deterioration in the 2 weeks prior to first dose/randomization.
• Has adequate organ function.
• All participants, or their legal guardians, must provide signed informed consent and agree to follow the study protocol before starting any study activities

Exclusion Criteria

• Has received any prior therapy with an antibody-drug-conjugate (ADC) with a TOPO1-inhibitor payload.
• Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
• Has severe, uncontrolled or active cardiovascular disorders.
• Known active infectious diseases requiring systemic treatment or known Human immunodeficiency virus (HIV).
• Has symptomatic brain metastases or untreated progression exclusively due to brain metastasis during or after the last treatment prior to screening, evidence of leptomeningeal/meningeal/brainstem metastasis or evidence of spinal cord metastases.
• Has received treatment with an investigational agent within 4 weeks of the first dose of study intervention.
• Is pregnant or breastfeeding.

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Study Description

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

Patients will be enrolled on either Cohort A for newly diagnosed DIPG or on Cohort B for those with progressive / refractory DIPG or progressive / recurrent / refractory H3K27-altered HGG. Each cohort will receive ACT001 at 875 mg/m2 orally BID for 28 days (1 cycle of treatment), up to a maximum dose of 1700 mg BID. If patients are experiencing clinical benefit from study therapy, they will continue to receive ACT001 in repeat 28-day cycles for up to 26 cycles (approximately 2 years) or until disease progression, whichever occurs first. Continuation of treatment beyond 26 cycles may be considered if patients are receiving clinical benefit from the study, at the discretion of the sponsor and treating physician.

Inclusion Criteria

• Patients must be ≥ 12 months and ≤ 39 years of age at the time of study enrollment.
• Diagnosis:
  • Cohort A: Newly Diagnosed DIPG
    • Patients with newly-diagnosed DIPG with typical MRI findings (tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons) with or without biopsy and have completed radiation therapy (RT) within 28 to 35 calendar day prior to start of therapy.
    • Patients must have started RT <42 calendar days of radiographic diagnosis (for non-biopsied DIPG patients only) or definitive surgery, whichever is later. It is strongly recommended patients begin RT within 31 days of diagnosis/definitive surgery.
      • If a biopsy was performed, the date of surgical biopsy will be considered the date of definitive diagnostic surgery; if a patient underwent two upfront surgeries [e.g., biopsy then debulking], this is the date of the second surgery)
    • Patients must have received RT, but no other anti-cancer therapy other than surgery, and/or steroids prior to enrollment.
  • Cohort B: progressive/refractory/recurrent DIPG or H3K27-altered HGG
    • Patients with DIPG (no biopsy required) or pathologically-confirmed (at diagnosis or recurrence) extra-pontine H3K27-altered HGG who have progressive, refractory or recurrent disease following frontline treatment that included at least focal RT. Patients with refractory disease must have completed RT >6 months prior to study enrollment.
    • Patients with progressive disease only at the primary site(s) must have completed RT more than 3 months prior to enrollment.
    • Patients with progressive disease only at the primary site(s) who completed radiation therapy 3 to 6 months prior to enrollment must have had at least one follow up MRI to confirm progression (rather than pseudo- progression)
    • Patients with progressive disease due to the development a new metastatic site are eligible as long as eligibility criteria 3 (disease status) and 5 (prior RT) are met.
    • Patients with metastatic disease are eligible.
• Disease Status
  • Cohort A: patients may have any disease status but must have completed initial radiation therapy (RT) before enrollment.
  • Cohort B: Patients must have measurable disease assessable by MRI imaging. Patients may have metastatic disease. Lesions irradiated within the last 6 months are not considered measurable unless they show definitive progression following RT.
• Performance Level: Karnofsky Performance Scale score ≥ 50% for patients > 16 years of age and Lansky Performance Scale score > 50% for patients ≤ 16 years of age (applies to all patients) Note: Patients who are unable to walk because of paralysis, but who are capable of using a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior anti-cancer therapy:
  • For Cohort A ONLY:
    • Patients must not have received any prior therapy other than surgery, radiation (focal to disease) and/or steroids (dexamethasone with goal to wean dexamethasone throughout protocol therapy).
    • Patients must enroll and start treatment on study between 28 and 35 calendar days post-completion of RT.
    • Patients must have started RT <42 calendar days of initial diagnosis (defined as the date of diagnostic biopsy or resection; if a patient underwent two upfront surgeries [e.g., biopsy then resection or debulking], this is the date of the second surgery).
    • Radiotherapy must have been administered at standard dose of 54 Gy for DIPG patients. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Study Chair (or their delegate) to confirm eligibility prior to study enrollment.
  • For Cohort B ONLY: Patients must have fully recovered from adverse events due to prior treatment with investigational or conventional agents must have recovered to a severity of Grade 0 or Grade 1 (per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 or higher), with the exception of alopecia.
    • Notes to the above for Cohort B: Patients with chronic Grade 2 toxicities may be eligible per discretion of the Investigator and Sponsor (e.g., Grade 2 chemotherapy-induced neuropathy). Grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible - defined as having been present and stable for > 6 months (such as ifosfamide-related proteinuria) may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the Investigator and Sponsor.)
• The wash out period between the prior anti-cancer chemotherapy, and first dose of ACT001 (cycle 1 day 1) must be:
  • Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).
  • Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor.
  • Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
  • Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines.
  • Monoclonal antibodies: > 21 days must have elapsed from the infusion of last dose of antibody and toxicity related to antibody therapy must be recovered to Grade ≤ 1
  • Radiation therapy:
    • For Cohort B, patients with refractory disease must have received their last fraction of frontline craniospinal or focal RT > 6 months prior to study enrollment. Patients that have received re-irradiation for progression must have received their last fraction of focal radiation >6 weeks or craniospinal radiation >6 weeks prior to study enrollment.
  • Stem Cell Transplant: Patients must be ≥ 3 months since autologous stem cell transplant. Patients who received allogenic stem cell transplant or solid organ transplant are not eligible for study
• Organ Function Requirements (applies to all patients)
  • Adequate bone marrow function defined as:
    • Peripheral absolute neutrophil count (ANC) > 1000/mm³
    • Platelet count > 100,000/mm³ (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Adequate renal function defined as:
    • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m² or
    • A serum creatinine based on age/gender as follows (Schwartz et al. J. Peds, 106:522, 1985): Age Maximum Serum Creatinine (mg/dL) Male Female 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1.0 1.0 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4 ≥ 16 years 1.7 1.4
    • Adequate liver function defined as:
      • total bilirubin within normal institutional limits
      • AST (serum glutamic-oxaloacetic transaminase [SGOT]) / ALT (serum glutamic-oxaloacetic transaminase [SGPT]) ≤ 2.5 × institutional upper limit of normal
      • Serum albumin ≥ 2 g/dL
  • Adequate cardiac function defined as
    • Ejection fraction of ≥ 50% by echocardiogram
    • QTc ≤ 480 msec (by Bazett formula)
  • For Cohort B: Adequate neurologic function defined as:
    • Patients with seizure disorders may be enrolled if seizures are well- controlled. Well controlled is defined by no increase in seizure frequency in the 7 days prior to enrollment.
    • Patients with neurological deficits should have deficits that are stable for at least the 7 days prior to enrollment.
• Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Absence of other clinically significant concomitant active medical disorder, based on the investigator's judgement.

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

Exclusion Criteria

• Cohort A only: Patients with metastatic disease.
• Concomitant medications:
  • Corticosteroids:
    • Cohort A - Patients receiving corticosteroids are eligible regardless of dosing
    • Cohort B - Patients receiving corticosteroids who have been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are eligible
  • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible (Refer study inclusion criteria relating to anti-cancer therapies)
    • Cohort A - Patients that have received any anti-cancer treatment other than RT are not eligible.
  • Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
  • Anticonvulsants should be used as clinically indicated. The use of enzyme inducing anticonvulsants is not permitted
  • LHRH agonist / antagonists are not permitted
  • High Dose Biotin (B7) supplements are not permitted
• Concomitant medications used with caution: selective serotonin reuptake inhibitor (SSRI) such as Lexapro, Fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and escitalopram should be used with caution.
• Infection: Patients who currently have an uncontrolled infection (in the opinion of the PI) are not eligible.
• Patients who have received a prior solid organ transplantation are not eligible.
• Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are postmenarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
• Patients of childbearing or child fathering potential must agree to use adequate contraceptive methods (hormonal or barrier method of birth control; abstinence) while being treated on this study and for 3 months after completing therapy. Note: The definition of effective contraception will be based on the judgement of the principal investigator or a designated associate.
• Patients who are in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
• Patients who have previously received either ACT001 or parthenolide are not eligible.

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

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Study Description

Substudy 01A is part of a platform study. The purpose of this study is to assess the efficacy and safety of zilovertamab vedotin in pediatric participants with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, or neuroblastoma and in pediatric and young adult participants with Ewing sarcoma.

Inclusion Criteria

• For hematological malignancies: Confirmed diagnosis of B-precursor B-ALL or DLBCL/Burkitt lymphoma according to World Health Organization (WHO) classification of neoplasms of the lymphoid tissues.
• For solid tumor malignancies: Histologically confirmed diagnosis of neuroblastoma or Ewing sarcoma.

Exclusion Criteria

• History of solid organ transplant.
• Clinically significant (ie, active) cardiovascular disease.
• Known history of liver cirrhosis.
• Ongoing Grade >1 peripheral neuropathy.
• Demyelinating form of Charcot-Marie-Tooth disease.
• Diagnosed with Down syndrome.
• Ongoing graft-versus-host disease (GVHD) of any grade or receiving systemic GVHD treatment or prophylaxis.
• History of human immunodeficiency virus (HIV) infection.
• Contraindication or hypersensitivity to any of the study intervention components.
• Received prior radiotherapy within 4 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities.
• Ongoing, chronic corticosteroid therapy (exceeding 10 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 4 weeks before Cycle 1 Day 1 (C1D1).
• Received a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 7 days or a strong CYP3A4 inducer within 14 days before the start of study intervention or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer during the study intervention period and for 30 days after the last dose of study intervention
• Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention (except for prophylactic intrathecal chemotherapy and/or cytoreductive therapy with steroids/hydroxyurea.
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Known additional malignancy that is progressing or has required active treatment within the past 1 year.
• Active infection requiring systemic therapy.
• Known history of Hepatitis B or known active Hepatitis C virus infection.
• Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

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Study Description

Brief Summary:

The study evaluates CLR 131 in children, adolescents, and young adults with relapsed or refractory High Grade Glioma (HGG) for which there are no standard treatment options with curative potential.

Part A for Solid Tumors, Lymphoma, and Malignant  Brain Tumors is now closed. This study is exclusively enrolling on Part B for HGG

Detailed Description:

Even with standard, highly toxic multimodality therapies and salvage regimen, most pediatric patients with primary metastatic or relapsed solid tumors are confronted with a poor prognosis. For these patients there is currently no accepted successful treatment regimen. There is a need for new drugs, including targeted radiopharmaceuticals, preferably with cancer-specific uptake and broad applicability for these rare pediatric malignancies.

CLR 131 is a radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Cellectar Biosciences' novel cancer-targeted small-molecule compound (CLR1404) is radiolabeled with the isotope iodine-131 (I-131). CLR 131 has demonstrated tumor selective uptake across numerous adult and pediatric cancer cell types. Therapeutic efficacy has been demonstrated in various pediatric and adult-type cancer xenograft models, confirming the ability of CLR 131 to target tumors.

Based on the critical unmet medical need for effective agents with novel mechanisms of action in relapsed pediatric cancers and initial preclinical and clinical experience with radioiodinated CLR1404, Cellectar Biosciences has chosen to assess CLR 131 in a phase 1 pediatric trial.

Inclusion Criteria

• Previously confirmed (histologically or cytologically) HGG that is clinically or radiographically suspected to be relapsed, refractory, or recurrent. Patients with DIPG are exempt from histologic verification if they have typical MRI findings of DIPG (i.e., hypo- or isointense on T1-weighted imaging, hyperintense on FLAIR or T2-weighted imaging, epicenter in the pons, greater than 50% of pons involved) and the risk of tumor biopsy is prohibitive. Patients with a diagnosis of ependymoma may enroll with prior Sponsor approval.
  • Refractory is defined as:
    • Lack of response (stable disease) or disease progression while on therapy
    • Disease progression within 3 months of cessation of therapy
• Patient is ≥ 10 years and ≤ 25 years of age at time of consent/assent
• Patients ≥ age 16 years must have a Karnofsky performance status of ≥ 60. Patients < age 16 years must have a Lansky performance status of ≥ 60
• Patients must meet the following lab criteria:
  • Platelets ≥ 75,000/µL [75 x 10⁹ /L] (last transfusion, if any, must be at least 1 week prior to study registration, and, unless deemed medically necessary, no transfusions are allowed between registration and dosing)
  • Absolute neutrophil count ≥ 750/µL [0.75 x10⁹/L]
  • Hemoglobin ≥ 8 g/dL [80 g/L] (last transfusion must be at least 1 week prior to study registration, and, unless deemed medically necessary, no transfusions are allowed between registration and dosing)
  • Using the bedside Schwartz formula [Schwartz 2009], estimated GFR (creatinine clearance) > 60 ml/min/1.73m²
  • Alanine aminotransferase < 3 × ULN
  • Bilirubin < 2 × ULN
• At least 1 measurable intracranial lesion with longest diameter of at least 10 mm on any imaging sequence.
• Patients with previously known neurological deficits must be clinically stable for one week prior to enrollment and be able to complete all study related procedures
• If patient receives steroids for neurological symptom control, the dose must be stable (unchanged for one week prior to enrollment) or on a steroid tapering regimen. Initiation of steroids per routine care immediately prior to CLR 131 dosing is acceptable.
• Patient or his or her legal representative is judged by the Investigator to have the initiative and means to be compliant with the protocol.
• Patient or his or her legal representative has the ability to read, understand, and provide written informed consent for the initiation of any study-related procedures.
• Female patients of childbearing potential must have a negative pregnancy test at screening and within 24 hours of dosing. It is recommended that female caregivers of childbearing potential have a negative pregnancy test within one week of dosing.
• Patients of childbearing potential must practice an effective method of birth control while participating on this study to avoid possible harm to the fetus.

Exclusion Criteria

• Antitumor therapy or investigational therapy, within three-half-lives of the agent preceding the present study. For certain types of radiation (craniospinal, total abdominal, whole lung [spot irradiation to skull-based metastases is not considered craniospinal radiation for the purposes of this study]), at least 3 months must have elapsed. Palliative focal radiation to non-target lesions should be completed at least 2 weeks prior to dosing. NOTE: Patients participating in non-interventional clinical trials (i.e., non-drug) are allowed to participate in this trial.
• History of hypersensitivity to thyroid protection medication (e.g., potassium iodide, Lugol’s solution, etc.)
• Any other concomitant serious illness or organ system dysfunction (including cardiac and pulmonary dysfunction) that in the opinion of the Investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug.
• Major surgery within 6 weeks of enrollment unless delay in therapy poses unacceptable risk to the patient due to clinical progression (enrollment of such patients should be discussed with Medical Monitor).
• Known history of human immunodeficiency virus or uncontrolled, serious, active infection.
• Pregnancy or breastfeeding
   

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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. 

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

If you are a long-distance patient of >160 km, round trip - you may be eligible for STEP-1 travel funding. Find more information here. 

This is a pilot study to determine feasibility of adding intrathecal (IT) chemotherapy and maintenance therapy after high dose chemotherapy for treatment of newly diagnosed HR-EBTs in patients less than 6 years of age. Patients meeting all inclusion criteria will receive 3 cycles of multiagent chemotherapy induction (vinCRIStine, cyclophosphamide, CISplatin, etoposide) with IT cytarabine and hydrocortisone, and 3 cycles of consolidation with CARBOplatin, thiotepa, and autologous stem cell rescue (as per CCG 99703). Maintenance chemotherapy will then be given immediately after the completion of consolidation therapy and consist of risk-stratified oral chemotherapy using either "Maintenance A" (48 weeks) using tamoxifen and retinoic acid or "Maintenance B" (54 weeks) using metronomic isotretinoin, celecoxib, etoposide, temozolomide, and cyclophosphamide. Both arms of maintenance will receive monthly IT topotecan.

Following the end of treatment, patients will be scheduled for a follow-up visit every 3 months for 24 months to evaluate PFS and OS. Approximately 15 patients will be recruited as part of this clinical study.

Patients aged between 0 and 6 years old at the time of enrollment will be eligible. This study will only enrol patients with high risk Central Nervous System Embryonal Brain Tumors (CNS-EBTs) with histologic and/or molecular confirmation of diagnosis for ATRT intrinsic to the brain and spinal cord, group 3 and group 4 MB, pineoblastoma, CNS neuroblastoma, ETMR, including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified.

Response to treatment will be evaluated using the modified RAPNO (Response Assessment in Pediatric Neuro-Oncology) 1.

This study will also explore the genetic landscape of CNS HR-EBTs. Our biological study will include genomic analyses of tumor and CSF with use of epigenomic analyses (methylation profiling) arrays, Nanostring sub-typing studies, Next generation sequencing analyses for DNA and/or RNA.

Inclusion Criteria

• Tumor Tissue Sample
• Age: Patient must be aged ≥ 0 years to ≤ 6 years at the time of definitive confirmation of histologic diagnosis of eligible CNS tumor.
• Diagnoses. Participants must have Central nervous system (CNS) HR-EBT including atypical teratoid rhabdoid tumour (ATRT), group 3 and group 4 medulloblastoma (MB), pineoblastoma, CNS neuroblastoma, embryonal tumor with multi-layered rosettes (ETMR including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified. Metastatic disease included. Any extent of resection included.
• Cranial and Spine MRI. A baseline MRI brain and spine with and without contrast is required for all patients. cranial MRI (with and without gadolinium) must be done pre-operatively. Post-operatively, cranial MRI (with and without gadolinium) must be done.
• Lumbar Puncture (LP) CSF for cytopathology (strongly recommended but not mandatory; if medically feasible). A baseline LP CSF cytology either pre-operatively or post-operatively at least 10 days after definitive surgery for all patients if medically feasible (This is not mandatory and will not make the patient ineligible).
• Life expectancy: Patients must have a life expectancy of greater than 8 weeks from diagnosis.
• Performance level: Patients must have a performance status corresponding of a Lansky score ≥ 50.
• Organ Function Requirements: Participants must have normal organ and marrow function as defined below:
  • Adequate renal function defined as:
    • Creatinine clearance (12-24-hour urine collection) or radioisotope glomerular filtration rate (GFR) ≥ 60 ml/min/1.73m2
  • Adequate cardiac function defined as:
    • Shortening fraction of ≥ 27% by echocardiogram, or
    • Ejection fraction of ≥ 47% by radionuclide angiogram.
  • Adequate pulmonary function defined as:
    • No evidence of dyspnea at rest and a pulse oximetry > 94% on room air.
  • Adequate Bone Marrow Function defined as:
    • Peripheral absolute neutrophil count (ANC) > 1000/μL
    • Platelet Count > 100,000/μL (without transfusion for 3 days)
    • Hemoglobin greater than 8 gm/dL (may have received red blood cell (RBC) transfusions)
  • Adequate liver function defined as:
    • Total bilirubin ≤ 1.5X upper limit of normal (ULN) within normal institutional limits for age (patients with documented Gilbert's Disease may be enrolled with Study Chair approval and total bilirubin ≤ 2.0 × ULN)
    • Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 100 U/L

Other inclusion and exclusion criteria may apply. 

Exclusion Criteria

• Patients who are receiving any other conventional anti-cancer agents or investigational agents.
• Patients who received previous therapy including radiotherapy or chemotherapy other than corticosteroids.
• Presence of another malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Concomitant medications restrictions: Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine), selected strong inhibitors of cytochrome P450 3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John's wort or CYP450 3A4 stimulators or inhibitors.
• Other uncontrollable medical disease: Patient has a severe and uncontrollable medical disease (i.e., uncontrolled diabetes, hyperglycemia, chronic renal disease or active uncontrolled infection), has chronic liver disease (i.e., chronic active hepatitis and cirrhosis), hypercholesterolemia (serum cholesterol >300 mg/dL), intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active hyperparathyroidism, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who have a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C.
• Ineligible diagnoses for study entry by neuropathology: This includes sonic hedgehog (SHH) and wingless (WNT) MBs, all ependymomas, all choroid plexus carcinomas, all high grade glial and glio-neuronal tumors, all diffuse midline gliomas, all primary CNS germ cell tumors, all primary CNS sarcomas, all primary or metastatic CNS lymphomas and solid leukemic lesions (chloromas, granulocytic sarcomas).
• The participant or parent(s)/guardian(s) cannot comply with the study visit schedule and other protocol requirements, in the investigator's opinion.

Other inclusion and exclusion criteria may apply. 

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Study Description

Brief Summary:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

Detailed Description:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

In this study subjects will receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone.

Subjects will be evaluated in 3 arms:

• Arm 1: Subjects who show no active disease after receiving any additional therapy for neuroblastoma that was refractory to standard induction/consolidation therapy.

Refractory: Subjects with progressive disease on upfront therapy OR did not have at least PR on induction OR required additional second line therapy to achieve remission who are now in first remission.

• Arm 2: Subjects who have previously relapsed and currently show no active disease (in CR2 or greater).
• Arm 3: Subjects who are relapsed or refractory with active disease.

Inclusion Criteria

• All patients must have a pathologically confirmed diagnosis of neuroblastoma, ≤ 30.99 years of age with history of relapsed/refractory neuroblastoma.
• All patients must have completed upfront therapy with at least 4 cycles of aggressive multi-drug chemotherapy.
• Specific Criteria by Arm:

Arms 1 and 2:

Subjects with no active disease:

i. No evidence of residual disease by CT/MRI and MIBG scan (or PET for patients who have a history of MIBG non-avid disease).

o Note: Patients with residual masses detected by CT/MRI may be considered in CR if their MIBG is negative or if MIBG positive and evaluated by PET and found to have negative PET scans; biopsy confirmation may be considered if there is still reasonable concern for persistent disease but is not required.

ii. No evidence of disease metastatic to bone marrow.

Arm 3:

Measurable or evaluable disease, including at least one of the following:

Measurable tumor by CT or MRI; or a positive MIBG and PET; or positive bone marrow biopsy/aspirate in at least one site.

• Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days from last dose of the most recent therapy.

• Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:

  1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
  2. Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor.
  3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the Study Chair.
  4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells.
  5. Anti-GD2 Monoclonal antibodies: At least 2 weeks must have elapsed since prior treatment with a monoclonal antibody.
  6. XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.

  7. Stem Cell Transplant:

     1. Allogeneic: No evidence of active graft vs. host disease
     2. Allo/Auto: ≥ 2 months must have elapsed since transplant.
  8. MIBG Therapy: At least 8 weeks since treatment with MIBG therapy
• Subjects must have a Lansky or Karnofsky Performance Scale score of 60% or higher.
• Life expectancy > 2 months
• All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to first dose of study drug unless otherwise indicated below.

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

  • Hematological: Total absolute neutrophil count ANC ≥750/μL
  • Liver: Subjects must have adequate liver function as defined by AST and ALT <5x upper limit of normal (Normal=45), Bilirubin <1.5x upper limit normal (Normal=1.0). Normal PT, PTT, fibrinogen.
  • Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or greater or a serum creatinine based on age/gender
• 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 guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria

• BSA of <0.25 m2.
• Subjects that received DFMO at a dose higher than 1000mg/m2 BID prior to this study are not eligible.
• Subjects that received a dose of DFMO in combination with etoposide are not eligible.
• 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.