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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).