Canadian clinical trial registry

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Study Description

ACTEMRA (tocilizumab) is an IL-6 receptor antagonist used for the treatment of adult Rheumatoid Arthritis as well as Polyarticular (PJIA) and Systemic (SJIA) Juvenile Idiopathic Arthritis. In this Phase II, the drug will be used to treat pediatric patients diagnosed with recurrent Adamantinomatous Craniopharyngioma including patients who have undergone surgery and/or radiation therapy.

Adamantinomatous Craniopharyngioma (ACP) is a highly debilitating pediatric brain tumor that lacks medical anti-tumor therapies. Current therapy, which depends largely on surgery and radiation, is associated with poor quality of life and becomes more challenging and risky in the setting of recurrent disease. Recent discoveries regarding the biological characteristics of ACP indicate that available agents, including IL-6 pathway blockers may have efficacy in the control of ACP. We hypothesize that the IL6- receptor antagonist ACTEMRA (tocilizumab) will be safe and effective at inducing tumor response in children with residual ACP.

In this study, up to 38 patients will receive tocilizumab at the dose approved for pediatric Systemic Juvenile Idiopathic Arthritis (< 30 kg: 12 mg/kg IV every 2 weeks; ≥30 kg: 8 mg/kg IV every 2 weeks). Therapy may continue for up to two years (26 cycles).

It will be a multi-center Phase 2 trial with two strata for patients aged >1 year and <25 years with unresectable ACP who may have been previously treated with radiation (Stratum 1, 18 patients) or without radiation (Stratum 2, 18 patients).

Inclusion Criteria

1. Age: Patients must be ≥ 12 months and ≤ 25 years of age at the time of study enrollment.
2. Diagnosis: Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) Histologic confirmation of ACP may be made on solid tumor or, if no solid tumor can be safely obtained, cyst fluid with classic ACP characteristics of thick, cholesterol-rich, greenish-brown liquid in the context of imaging features consistent with craniopharyngioma, including lobulated, cystic/solid mass with calcifications that originates in the sellar/suprasellar region.
3. Disease Status: Patients must have measurable disease.
   • Stratum 1: Patients with progressive or recurrent ACP who demonstrate cystic and/or solid recurrence or progression at least 6 months post completion of radiation therapy
   • Stratum 2: Patients with measurable ACP who have undergone surgery but have NOT previously undergone irradiation (but may have received prior systemic or intracystic therapy). Progressive disease is allowed but not required.
4. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. 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.
5. Prior Therapy: Patients must have recovered or stabilized from the acute toxic effects of prior treatments
   • Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last (systemic or intracystic) 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 systemic immunotherapy, e.g. tumor vaccines.
   • Monoclonal antibodies: At least 21 days after the last dose of a monoclonal antibody.
   • Radiation therapy: Patients must have had their last (conventional or hypofractionated) fraction of: a) Focal irradiation > 6 months prior to enrollment and b) No prior craniospinal irradiation is permitted.
   • Corticosteroids: Patients receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
   • Myelosuppressive systemic therapy: At least 21 days must have elapsed after the last systemic myelosuppressive therapy.
   • Surgery: At least 6 weeks must have elapsed since surgery.
6. Organ Function Requirements
   • 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)
     • Hemoglobin >8 g/dL (may be transfused)
   • Adequate Renal Function Defined as:
     • Creatinine clearance or radioisotope GFR > 70ml/min/1.73 m2 or
     • A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6 to < 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females.
   • Adequate Liver Function Defined as:
     • Total bilirubin within normal institutional limits
     • AST (SGOT) ≤ 2.5 × institutional upper limit of normal
     • ALT (SGPT) ≤ 2.5 × institutional upper limit of normal
   • Adequate Neurologic Function Defined as:
     • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.
     • Patients with current seizure disorders may be enrolled if seizures are well-controlled on antiepileptic therapies.
7. 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.

Exclusion Criteria

1. Pregnancy or Breast-Feeding: 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 post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for at least 90 days after discontinuation of drug for females and at least 60 days for males. For females of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; hormonal contraceptive methods must be supplemented by a barrier method) and agreement to refrain from donating eggs are required. For males of reproductive potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.
2. Gastrointestinal Disease: Patients with a history of serious gastrointestinal disease, including inflammatory bowel disease or gastrointestinal perforation
3. Concomitant Medications
   • Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
   • Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
   • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
4. Study Specific:
   • Patients who have an uncontrolled infection are not eligible.
   • Patients who have received any live or attenuated vaccinations within three months prior to start of therapy are not eligible.
   • Any significant concurrent medical or surgical condition that would jeopardize the patient's safety or ability to complete the study, including, but not limited to, disease of the nervous, renal, hepatic, cardiac (such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), pulmonary, or endocrine system
   • Patients who have a history of Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus or Tuberculosis infection are not eligible.
   • Patients who have received a prior solid organ transplantation are not eligible.
   • Patients who 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 a history of alcohol, drug, or chemical abuse within 6 months of screening.
   • Patients who have had surgery within the last 6 weeks or who have concerns for poor postsurgical wound healing.
   • Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tocilizumab and its excipients are not eligible.

Other inclusion and exclusion criteria may apply.

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Centres

Study Description

This is an open-label, multicenter study to assess safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy of RO7428731 administered as a monotherapy in participants with newly diagnosed or recurrent epidermal growth factor receptor variant III (EGFRvIII)-positive glioblastoma (GBM).

Experimental: Part I: Dose Escalation

Participants with newly diagnosed GBM will receive RO7428731, intravenously (IV), up to one year or until disease progression, withdrawal of consent, unacceptable toxicity, or death, whichever occurs first.

Experimental: Part II: Dose-Expansion(s)

Participants with newly diagnosed GBM will receive RO7428731, IV, in maximum of two dose expansion cohorts at a dose(s) not exceeding the maximum tolerated dose (MTD) established in Part I.

Experimental: Part III: Safety Run-in

Participants with recurrent GBM will receive RO7428731, IV in a dosing schedule determined in Part I. At the end of the Safety Run-in period, a decision will be made as to whether to open the Dose-Expansion Cohort Part IVA or open a second Safety Run-in Cohort at a lower dose.

Experimental: Part IV A: Dose-Expansions Cohort

Participants with recurrent GBM will receive RO7428731, IV at specified doses and dosing schedules.

Inclusion Criteria

Inclusion criteria for all participants:

• Life expectancy of greater than or equal to 12 weeks, in the opinion of the Investigator
• Diagnosis of GBM based on World Health Organization (WHO) classification of central nervous system (CNS) tumors, 5th edition
• Participants must have confirmed EGFRvIII-expression
• Karnofsky Performance Status (KPS) Score of >=70%
• Adequate organ functions prior to start of study treatment
• Willingness to abide by contraceptive measures for the duration of the study.

Inclusion criteria for Part I and Part II only:

• Participants whose tumors have an unmethylated (Part I and Part II) or methylated (Part I only) O6-methylguanine-DNA methyltransferase (MGMT) promotor status based on local assessment
• Participants (in Part I): Adult participants with newly diagnosed EGFRvIII-positive GBM with unmethylated MGMT promotor status who have completed standard of care therapy with surgical resection and adjuvant radiotherapy with or without concomitant temozolomide. Participants are allowed to have received any number of cycles of temozolomide maintenance. Adult participants with newly diagnosed EGFRvIII-positive GBM with methylated MGMT promotor status who have completed standard of care with surgical resection and adjuvant radiotherapy with concomitant and maintenance temozolomide or discontinued temozolomide maintenance due to reasons other than progressive disease.
• Participants (in Part II): Adult participants with newly diagnosed EGFRvIII-positive GBM with unmethylated MGMT promotor status who have completed standard of care therapy with surgical resection and adjuvant radiotherapy with or without concomitant temozolomide.

Inclusion criteria for Part III and Part IV A only:

• Documented first or second recurrence of GBM
• At least one measurable GBM lesion as per Response Assessment in Neuro-Oncology (RANO) criteria prior to initiation of study treatment.

Exclusion Criteria

Exclusion criteria for all participants:

• Participants with infratentorial tumors and tumors primarily located in or close to critical structures (e.g., brain stem)
• Presence of extracranial metastatic or leptomeningeal disease
• Known hypersensitivity to immunoglobulins or to any other component of the investigational medicinal product formulation
• Active bleeding or pathological condition that carries a high risk of bleeding, including inherited and acquired coagulopathies
• Participants unable to undergo an MRI with contrast.

Exclusion criteria for Part I and Part II only:

• Recurrent malignant gliomas
• Any prior anti-tumor treatment for GBM: tumor resection, adjuvant radiotherapy with or without concomitant temozolomide and temozolomide maintenance (Part I only) must be the only tumor-directed treatment that the participant has received for GBM.

Exclusion criteria for Part III and Part IV A only:

• More than two recurrences of GBM
• Prior anti-EGFRvIII-targeting agents (including vaccines), anti-angiogenic therapy, and/or gene therapy for the treatment of GBM and gliomas.

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Centres

Study Description

This phase I/II trial studies how well tiragolumab and atezolizumab works when given to children and adults with SMARCB1 or SMARCA4 deficient tumors that that has either come back (relapsed) or does not respond to therapy (refractory). SMARCB1 or SMARCA4 deficiency means that tumor cells are missing the SMARCB1 and SMARCA4 genes, seen with some aggressive cancers that are typically hard to treat. Immunotherapy with monoclonal antibodies, such as tiragolumab and atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

OUTLINE: Patients are assigned to Part A or Part B.

PART A: Patients receive tiragolumab intravenously (IV) over 30-90 minutes on day 1 of each cycle and atezolizumab IV over 30-60 minutes on day 1 of each cycle starting in cycle 2. Treatment repeats every 21 days for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients undergo standard imaging scans including x-rays, computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET)-CT throughout the trial. Patients also undergo blood sample collection on study.

PART B: Patients receive atezolizumab IV over 30-60 minutes on day 1 and tiragolumab IV over 30-90 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients also undergo standard imaging scans including x-rays, CT, MRI, and/or FDG PET-CT, throughout the trial. Patients also undergo blood sample collection on study.

After completion of study treatment, patients are followed up at months 3, 6, 9, 12, 18, 24, 36, 48, and 60, up to 5 years.

PRIMARY OBJECTIVES:

I. To evaluate the safety of tiragolumab as monotherapy in pediatric patients (<18 years) with SMARCB1 or SMARCA4 deficient tumors. (Part A) II. To evaluate antitumor activity of the combination of tiragolumab and atezolizumab as assessed by objective response rate in patients with SMARCB1 or SMARCA4 deficient tumors per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 (for non-central nervous system [CNS] tumors) or CNS response criteria (for CNS tumors). (Part B) III. To evaluate the safety and adverse event profile of this combination therapy in subjects with SMARCB1 or SMARCA4 deficient tumors, with a particular focus in pediatric patients < 12 years of age.

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetics of tiragolumab alone in part A and tiragolumab and atezolizumab (part A and B) when given in combination in pediatric, adolescents and young adults, and adult patients.

II. To estimate the PFS (progression free survival), OS (overall survival), and duration of response of combination tiragolumab and atezolizumab in patients with SMARCB1 or SMARCA4 deficient tumors.

EXPLORATORY OBJECTIVES:

I. To assess the association of response rate to somatic genetic mutations of SMARCB1 or SMARCA4 and PD-L1 expression.

II. To assess the association of response rate to the molecular subtypes of rhabdoid/atypical teratoid rhabdoid tumor (ATRT).

III. To assess changes in circulating and tumoral immune markers in patients treated with this combination therapy and correlate to response when feasible.

Inclusion Criteria

• Patients must be >= 12 months of age at the time of study enrollment. For part A, patients must be <18 years old at enrollment. For part B, there is no upper age limit
  • The Part B (phase 2) cohorts will initially open concurrently with the part A but will only enroll patients at least 18 years of age. Patients <18 years of age will be included in the part B cohorts only after the tiragolumab monotherapy dose has been assessed to be safe in the part A portion
• Patients must have SMARCB1 (INI1) or SMARCA4 deficient tumors verified through institutional immunohistochemistry (IHC) or molecular confirmation of a pathologic tumor bi-allelic SMARCB1 (INI1) or SMARCA4 loss or mutation from a Clinical Laboratory Improvement Act (CLIA) certified lab with the following disease histologies:
  • Renal medullary carcinoma
  • Malignant rhabdoid tumor (extra-CNS)
  • Atypical teratoid rhabdoid tumor (CNS)
  • Poorly differentiated chordoma
  • Epithelioid sarcoma
  • Other SMARCB1 or SMARCA4 deficient tumors
• Part A: Patients must have either measurable or evaluable disease Part B: Patients must have either measurable disease per RECIST v1.1 for non-CNS tumors or CNS response criteria for CNS tumors
• Patients must have relapsed, refractory disease or newly diagnosed disease for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (Karnofsky/Lansky score of > 50). Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. 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
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately
  • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: See Developmental Therapeutics (DVL) homepage on the Children's Oncology Group (COG) Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment
    • >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea). Please refer to the table of myelosuppressive/Anticancer Agents on the COG website: https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyelosuppressiveAnti-CancerAgents.pdf
  • Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent. See the DVL homepage on the COG Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment
  • 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
  • Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. 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
  • 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 total-body irradiation [TBI]):
    • Autologous stem cell infusion including boost infusion: >= 30 days
  • Cellular therapy: >= 30 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • External radiation therapy (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 bone marrow (BM) radiation
  • Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131 metaiodobenzylguanidine [131I MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
  • Patients must not have had prior TIGIT targeting therapy
  • Patients must not have received prior therapy with an anti- PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA4 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (i.e. OX-40, CD137)
  • Patients must not have received live/attenuated vaccine within 30 days of first dose of treatment
  • Patients must not be receiving concomitant systemic steroid medications and > 14 days must have elapsed since last dose of systemic corticosteroid with the following exceptions:
    • The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10 mg/day of prednisone equivalent) is acceptable
    • The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
    • The use of acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are acceptable
  • Treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha [TNF-alpha] agents) must have concluded >= 14 days prior to study enrollment
• For patients with solid tumors without known bone marrow involvement
  • Peripheral absolute neutrophil count (ANC) >= 1000/uL (must be performed within 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement
  • Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (must be performed within 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts above (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity
• A creatinine based on age/gender as follows (must be performed within 7 days prior to enrollment):
  • Age; Maximum Serum Creatinine (mg/dL)
    • 1 to < 2 years; Male: 0.6; Female: 0.6
    • 2 to < 6 years; Male: 0.8; Female: 0.8
    • 6 to < 10 years; Male: 1; Female: 1
    • 10 to < 13 years; Male: 1.2; Female: 1.2
    • 13 to < 16 years; Male: 1.5; Female: 1.4
    • >= 16 years; Male: 1.7; Female: 1.4 OR- a 24 hour urine creatinine clearance >= 70 mL/min/1.73 m^2 (must be performed within 7 days prior to enrollment) OR- a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard) (must be performed within 7 days prior to enrollment)
  • Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment)
  • Patients with known Gilbert disease: Total bilirubin < 3 x ULN
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (must be performed within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (must be performed within 7 days prior to enrollment)
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v5) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
• International normalized ratio (INR) =< 1.5 (must be performed within 7 days prior to enrollment)
• Serum amylase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Serum lipase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Grade 1 or lower calcium level
  • Note: can have history of hypercalcemia as long as controlled and asymptomatic

Exclusion Criteria

• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. 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 effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of therapy and at least 90 days after final dose of tiragolumab and 150 days after final dose of atezolizumab, whichever is later. Abstinence is an acceptable method of birth control.
  • It is not known if atezolizumab or tiragolumab are present in breast milk; however, IgG immunoglobulins are found in milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during therapy and for at least 150 days after the last dose of atezolizumab and 90 days after the last dose of tiragolumab, whichever is later
• Concomitant medications:
  • Corticosteroids:
    • Patients must not be receiving concomitant systemic steroid medications and >= 14 days must have elapsed since last dose of systemic corticosteroid with the following exceptions:
      • The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10 mg/day of prednisone equivalent) is acceptable
      • The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
      • The use of acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g. 48 hours of corticosteroids for a contrast allergy) are acceptable
  • Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
  • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible
  • Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study treatment because these agents could potentially alter the efficacy and safety of study treatments would not be eligible
• Patients must not have a known hypersensitivity to any component of tiragolumab or atezolizumab injection
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation
• Patients who have undergone allogeneic bone marrow or stem cell transplant are not eligible
• Patients with known, untreated CNS metastases will be excluded with the following exceptions:
  • Patients with a history of CNS metastases that have been previously treated may enroll if sequential imaging shows no evidence for active disease in the CNS
• Patients must not have active autoimmune disease that has required systemic treatment in the past 12 months, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy are not excluded. Replacement therapy (e.g. thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and these patients are eligible
• Patients who have active immune deficiency are not eligible
• Patients who have known active tuberculosis are not eligible
• Hepatitis B or C infection:
  • Patients < 18 years old at enrollment, who have known hepatitis B or C
  • Patients >= 18 years old at enrollment with:
    • Positive hepatitis B surface antigen (HBsAg), OR
    • Positive total hepatitis B core antibody (HBcAb) who have a quantitative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) >= 500 IU/mL, OR
    • Positive hepatitis C virus (HCV) antibody with a positive HCV ribonucleic acid (RNA) test
    • Note: For adults (>= 18 years old at enrollment), hepatitis B serology testing is required to determine eligibility. The HBV DNA test is required only for patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test. For adults (>= 18 years old at enrollment), hepatitis C serology testing is required to determine eligibility. The HCV RNA test is required only for patients who have a positive HCV antibody test
• Patients who have a known, recent Epstein-Barr virus (EBV) infection or known history of chronic, active infection are not eligible
• Patients who have history of or active human immunodeficiency virus (HIV) are not eligible except patients who are stable on anti-retroviral therapy, have a CD4 count >= 200/uL, and have an undetectable viral load
• Patients who have significant cardiovascular disease (such as New York Heart Association class III or IV congestive heart failure, myocardial infarction, or cerebrovascular accident) within 3 months prior to study enrollment, unstable arrhythmia, or unstable angina are not eligible
• Patients who have a major surgical procedure, other than for diagnosis, within 4 weeks prior to study enrollment, or the anticipation of the need for a major surgical procedure during the study are not eligible
• Patients who have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or known active pneumonitis are not eligible. History of radiation pneumonitis in the radiation field is permitted
• Patients who have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) are not eligible. Patients with indwelling catheters (e.g., PleurX) are allowed
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

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Centres

Study Description

This is a multicenter, open-label, single-arm study to evaluate the safety and dosimetry of Lutathera in adolescent patients 12 to <18 years old with somatostatin receptor positive GEP-NETs and PPGLs. The study will enroll at least 8 patients in the GEP-NET cohort and as many adolescents with PPGL as possible in the exploratory PPGL cohort.

The study schedule for each patient consists of the screening period (up to 2 weeks) followed by the treatment period (4 treatment administrations at 8-week interval), and the follow-up period (5 years).

The treatment period will consist of 4 Lutathera treatments administered at 8-week intervals. Lutathera administration will occur on Week 1 Day 1 of each cycle. Each patient will receive a total of 4 doses of Lutathera (7.4 GBq/200 mCi x 4 administrations every 8 weeks; cumulative dose: 29.6 GBq/800 mCi). An infusion of 2.5% Lysine - Arginine amino acid (AA) solution will be co-administered with each Lutathera dose for renal protection according to the approved Lutathera local prescribing information. An antiemetic will be administered prior to infusion of the AA solution for prevention of infusion-related nausea and vomiting.

The dosimetry and PK assessments will be performed during the first week after the 1st Lutathera dose, i.e. one time during the study treatment period for each patient. The dosimetry analysis will allow for estimation from the 1st Lutathera administration of the cumulative absorbed radiation dose from 4 Lutathera doses and also for taking a decision on the next dose levels. In the exceptional circumstances when dosimetry cannot be performed in a particular patient after the first Lutathera dose, it should be completed as soon as feasible upon a later dose. In order to minimize risk for each study subject, an accelerated analysis of dosimetry and safety data will be performed for each patient in the study, to enable the Investigator to take a decision for the subsequent Lutathera doses. The results of dosimetry assessments (imaging and blood dosimetry) will be provided to the investigators for their evaluation prior to administration of subsequent therapeutic cycles in each patient.

A total follow-up period of 5 years (60 months) after the last Lutathera dose will take place for each patient who received at least one dose of Lutathera. This follow-up period will be comprised of a short-term follow-up of 6 months to evaluate cumulative Lutathera toxicities, followed by a long-term follow up of another 54 months.

Inclusion Criteria

• GEP-NET cohort: presence of metastasized or locally advanced, inoperable (curative intent), histologically proven, G1 or G2 (Ki-67 index =< 20%), well differentiated GEP-NET.

  or PPGL cohort: presence of metastasized or locally advanced, inoperable (curative intent), histologically proven PPGL.

• Patients from 12 to < 18 years of age at the time of enrollment.
• Expression of somatostatin receptors confirmed by a somatostatin receptor imaging (SRI) modality within 3 months prior to enrollment, with tumor uptake Laboratory parameters:observed in the target lesions more or equal to the normal liver uptake.
• Performance status as determined by Karnofsky score >= 50 or Lansky Play-Performance Scale score >= 50.
• Parent's ability to understand and the willingness to sign a written informed consent document for adolescents as determined by local regulations. Adolescents will sign assent along with parental/legal guardian consent or will co-sign consent with parent/legal guardian in accordance with local regulation, prior to participation in the study.

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

Exclusion Criteria

• Laboratory parameters:
  • Estimated creatinine clearance calculated by the Cockroft-Gault method < 70 mL/min
  • Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L; platelets <75x109/L.
  • Total bilirubin >3 x ULN for age.
  • Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
• Established or suspected pregnancy.
• Breastfeeding female patients unless they accept to discontinue breastfeeding from the 1st dose until 3 months after the last administration of study drug.
• Female patients of child-bearing potential, unless they are using highly effective methods of contraception during treatment and for 6 months after the last dose of Lutathera.
• Sexually active male patients, unless they agree to remain abstinent or be willing to use effective methods of contraception.
• Patients for whom in the opinion of the investigator other therapeutic options are considered more appropriate than the therapy offered in the study, based on patient and disease characteristics.
• Current spontaneous urinary incontinence.
• Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
• Hypersensitivity to the study drug active substance or to any of the excipients.
• Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
• Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
• Patients who received any investigational agent within the last 30 days.

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

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Study Description

This is a Phase 1b/2, multi-center, open label umbrella study of patients ≥12 years of age with recurrent or progressive solid (including CNS) tumors with alterations in the key proteins of the RAS/RAF/MEK/ERK pathway, referred to as the MAPK pathway. Study DAY101-102 (master study) and sub-studies will consist of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period where survival, status and subsequent anticancer therapies are collected.

DAY101 will be evaluated alone (sub-study A) or combined with a different targeted therapy (sub-study B) in each sub-study. The Phase 1b part of each sub-study will evaluate the safety of the combination and select the dose for the Phase 2 part. The Phase 2 part of each sub-study will evaluate anti-tumor activity.

Inclusion Criteria

• Signed assent for patients ≥ 12 up to < 18 years of age
• Patients must have a histologically confirmed diagnosis of non-hematological tumor with concurrent MAPK pathway alteration as assessed by sequencing, PCR, FISH, or another clinically accepted molecular diagnostic method recognized by local laboratory or regulatory agency
• Patients must have radiographically-recurrent or radiographically-progressive disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1)
• Archival tumor tissue (preferably less than 3 years old) or fresh tumor tissue for correlative studies is required
• If brain metastases are present, they must have been previously treated and be stable as assessed by radiographic imaging

Other inclusion criteria may apply

Exclusion Criteria

• Known presence of concurrent activating mutation
• Patients with current evidence or a history of central serous retinopathy (CSR), retinal vein occlusion (RVO)

Substudy A-specific exclusion criterion:

• Prior therapy of any RAS- RAF-, MEK-, or ERK-directed inhibitor therapy

Substudy B-specific exclusion criterion:

• Prior receipt of any Type-II pan-RAF inhibitor therapy (e.g., LXH254/naporafenib, BGB- 283, BGB-3245, belvarafenib)

Other exclusion criteria may apply 

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Study Description

This is a randomized, double-blind, placebo-controlled, parallel-group, international, Phase 3 study in patients with newly diagnosed H3 K27M-mutant diffuse glioma to assess whether treatment with ONC201 following frontline radiotherapy will extend overall survival and progression-free survival in this population. Eligible participants will have histologically diagnosed H3 K27M-mutant diffuse glioma and have completed standard frontline radiotherapy.

The study has three study arms

• Experimental: ONC201 Twice Weekly Group - Intervention: Drug: ONC201
• Experimental: ONC201 Once Weekly Group - Intervention: Drug: ONC201 + Placebo
• Placebo Comparator: Placebo Group - Intervention: Other: Placebo

Inclusion Criteria

1. Able to understand the study procedures and agree to participate in the study by providing written informed consent (by participant or legally authorized representative), and assent when applicable.
2. Body weight ≥ 10 kg at time of randomization.
3. Histologically diagnosed H3 K27M-mutant diffuse glioma (new diagnosis). Detection of a missense K27M mutation in any histone H3-encoding gene detected by testing of tumor tissue (immunohistochemistry [IHC] or next-generation sequencing [NGS] in a Clinical Laboratory Improvement Amendments [CLIA]-certified or equivalent laboratory). [Site to provide (as available): ≥ 10 unstained formalin-fixed paraffin-embedded (FFPE) slides from tumor tissue.]
4. At least one, high-quality, contrast-enhanced MRI of the brain obtained prior to starting radiotherapy for submission to sponsor's imaging vendor for central read. For participants who had a surgical resection, this scan must be post-resection; for participants who did not have a resection, this scan may be pre- or post-biopsy.
5. At least one, high-quality, contrast-enhanced MRI of the brain obtained 2 to 6 weeks after completion of frontline radiotherapy. If unable to obtain contrast-enhanced imaging due to lack of venous access after multiple attempts, a patient may still be eligible after collection of a nonenhanced MRI of the brain. [Site to also provide all available MRIs completed prior to initiating treatment with study intervention.]
6. Received frontline radiotherapy
   • Initiated radiotherapy within 12 weeks from the initial diagnosis of H3 K27M-mutant diffuse glioma.
   • Completed radiotherapy within 2 to 6 weeks prior to randomization
   • Completed standard fractionated radiotherapy (eg. 54 to 60 Gy in 28 to 33 fractions given over approximately 6 weeks or hypofractionated radiotherapy (eg. 40 Gy in 15 fractions given over approximately 3 weeks).
7. Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time of randomization.
8. Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 days prior to randomization, if applicable. Stable steroid dose is defined as ≤ 2 mg/day increase (based on dexamethasone dose or equivalent dose of an alternative steroid).

Exclusion Criteria

1. Primary spinal tumor.
2. Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons.
3. Evidence of leptomeningeal spread of disease or cerebrospinal fluid dissemination.
4. Any known concurrent malignancy.
5. New lesion(s) outside of the radiation field.
6. Received whole-brain radiotherapy.
7. Received proton therapy for glioma.
8. Use of any of the following treatments within the specified time periods prior to randomization
   • ONC201 or ONC206 at any time.
   • Systemic bevacizumab (includes biosimilars) at any time since the initial diagnosis of H3 K27M-mutant diffuse glioma.
   • Temozolomide within past 3 weeks.
   • Tumor treating fields at any time.
   • DRD2 antagonist within past 2 weeks.
   • Any investigational therapy within past 4 weeks.
   • Strong CYP3A4 inhibitors within 3 days.
   • Strong CYP3A4 inducers (includes enzyme-inducing antiepileptic drugs) within 2 weeks.
9. Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization:
   • Absolute neutrophil count < 1.0 × 109/L or platelets < 75 × 109/L.
   • Total bilirubin > 1.5 × upper limit of normal (ULN) (participants with Gilbert's syndrome may be included with total bilirubin > 1.5 × ULN if direct bilirubin is ≤ 1.5 × ULN).
   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN.
   • Creatinine clearance ≤ 60 mL/min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate < 60 mL/min/1.73 m2).
10. QTc > 480 msec (based on mean from triplicate electrocardiograms) during screening.
11. Known hypersensitivity to any excipients used in the study intervention formulation.
12. Pregnant, breastfeeding, or planning to become pregnant while receiving study intervention or within 3 months after the last dose. Participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study intervention.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy or psychiatric illness/social situations that would limit compliance with study requirements.
14. Any other condition (eg, medical, psychiatric, or social) that, in the opinion of the investigator, may interfere with participant safety or the ability to complete the study according to the protocol.

Other exclusion criteria may apply 

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Study Description

TAPISTRY is a Phase II, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in rational, specified combinations in participants with unresectable, locally advanced or metastatic solid tumors determined to harbor specific oncogenic genomic alterations or who are tumor mutational burden (TMB)-high as identified by a validated next-generation sequencing (NGS) assay.

Participants with solid tumors will be treated with a drug or drug regimen tailored to their NGS assay results at screening.

Participants will be assigned to the appropriate cohort based on their genetic alteration(s). Treatment will be assigned on the basis of relevant oncogenotype, will have cohort-specific inclusion/exclusion criteria, and, unless otherwise specified, will continue until disease progression, loss of clinical benefit, unacceptable toxicity, participant or physician decision to discontinue, or death, whichever occurs first.

Cohort A: ROS1 fusion-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors, with the exception of NSCLC will receive entrectinib once daily in repeated 28-day cycles at a dose of 600 milligram per day (mg/day) for pediatric participants with a body surface area (BSA) >/= 1.51 m²

Cohort B: Cohort B: NTRK1/2/3 fusion-positive tumors - Open

Participants with metastatic or advanced solid tumors will receive entrectinib once daily in repeated 28-day cycles at a dose of 600 mg/day for adults and pediatric participants with a BSA >/= 1.51 m²

Cohort C: ALK fusion-positive tumors (excluding NSCLC) - Closed to Accrual

Participants with metastatic or advanced solid tumors, with the exception of NSCLC, will receive alectinib at a dosage of 600 mg orally twice a day (BID), taken with food, in repeated 28-day cycles.

Cohort D: TMB-high tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive atezolizumab intravenously (IV) at a dose of 15 mg/kg (maximum 1200 mg) for participants aged < 18 years on Day 1 of each 21-day cycle.

Cohort E: AKT1/2/3 mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive ipatasertib orally once daily (QD). For participants 12-17 years of age, ipatasertib will be administered at the starting dose of 200 mg for participants <35 kg, 300 mg for participants >/= 35 and <45 kg, 400 mg for those >/=45 kg orally QD in repeated 28-day cycles until the participant experiences disease progression, intolerable toxicity, or withdraws consent.

Cohort F: HER2 mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive trastuzumab emtansine IV at a dose of 3.6 mg/kg every 21 days. This dosage and administration method also applies for pediatric participants 12-17 years of age.

Cohort H: PIK3CA multiple mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive GDC-0077 daily at a starting dose of 9 mg by mouth (PO) in repeated 28-day cycles. This dosage and administration method also applies for pediatric participants 12-17 years of age.

Cohort I: BRAF class II mutant or fusion-positive tumors - Closed to Accrual

Participants with BRAF class II mutant/fusion-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib by mouth (PO) BID (twice a day) with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle.

Cohort J: BRAF class III mutant-positive tumors - Closed to Accrual

Participants with BRAF class III mutant-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib by mouth (PO) BID (twice a day) with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle.

Cohort K: RET fusion-positive tumors - Closed to Accrual

Participants with RET fusion-positive tumors will self-administer Pralsetinib orally at home (except on clinic days) on a continuous daily dosing regimen at a dose of 400 mg/day (four 100-mg capsules per day) for adult and pediatric patients ≥ 12 and < 18 years of age. A treatment cycle consists of 4 weeks (28 days).

Inclusion Criteria

• In addition to the general inclusion criteria below, participants must meet all of the cohort-specific inclusion criteria for the respective cohort
• Briefly - for arm A, a ROS1 fusion is required; for arm B, a NTRK1/2/3 fusion is required; for arm D, a TMB >16mut/Mb is required; for arm E: specific mutations in the AKT gene are required; for arm F: specific mutations in the HER2 gene are required; for arm H, specific mutations in the PIK3CA gene are required; for arm I, a BRAF Class II mutation or fusion is required; for arm J, a BRAF Class III mutation is required; for Cohort K; a RET fusion is required. 
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participants aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria

Exclusion Criteria

• Current participation or enrollment in another therapeutic clinical trial
• Any anticancer treatment within 2 weeks or 5 half-lives prior to start of study treatment
• Whole brain radiotherapy within 14 days prior to start of study treatment
• Stereotactic radiosurgery within 7 days prior to start of study treatment
• Pregnant or breastfeeding, or intending to become pregnant during the study
• History of or concurrent serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study or confounds the ability to interpret data from the study
• Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of study treatment
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months prior to enrollment, unstable arrhythmias, or unstable angina
• History of another active cancer within 5 years prior to screening that may interfere with the determination of safety or efficacy of study treatment with respect to the qualifying solid tumor malignancy
• In addition to the general exclusion criteria above, in order to be enrolled in a treatment cohort of the study, participants must not meet any of the cohort-specific exclusion criteria

Multiple other inclusion and exclusion criteria could apply and will be reviewed by your treating team

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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