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Title
Status

 

PEPN2121 - A Phase 1/2 Study of Tiragolumab (NSC# 827799) and Atezolizumab (NSC# 783608) in Patients With Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors

Open

PEPN2121 - A Phase 1/2 Study of Tiragolumab (NSC# 827799) and Atezolizumab (NSC# 783608) in Patients With Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors

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DiagnosisRecurrent/Refractory Atypical Teratoid/Rhabdoid Tumor, Kidney Medullary Carcinoma, Malignant Solid Neoplasm, Poorly Differentiated ChordomaStudy StatusOpen
PhaseI/II
Age18 Years and Older until completion of Part ARandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationAtezolizumab and tiragolumab are given intravenously (IV) as infusions
Last Posted Update2024-04-22
ClinicalTrials.gov #NCT05286801
International Sponsor
National Cancer Institute (NCI)
Principal Investigators for Canadian Sites
Patients 18+ years of age until completion of Part A.

CHU Ste Justine - Dr. Monia Marzouki
The Hospital for Sick Children - Dr. Daniel Morgenstern
Centres
Medical contact
Dr. Henrique Bittencourt
Dr. Monia Marzouki
Dr. Sebastien Perreault (neuro-onc)
 
Social worker/patient navigator contact
Marie-Claude Charrette
 
Clinical research contact
Marie Saint-Jacques
 
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

 

 

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

ONC201 - ONC201 for the Treatment of Newly Diagnosed H3 K27M-mutant Diffuse Glioma Following Completion of Radiotherapy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

Open

ONC201 - ONC201 for the Treatment of Newly Diagnosed H3 K27M-mutant Diffuse Glioma Following Completion of Radiotherapy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

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DiagnosisGliomaStudy StatusOpen
PhaseIII
AgeN/ARandomisationYES
Line of treatmentFirst line treatment
Routes of Treatment AdministrationONC201 and placebo medication are capsules, taken by mouth
Last Posted Update2024-04-16
ClinicalTrials.gov #NCT05580562
International Sponsor
Chimerix
Principal Investigators for Canadian Sites
London Health Sciences Centre - Dr. Seth Climans (Adult only)
Children's Hospital Eastern Ontario (CHEO) - Dr. Donna Johnston
Sunnybrook Health Sciences Centre - Dr. Mary Jane Lim Fat
Princess Margaret Hospital - Dr. Julie Bennett
Centres
Medical contact
Dr. Donna Johnston
Dr. Lesleigh Abbott
Dr. Doaa Abdel Fattah
 
Social worker/patient navigator contact
Sherley Telisma
 
Clinical research contact
Carol Duchenne
 
Medical contact
Dr. Alexandra Zorzi
Dr. Shayna Zelcer
 
Social worker/patient navigator contact
Cindy Milne Wren
Jessica Mackenzie Harris
 
Clinical research contact
Mariam Mikhail
Medical contact
N/A
Social worker/patient navigator contact
N/A
Clinical research contact
N/A
Medical contact
N/A
Social worker/patient navigator contact
N/A
Clinical research contact
N/A

 

 

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 

PBTC-058 - Phase 2 Study of Intraventricular Omburtamab-based Radioimmunotherapy for Pediatric Patients With Recurrent Medulloblastoma and Ependymoma

Open

PBTC-058 - Phase 2 Study of Intraventricular Omburtamab-based Radioimmunotherapy for Pediatric Patients With Recurrent Medulloblastoma and Ependymoma

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DiagnosisRecurrent Medulloblastoma Recurrent EpendymomaStudy StatusOpen
PhaseII
Ageup to 21 YearsRandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationDrug: Irinotecan (IV) Drug: Temozolomide (Oral) Drug: Bevacizumab (IV) Drug: Omburtamab I-131 (via Intraventricular Access Device) Pre-medication: Drug: Liothyronine (Orally, NG, or G-tube) Drug: SSKI (Orally, NG, or G-tube) Drug: Dexamethasone (Oral) Drug: Antipyretic (Oral acetaminophen [15 mg/kg, 650 mg maximum] or equivalent) Drug: Antihistamine (IV diphenhydramine [1 mg/kg, 50 mg maximum] or equivalent) Drug: Anti-emetics (IV ondansetron [0.25 mg/kg, 16 mg maximum] or equivalent)
Last Posted Update2024-04-10
ClinicalTrials.gov #NCT04743661
International Sponsor
Sponsor:
Pediatric Brain Tumor Consortium

Collaborators:
National Cancer Institute (NCI)
Memorial Sloan Kettering Cancer Center
Y-mAbs Therapeutics, Inc
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Vijay Ramaswamy
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

 

 

Study Description

 

Stratum 1: This is a phase 2 single-arm open-label study that will define event-free survival (EFS) and overall survival (OS) following therapy with irinotecan, temozolomide, bevacizumab, and compartmental radioimmunotherapy (cRIT) 131I-omburtamab in patients with recurrent medulloblastoma. Patients with recurrent medulloblastoma will undergo surgery if feasible prior to study entry, followed by Induction Chemotherapy with irinotecan, temozolomide, and bevacizumab on study as per the Children's Oncology Group (COG) trial ACNS0821. Following 2 or 4 courses of chemotherapy and if radiographic disease status is stable or improved, patients may continue to Radioimmunotherapy to receive 2 therapeutic doses (50 mCi each) of cRIT 131I-omburtamab. Following Radioimmunotherapy, patients may resume to Maintenance Chemotherapy with irinotecan, temozolomide, and bevacizumab for up to 12 total courses of chemotherapy or until disease progression, whichever occurs sooner. The primary comparison for this study will be the medulloblastoma cohort treated on ACNS0821 on the irinotecan + temozolomide + bevacizumab arm (N=52).

Stratum 2: This is a feasibility cohort. The primary objective is to assess feasibility of incorporating cRIT 131I-omburtamab for patients with recurrent ependymoma and to assess dosimetry. Patients must have progressed after initial surgery, radiation therapy, or other therapies. Patients will undergo surgery (if feasible) prior to study entry with the goal of achieving stable or better disease. Tumors (archived or new) will be tested for B7H3 prior to enrollment. If positive, patients will enroll on Stratum 2 and receive one dosimetry dose (2 mCi) of cRIT 131I-omburtamab with nuclear medicine scintigraphy using SPECT during the Dosimetry Course (14 days in length). Following the Dosimetry Course and within 2 weeks of the dosimetry dose, patients may continue to Radioimmunotherapy to receive 2 therapeutic doses (50 mCi each) of cRIT 131I-omburtamab.

Inclusion Criteria

Inclusion Criteria Stratum 1:

  • Patients with histologically confirmed diagnosis of medulloblastoma that is recurrent, progressive, or refractory to standard therapy. All tumors must have histologic verification at either time of initial diagnosis or recurrence. Note: For this study, refractory disease is specifically defined as presence of persistent abnormality on conventional MRI that is further distinguished by histology (tissue sample) or advanced imaging, i.e., diffusion weighted sequences or MR spectroscopy.
  • Patients must have disease, defined as tumor measurable in two perpendicular diameters on MRI, OR diffuse leptomeningeal disease, OR clear MRI evidence of disease that may not be measurable in two perpendicular diameters. Patients may have tumor cells in CSF with or without radiographic evidence of disease at time of enrollment.
  • Patients must be < 22 years of age at time of enrollment.
  • Protocol treatment with radioimmunotherapy (131I-omburtamab) will require the presence of an appropriate intraventricular access device (e.g., programmable ventriculoperitoneal [VP] shunt or reservoir). Patients are not required to have an existing programmable VP shunt or reservoir at time of study enrollment but must be willing and able to undergo a surgical procedure to have one placed prior to Radioimmunotherapy. Note: Patients with an existing intraventricular VP shunt without a programmable component must be willing and able to undergo modification of the shunt before treatment with 131I-omburtamab.
  • Patients must have recurrent, progressive, or refractory medulloblastoma after prior craniospinal irradiation (CSI) therapy with or without prior chemotherapy, unless CSI is contraindicated or determined to be not in the best interest of patient due to underlying medical conditions or declined by patient/family. Patients must have experienced no more than two recurrences of medulloblastoma or have refractory disease. Note: Patients with contraindications to radiation therapy are still eligible.
  • Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if prior nitrosourea.
  • Biologic or investigational agent (anti-neoplastic) - Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. 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.
  • Monoclonal antibody treatment and agents with known prolonged half-lives - Patient must have recovered from any acute toxicity potentially related to the agent and received last dose of the agent ≥ 21 days prior to study enrollment.
  • Radiation - Patients must have had their last fraction of:
    • Craniospinal irradiation, whole brain radiation, total body irradiation, or radiation to >= 50% of pelvis or spine 24 weeks prior to study enrollment. Tumor designated as "measurable" for protocol purposes must not have received radiation within 12 weeks prior to study enrollment.
    • Focal radiation to areas of symptomatic metastatic disease at least 14 days prior to study enrollment.
  • Stem Cell Transplant (SCT) - For autologous SCT >= 3 months must have elapsed prior to study enrollment.
  • Patients with neurological deficits should have deficits stable for a minimum of 1 week prior to enrollment. A baseline detailed neurological exam should clearly document neurological status of the patient at time of study enrollment. Patients with seizure disorders may be enrolled if seizures are controlled and on non-enzyme inducing anticonvulsants. Patients must not be taking enzyme-inducing antiepileptic medicines within 1 week prior to study enrollment.
  • Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 2 weeks prior to study enrollment must be ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • Organ Function - Patients must have:
    • Peripheral absolute neutrophil count (ANC) ≥ 1 x 10^9/ L (must not have received G-CSF within 7 days prior to enrollment or pegfilgrastim within 14 days prior to enrollment)
    • Platelet count ≥ 100 x 10^9/ L (unsupported, defined as no platelet transfusion within 7 days prior to study enrollment)
    • Hemoglobin ≥ 8.0 g/dL (may receive packed red blood cell [PRBC] transfusions)
    • Serum creatinine based on age/gender. Patients that do not meet the criteria in Table 1 but have a 24 hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m^2 are eligible.
    • Urine protein should be screened by dipstick analysis. If protein ≥ 2+ on dipstick, then Urine Protein Creatinine (UPC) ratio should be calculated. If UPC ratio > 0.5, 24-hour urine protein should be obtained, and the level should be < 1000 mg/24 hours for patient enrollment.
    • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
    • ALT (SGPT) and AST (SGOT) < 5 x institutional upper limit of normal (ULN)
    • INR/PT ≤ 1.5 x institutional upper limit of normal (ULN)
  • Hypertension must be well controlled (≤ 95th percentile) on stable doses of medication.
  • Patients must have recovered from any surgical procedure before enrolling on this study.
  • HIV Infected Individuals - Patients who are known to be Human immunodeficiency virus (HIV)-infected must be on effective anti-retroviral therapy with undetectable viral load within 6 months prior to study enrollment.
  • Hep B Chronically Infected Individuals - For patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Hep C (HCV) Infected Individuals - Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with known HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
  • Corticosteroids - Patients who are receiving dexamethasone at a stable or decreasing dose for at least 7 days prior to study enrollment are eligible.
  • Growth Factors - Patients must be off all colony-forming growth factor(s) for at least 1 week prior to enrollment (e.g., filgrastim, sargramostim, or erythropoietin) or at least 2 weeks for pegfilgrastim.
  • Pregnant women are excluded from this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Female patients of childbearing potential must have a negative serum or urine pregnancy test prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for at least 6 months after the completion of bevacizumab therapy.
  • The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines.

 

Inclusion Criteria Stratum 2: 

  • For patients with histological diagnosis of ependymoma, screening consent for B7H3 must be obtained prior to enrollment on PBTC-058.
  • Patients must have evidence of tumor reactivity for B7H3 (CD276) to be eligible for treatment. Results from prior testing of tumor reactivity for B7H3 (CD276) using a CLIA-certified immunohistochemistry (IHC) assay may be used. For patients who do not have prior B7H3 testing results from a CLIA lab, samples must be sent to MSKCC.
  • Patients with a histologically confirmed diagnosis of ependymoma that is recurrent, progressive, or refractory to standard therapy. All tumors must have histologic verification at either the time of initial diagnosis or recurrence. Note: For this study, refractory disease is specifically defined as presence of persistent abnormality on conventional MRI that is further distinguished by histology (tissue sample) or advanced imaging, i.e., diffusion weighted sequences or MR spectroscopy.
  • Patients may have tumor cells in CSF with or without radiographic evidence of disease at time of screening.
  • Patients must be < 22 years of age at the time of screening.
  • Potential Eligibility for Study Enrollment - Patients screened for this trial should be expected to meet criteria for treatment as outlined in the protocol.

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

Exclusion Criteria

EXCLUSION CRITERIA: Stratum 1

  • Patients must not have previously received the combination of bevacizumab, irinotecan, and temozolomide therapy.
  • Patients with a serious or non-healing wound, ulcer, or bone fracture are not eligible for this study.
  • Patients must not have a history of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior to study enrollment.
  • Patients must not have a known bleeding diathesis or coagulopathy.
  • Patients must not have had significant vascular disease (e.g., aortic aneurysm requiring surgical repair, deep venous or arterial thrombosis) within the last 6 months prior to study enrollment.
  • Patients must not have a known thrombophilic condition (i.e., protein S, protein C or antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, homocysteinemia or antiphospholipid antibody syndrome). Testing is not required in patients without thrombophilic history.
  • Patients must not have evidence of new CNS hemorrhage on baseline MRI obtained within 14 days prior to study enrollment.
  • Patients with history of stroke, myocardial infarction, transient ischemic attack (TIA), severe or unstable angina, peripheral vascular disease, or grade II or greater congestive heart failure within the past 6 months are not eligible.
  • Patients must not have serious and inadequately controlled cardiac arrhythmia.
  • Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies are not eligible.
  • Patients must not be currently taking NSAIDS, clopidrogel, dipyridamole, or aspirin therapy > 81 mg/day.
  • Female patients who are breastfeeding are not eligible for this study unless they agree not to breastfeed.
  • Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity, or would interfere with the study procedures or results. Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial.
  • Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
  • Patients currently receiving any of the following medications and cannot be discontinued 7 days prior to enrollment are ineligible:
    • Known strong and moderate inducers or inhibitors of CYP3A4/5, including enzyme-inducing anti-convulsant drugs (EIACDs), grapefruit, echinacea, grapefruit hybrids, pummelos, starfruit, and Seville oranges
    • Substrates of CYP3A4/5 with a narrow therapeutic index
    • Herbal preparations/medications (except for vitamins) including, but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. Patients should stop using all herbal medications and dietary supplements at least 7 days prior to enrollment.
  • Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions.

 

EXCLUSION CRITERIA: Stratum 2

  • Female patients who are breastfeeding are not eligible for this study unless they agree not to breastfeed.
  • Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results. Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial.
  • Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
  • Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions.

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

PED-CITN-01 - 3CI Study: Childhood Cancer Combination Immunotherapy.

Completed

PED-CITN-01 - 3CI Study: Childhood Cancer Combination Immunotherapy.

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DiagnosisLymphoma, brain tumours except diffuse intrinsic pontine glioma, solid tumoursStudy StatusCompleted
PhaseI
AgeChild, Adult - (1 to 25 Years) RandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment Administrationintravenous
Last Posted Update2024-04-10
ClinicalTrials.gov #NCT04500548
International Sponsor
National Cancer Institute (NCI)
Principal Investigators for Canadian Sites
The Hospital for Sick Children – Dr. Daniel Morgenstern


Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

 

 

Study Description

Brief Summary:

This phase Ib trial investigates the side effects of the combination of nivolumab and ipilimumab, and to see how well they work in treating patients with cancers that have come back (relapsed) or does not respond to treatment (refractory) and have an increased number of genetic changes. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Tumor mutational burden (TMB) is the total amount of genetic changes or "mutations" found in tumor cells. Some studies in adults with cancer have shown that patients with a higher TMB (an increased number of genetic changes) are more likely to respond to immunotherapy drugs. There is also evidence that nivolumab and ipilimumab can shrink or stabilize cancer in adult patients with cancer. This study is being done to help doctors learn if the combination of nivolumab and ipilimumab can help children, adolescents, and young adults patients live longer.

PART I: Patients undergo collection of tissue samples for TMB level. Patients with elevated TMB may be eligible for Part II.

PART II: 

Dose level -1 (nivolumab). Patients receive nivolumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Dose level 1 (nivolumab, ipilimumab). Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria
  • PART 1: Patients must have histologically or cytologically confirmed malignancy at the time of initial diagnosis, relapse, or recurrence. Patients must have recurrent or refractory cancer for which standard curative or palliative measures do not exist or are no longer effective

    • Patients with multiple concurrent and/or sequential neoplasms are eligible
    • Patients with central nervous system (CNS) tumors are eligible, except those with diffuse intrinsic pontine glioma
    • Patients with lymphoma are eligible; patients with leukemia are excluded
    • Chemotherapy-naïve patients are eligible in cases where first-line therapy does not include chemotherapy (e.g., surgery only for ependymoma management)
  • PART 1: Patients must have evidence of one or more of the following criteria in current or previous tumor:

    • Microsatellite instability (MSI-H)
    • Mutation causing functional loss of mismatch repair gene expression (MLH1, MSH2, MSH6, PMS2, EPCAM, MSH3)
    • Hypermutation in any tumor (including primary malignancy for patients with relapse or previous cancer diagnoses)
    • Functional mutation of POLE or POLD1 genes
    • A syndrome linked to hypermutant cancer predisposition such as congenital mismatch repair deficiency (CMMRD), Lynch syndrome, or xeroderma pigmentosum (XP) is also permitted
    • Other factors or sequencing evidence not listed above but which may be predictive of hypermutant cancer may be permitted after discussion with the protocol principal investigator
  • PART 1: A tumor tissue specimen must be provided for molecular profiling, including TMB analysis. The specimen may be archival or prospective, from a medically necessary surgery, biopsy, or excision. Tissue will not be obtained solely for this trial. A specimen from the time of most recent relapse/progression is preferred, but not mandatory

    • Tissue is preferred. However, if necessary, previously extracted DNA may be used with the approval of the protocol principal investigator if extracted in a clinically certified laboratory and prepared in an Foundation Medicine Inc. (FMI), TMB assay-compatible manner
  • PART 1: All patients and/or their parents or legally authorized representatives must have the ability to understand and the willingness to sign a written informed consent. Assent, where appropriate, will be obtained according to local policy. Patients with impaired decision-making capacity will not be excluded
  • PART 2: Patients must have histologically or cytologically confirmed malignancy at the time of initial diagnosis, relapse, or recurrence. Patients must have recurrent or refractory cancer for which standard curative or palliative measures do not exist or are no longer effective

    • Patients with multiple concurrent and/or sequential neoplasms are eligible
    • Patients with CNS tumors are eligible, except those with diffuse intrinsic pontine glioma or bulky tumors
    • Patients with lymphoma are eligible (provided other criteria, such as bone marrow function, are met); patients with leukemia are excluded
    • Chemotherapy-naive patients are eligible in cases where first-line therapy does not include chemotherapy (e.g., surgery only for ependymoma management)
  • PART 2: Patients must have measurable disease

    • Patients with neuroblastoma without measurable soft tissue but with iobenguane (MIBG) avid disease are eligible
    • Patients with bone marrow only disease are excluded
  • PART 2: Patients must have confirmation of cancer with a TMB of >= 10 mutations (mut)/megabase (Mb) as determined by an next generation sequencing (NGS) targeted cancer gene panel performed by Foundation Medicine Inc. (FMI). Proof of TMB eligibility can be from Part 1 participation or a previously acquired FMI report
  • PART 2: Patients must have recovered from the acute toxic effects of all prior anti-cancer therapies (with the exception of alopecia and lymphopenia)

    • Previous treatment with nivolumab and/or other anti-PD-1/PD-L1 inhibitors is permitted
    • Previous treatment with ipilimumab and/or other anti-CTLA-4 inhibitors is permitted
    • Previous treatment with combined anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors is not be permitted
  • PART 2: The following time periods apply for prior therapy. Patients must have:

    • Cytotoxic chemotherapy: At least 21 days prior to treatment initiation from the last dose of cytotoxic or myelosuppressive chemotherapy; at least 42 days if prior nitrosourea (such as lomustine, CCNU)
    • Hematopoietic growth factors: At least 7 days prior to treatment initiation from the last dose of short-acting growth factor; at least 14 days for long-acting
    • Anti-cancer agents not known to be myelosuppressive: At least 7 days prior to treatment initiation from the last dose
    • Interleukins, interferons, and cytokines (other than hematopoietic growth factors): At least 21 days prior to treatment initiation from the last dose
    • Antibodies: At least 21 days prior to treatment initiation from the last dose and toxicity related to prior antibody therapy must be recovered to grade =< 1
    • Radiotherapy: At least 14 days prior to treatment initiation from local radiotherapy; at least 150 days from total body irradiation (TBI), craniospinal radiotherapy, or radiation to >= 50% of the pelvis; at least 42 days from other substantial bone marrow radiation
    • Radiopharmaceutical therapy (e.g., 131I-MIBG): At least 42 days prior to treatment initiation from systemically administered radiopharmaceutical therapy
    • Autologous stem cell infusion including boost infusion: At least 42 days prior treatment initiation
    • Cellular therapy: At least 42 days prior to treatment initiation from any type of cellular therapy
  • PART 2: Lansky play score >= 50 if =<16 years of age; Karnofsky performance scale >= 50 if =< 16 years of age. Patients unable to walk due to paralysis but who are using a wheelchair will be considered ambulatory for the purpose of assessing performance status
  • PART 2: Peripheral absolute neutrophil count (ANC) >= 750/mm^3 (0.75 x 10^9/L)
  • PART 2: Platelet count >= 75,000/mm^3 (75 x 10^9/L), transfusion independent, defined as not receiving platelet transfusions at least 7 days prior to treatment initiation
  • PART 2: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2; OR serum creatinine based on age/gender as follows:

    • Age: 1 to < 2 years; Maximum serum creatinine: 0.6 mg/dL; 53 umol/L (male); 0.6 mg/dL; 53 umol/L (female)
    • Age: 2 to < 6 years; Maximum serum creatinine: 0.8 mg/dL; 71 umol/L (male); 0.8 mg/dL; 71 umol/L (female)
    • Age: 6 to < 10 years; Maximum serum creatinine: 1 mg/dL; 88 umol/L (male); 1 mg/dL; 88 umol/L (female)
    • Age: 10 to < 13 years; Maximum serum creatinine: 1.2 mg/dL; 106 umol/L (male); 1.2 mg/dL; 106 umol/L (female)
    • Age: 13 to < 16 years; Maximum serum creatinine: 1.5 mg/dL; 133 umol/L (male); 1.4 mg/dL; 124 umol/L (female)
    • Age: >= 16 years; Maximum serum creatinine: 1.7 mg/dL; 150 umol/L (male); 1.4 mg/dL; 124 umol/L (female)
  • PART 2: Bilirubin (sum of conjugated and unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • PART 2: Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 135 U/L (i.e., 3 x ULN). For the purposes of this study, the ULN for ALT (SGPT) is 45 U/L
  • PART 2: No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and pulse oximetry >= 92% while breathing room air
  • PART 2: No signs or symptoms of heart failure in a patient who has no history of congestive heart failure, no prior exposure to cardiotoxic drugs, and no radiotherapy to the heart; OR shortening fraction of >= 27% or ejection fraction of >= 50% by echocardiogram
  • PART 2: Serum lipase =< ULN at screening
  • PART 2: Patients with treated CNS metastasis are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during screening

    • Patients with new or progressive CNS metastasis (active metastasis) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS-directed treatment is not required and is unlikely to be required for at least 6 weeks after treatment initiation, and a risk-benefit analysis (discussion) by the patient and investigator favors participation in the trial
  • PART 2: Human immunodeficiency virus (HIV): Infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to treatment initiation are eligible

    • Note: Routine screening for HIV status prior to enrollment is not required
  • PART 2: Hepatitis B virus (HBV): Patients with evidence of chronic infection with undetectable viral load are eligible. Suppressive therapy, if indicated, is allowed

    • Note: Routine screening for HBV status prior to enrollment is not required
  • PART 2: Hepatitis C virus (HCV): Infected patients currently on treatment with undetectable viral load are eligible. Patients with history of infection must have been treated and cured

    • Note: Routine screening for HCV status prior to enrollment is not required
  • PART 2: Patients must provide a pre-treatment tumor tissue specimen (baseline sample) for correlative exploratory biology studies. The specimen may be archival or prospective, from a medically necessary surgery, biopsy, or excision. Tissue will not be obtained solely for this trial. A specimen from the time of most recent relapse/progression is preferred, but not mandatory. Submission of a representative sample from all available lesions (archival and prospective) is strongly encouraged. If available, residual tissue from Part 1 may be used to fulfill the baseline tissue sample requirement; however additional tissue may be required if residual tissue is insufficient
  • PART 2: All patients and/or their parents or legally authorized representatives must have the ability to understand and the willingness to sign a written informed consent. Assent, where appropriate, will be obtained according to local policy. Patients with impaired decision-making capacity will not be excluded
  • PART 2: Patients with previous grade 4 life-threatening reaction or other adverse reaction that in the opinion of the investigator would preclude administrating therapy
Exclusion Criteria
  • PART 1: Patients with history of autoimmune disease
  • PART 1: Patients with history of interstitial lung disease or pneumonitis are not eligible
  • PART 1: Patients who have received solid organ transplant or allogenic stem cell transplant are not eligible
  • PART 1: Patients who have been previously treated with a combination of anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors are not eligible
  • PART 2: Patients requiring systemic corticosteroids or other forms of immunosuppressive therapy within 7 days prior to treatment initiation are not eligible

    • Following treatment initiation, systemic corticosteroids or other forms of immunosuppressive therapy are permitted if administered for the treatment of toxicity, tumor flare, or pseudo-progression and can be tapered. In most cases study treatment must be held until the dose is tapered to 10 mg/day prednisone or equivalent. The protocol principal investigator must be consulted prior to resuming treatment
    • Physiologic corticosteroids up to 5 mg/day prednisone or equivalent are permitted
    • Topical, ocular, intra-articular, intra-nasal, inhaled corticosteroids are permitted
    • Patients with CNS tumors receiving steroids for intracranial mass effect must be able to discontinue these at least 7 days prior to treatment initiation
  • PART 2: Patients who are receiving other anticancer agent(s) are not eligible
  • PART 2: Patients who are receiving or have received any other investigational agent(s) within 14 days prior to treatment initiation are not eligible
  • PART 2: Patients with CNS tumors with any of the following characteristics on imaging are not eligible:

    • Tumor with any evidence of uncal herniation or mass effect leading to severe midline shift
    • Tumor > 6 cm in single maximal dimension
    • Tumor that in the opinion of the investigator shows significant mass effect
  • PART 2: Patients with uncontrolled intercurrent illness/condition that would limit compliance with the study requirements are not eligible. This includes, but is not limited to, ongoing active infection, symptomatic congestive heart failure (New York Heart Association class III or IV), unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situations
  • PART 2: The study agents have the potential for teratogenic or abortifacient effects. Females of reproductive potential must have a negative serum pregnancy test within 72 hours prior to treatment initiation. Additional pregnancy tests (serum or urine) should be obtained during study participation in accordance with local standards and guidelines

    • Males or females of reproductive potential may not participate unless they have agreed to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of treatment, and as follows:

      • Females receiving nivolumab must continue an effective method of contraception for a period of 5 months after the last dose of nivolumab
      • Males receiving nivolumab must continue an effective method of contraception for a period of 7 months after the last dose of nivolumab
    • Should a female patient become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform the investigator immediately
    • Due to the unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with the study agents, breastfeeding must be discontinued if the mother is treated on study
    • Note: Females of reproductive potential are defined as those who are past the onset of menarche and are not surgically sterile (i.e., bilateral salpingectomy, bilateral oophorectomy, complete hysterectomy)
  • PART 2: Patients with history of autoimmune disease (such as autoimmune thyroid disease or inflammatory bowel disease) that has required systemic treatment within 2 years prior to treatment initiation are not eligible

    • Asymptomatic laboratory abnormalities (e.g., antinuclear antibody [ANA], rheumatoid factor, altered thyroid studies) are permitted in the absence of an autoimmune disorder diagnosis
    • Atopy-related conditions (e.g., asthma, allergic rhinitis, atopic dermatitis) are permitted
    • Replacement therapy (e.g., thyroxine, insulin, physiological corticosteroid replacement therapy) is not considered a form of systemic treatment
  • PART 2: Patients with history of interstitial lung disease or pneumonitis are not eligible
  • PART 2: Patients who have received solid organ transplant or allogenic stem cell transplant are not eligible

BP42573 - An Open-label, Multicenter, Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Activity of RO7428731 in Participants With Glioblastoma Expressing Mutant Epidermal Growth Factor Receptor Variant III

Open

BP42573 - An Open-label, Multicenter, Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Activity of RO7428731 in Participants With Glioblastoma Expressing Mutant Epidermal Growth Factor Receptor Variant III

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DiagnosisGlioblastomaStudy StatusOpen
PhaseI
Age18 Years and olderRandomisationNO
Line of treatmentFirst line treatment, Disease relapse or progression
Routes of Treatment AdministrationDrug: RO7428731, intravenously (IV)
Last Posted Update2024-04-09
ClinicalTrials.gov #NCT05187624
International Sponsor
Hoffmann-La Roche
Principal Investigators for Canadian Sites
Princess Margaret Cancer Centre
Centres
Medical contact
N/A
Social worker/patient navigator contact
N/A
Clinical research contact
N/A

 

 

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.

ADP 0044-002 - A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T Cells in Subjects With Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma

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ADP 0044-002 - A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T Cells in Subjects With Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma

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DiagnosisSynovial Sarcoma, Myxoid Liposarcoma, Round Cell LiposarcomaStudy StatusOpen
PhaseII
Age10 Years to 75 Years RandomisationYES
Line of treatmentFirst line treatment, Disease relapse or progression
Routes of Treatment AdministrationGenetic: afamitresgene autoleucel (previously ADP-A2M4) Single infusion of autologous genetically modified afamitresgene autoleucel (previously ADP-A2M4) Dose: 1.0 x109 to 10x109 transduced by a single intravenous infusion
Last Posted Update2024-04-09
ClinicalTrials.gov #NCT04044768
International Sponsor
Adaptimmune
Principal Investigators for Canadian Sites
Princess Margaret Cancer Centre - Dr. A. Razak
Centres
Medical contact
N/A
Social worker/patient navigator contact
N/A
Clinical research contact
N/A

 

 

Study Description

 

This is a study to investigate the efficacy and safety of ADP-A2M4 in HLA-A*02 eligible and MAGE-A4 positive subjects with metastatic or inoperable (advanced) Synovial Sarcoma (Cohort 1, 2 and 3 ) or MRCLS (Cohort 1) .

Inclusion Criteria
  • Age ≥16 (10 years at selected sites) and <=75 years
  • Diagnosis of advanced synovial sarcoma (Cohort 1, Cohort 2 and Cohort 3) or myxoid liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) confirmed by cytogenetics.
  • Previously received either an anthracycline or ifosfamide containing regimen.
  • Measurable disease according to RECIST v1.1 prior to lymphodepletion
  • HLA-A*02:01, HLA-A*02:02, HLA-A*02:03 or HLA-A*02:06 positive
  • Tumor shows MAGE-A4 expression confirmed by central laboratory. North America Only (United States and Canada): Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 expression of ≥1+ staining in ≥10% of the cells by immunohistochemistry.
  • ECOG Performance Status of 0 or1. For subjects aged ≥10 to ≥16 years old: Lansky Score ≥60%.
  • Left ventricular ejection fraction (LVEF) ≥50%.

Note: other protocol defined Inclusion criteria may apply

Exclusion Criteria
  • HLA-A*02:05 in either allele
  • Received or plans to receive the following therapy/treatment prior to leukapheresis or lymphodepleting chemotherapy: Cytotoxic chemotherapy, Tyrosine kinase inhibitor (TKI) (e.g. pazopanib), Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors,), Anti-cancer Vaccine, Gene therapy using an integrating vector (subjects who have received a gene therapy using a lentiviral vector may be eligible for the study), Corticosteroids or any other immunosuppressive therapy, Investigational treatment or interventional clinical trial, Allogeneic hematopoietic stem cell transplant, Radiotherapy to the target lesions, Major surgery
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide or other agents used in the study.
  • History of autoimmune or immune mediated disease
  • Symptomatic CNS metastases including leptomeningeal disease.
  • Other prior malignancy that is not considered by the Investigator to be in complete remission
  • Clinically significant cardiovascular disease
  • Uncontrolled intercurrent illness
  • Active infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or human T cell leukemia virus
  • Pregnant or breastfeeding

Note: other protocol defined Exclusion criteria may apply.

Publications

A kinase-cGAS cascade to synthesize a therapeutic STING activator - PubMed (nih.gov)

CFI-400945-AML-201/TWT-202 - Phase 1b/2 Clinical Study of the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of CFI-400945 as a Single Agent or in Combination With Azacitidine in Patients With AML, MDS or CMML

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CFI-400945-AML-201/TWT-202 - Phase 1b/2 Clinical Study of the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of CFI-400945 as a Single Agent or in Combination With Azacitidine in Patients With AML, MDS or CMML

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DiagnosisAcute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML)Study StatusOpen
PhaseI/II
Age18 Years and older RandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationDrug: CFI-400945 (oral) Arm 2A only: Azacitidine (IV)
Last Posted Update2024-04-09
ClinicalTrials.gov #NCT04730258
International Sponsor
Treadwell Therapeutics, Inc
Principal Investigators for Canadian Sites
Princess Margaret Cancer Centre
Centres
Medical contact
N/A
Social worker/patient navigator contact
N/A
Clinical research contact
N/A

 

 

Study Description

 

This study will be evaluating the safety and tolerability of CFI-400945 in subjects with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia. The study is designed to build on encouraging data from another study and to obtain further safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) data of CFI-400945.

Inclusion Criteria
  1. Patients must be >18 years of age
  2. For Parts 1A and 1B, the following malignancy types will be included:
    • Relapsed or refractory AML.
    • MDS, after prior hypomethylating agents.
    • CMML, with progressive disease/lack of response after hypomethylating agents
  3. For Parts 2A and 2B, the following malignancy types will be included:
    • Relapsed or Refractory AML.
    • MDS patients should be limited to high risk disease
    • MDS or CMML should be previously untreated and patients with AML may have relapsed or refractory disease;
  4. Have clinically acceptable laboratory screening results (i.e., clinical chemistry, hematology, and urinalysis) within certain limits per protocol.
  5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Other inclusion criteria may apply 

Exclusion Criteria
  1. Patients who have received investigational therapy, radiotherapy, immunotherapy, monoclonal antibodies, or chemotherapy within 14 days or 5 half-lives (whichever is shorter)
  2. Allogeneic or autologous transplant for AML with infusion of stem cells within 90 days before Cycle 1 Day 1, or on active immunosuppressive therapy for graft-versus-host disease (GVHD) or GVHD prophylaxis within 2 weeks of Cycle 1 Day 1.
  3. Any Grade ≥ 2 persistent non-hematological toxicity related to allogeneic transplant, such as those requiring systemic immunosuppressive therapy.

IGNYTE-ESO - Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered NY-ESO-1-Specific (c259) T Cells, Alone or in Combination With Other Agents, in HLA-A2+ Participants With NY-ESO-1 and/or LAGE-1a Positive Solid Tumors (IGNYTE-ESO)

Closed to enrollment

IGNYTE-ESO - Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered NY-ESO-1-Specific (c259) T Cells, Alone or in Combination With Other Agents, in HLA-A2+ Participants With NY-ESO-1 and/or LAGE-1a Positive Solid Tumors (IGNYTE-ESO)

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DiagnosisAdvanced tumorsStudy StatusClosed to enrollment
PhaseII
Age10 Years and olderRandomisationNO
Line of treatmentFirst line treatment, Disease relapse or progression
Routes of Treatment AdministrationDrug: Letetresgene autoleucel (lete-cel, GSK3377794) letetresgene autoleucel will be administered. Drug: Fludarabine Fludarabine will be used as the lymphodepleting chemotherapy Drug: Cyclophosphamide Cyclophosphamide will be used as the lymphodepleting chemotherapy.
Last Posted Update2024-04-09
ClinicalTrials.gov #NCT03967223
International Sponsor
GlaxoSmithKline
Principal Investigators for Canadian Sites
Maisonneuve-Rosemont Hospital
Centres
Medical contact
N/A
Social worker/patient navigator contact
N/A
Clinical research contact
N/A

 

 

Study Description

 

New York esophageal antigen-1 (NY-ESO-1) and LAGE-1a antigens are tumor-associated proteins that have been found in several tumor types. Clinical trials using adoptively transferred T cells directed against NY-ESO-1/LAGE-1a have shown objective responses. Letetresgene autoleucel (lete-cel, GSK3377794) is the first generation of NY-ESO-1 specific T-cell receptor engineered T cells. This is a master protocol investigating T-cell therapies. It will initially consist of a core protocol with two independent substudies investigating Letetresgene autoleucel in previously untreated (1L) Human Leukocyte Antigen (HLA)-A*02+ participants with NY-ESO-1+ advanced (metastatic or unresectable) synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS) (Substudy 1) and Letetresgene autoleucel as second line or higher (2L+) treatment in HLA-A*02+ participants with NY-ESO-1+ advanced (metastatic or unresectable) SS or MRCLS who have progressed following treatment with anthracycline based chemotherapy (Substudy 2).

Inclusion Criteria
  • Participant must be greater than or equal to 10 years of age on the day of signing informed consent.
  • Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a designated central laboratory
  • Participant's tumor is positive for NY-ESO-1 expression by a designated central laboratory.
  • Participant has a diagnosis of synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS)
  • Performance status: dependent on age - Lansky > 60, Karnofsky > 60, Eastern Cooperative Oncology Group 0-1.
  • Participant must have adequate organ function and blood cell counts, within 7 days prior to leukapheresis.
  • At time of treatment, participant has measurable disease according to RECIST v1.1.
  • Consultation for prior history per protocol specifications.
Exclusion Criteria
  • Central nervous system metastases.
  • Any other prior malignancy that is not in complete remission.
  • Clinically significant systemic illness.
  • Prior or active demyelinating disease.
  • History of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease (e.g. Crohn's disease, systemic lupus) requiring steroids or other immunosuppressive treatments.
  • Previous treatment with genetically engineered NY-ESO-1-specific T cells.
  • Previous NY-ESO-1 vaccine or NY-ESO-1 targeting antibody.
  • Prior gene therapy using an integrating vector.
  • Previous allogeneic hematopoietic stem cell transplant.
  • Washout periods for prior radiotherapy and systemic chemotherapy must be followed.
  • Participant had major surgery in less than or equal to 28 days of first dose of study intervention.
  • Prior radiation exceeds protocol specified limits.