Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors

B
Brian Weiss

Primary Investigator

Enrolling By Invitation
12 years and older
All
Phase 1/2
86 participants needed
2 Locations

Brief description of study

What is the purpose of this study?
This phase I/II trial studies how well tiragolumab and atezolizumab works when given tohildren 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 meanshat tumor cells are missing the SMARCB1 and SMARCA4 genes, seen with some aggressive cancershat are typically hard to treat. Immunotherapy with monoclonal antibodies, such asgolumab and atezolizumab, may help the body's immune system attack the cancer, and maywith the ability of tumor cells to grow and spread.

THIS STUDY IS ENROLLING BY INVITATION ONLY - Consistent with most oncology trials, patients are not actively “recruited,” but are screened by their physician for appropriate clinical trial(s) at the time of their routine clinic visit. Occasionally, a patient may be a self-referral or physician referral, but are still screened for appropriate clinical trials at the time of their routine clinic visit. PI and staff may send copies of relevant consent forms to these patients to look over prior to actually consenting or enrolling them. This may take place at the patient's visit at which the consent is presented or the patient's next visit to the outpatient hematology/oncology clinic.

Interested in participating? For more information about this research study or other cancer-related clinical trials at IU Simon Comprehensive Cancer Center, please contact:
IU Clinical Trials Office 
Phone: (317) 278-5632

Detailed description of study

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 thebination of tiragolumab and atezolizumab as assessed by objective response rate inwith 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(for CNS tumors). (Part B) III. To evaluate the safety and adverse event profile ofhis combination therapy in subjects with SMARCB1 or SMARCA4 deficient tumors, with aular focus in pediatric patients < 12 years of age.
SECONDARY OBJECTIVES:
I. To characterize the pharmacokinetics of tiragolumab alone in part A and tiragolumab andzolizumab (part A and B) when given in combination in pediatric, AYA (adolescents and young adults), and adult patients.
II. To estimate the PFS (progression free survival), OS (overall survival), and duration ofbination 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 orARCA4 and PD-L1 expression.
II. To assess the association of response rate to the molecular subtypes of rhabdoid/atypicald rhabdoid tumor (ATRT).
III. To assess changes in circulating and tumoral immune markers in patients treated withhis combination therapy and correlate to response when feasible.

What will happen during the study?
  • Patients are assigned to Part A or Part B.
  • PART A: Patients receive tiragolumab intravenously (IV) over 30-90 minutes on day 1 of eachycle 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, computedgraphy (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 inhe absence of disease progression or unacceptable toxicity. Patients also undergo standardging scans including x-rays, CT, MRI, and/or FDG PET-CT, throughout the trial. Patientsundergo 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.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Riley, Atypical Teratoid/Rhabdoid Tumor, Epithelioid Sarcoma, Kidney Medullary Carcinoma, Malignant Solid Neoplasm, Poorly Differentiated Chordoma, Recurrent Atypical Teratoid/Rhabdoid Tumor, Recurrent Chordoma, Recurrent Epithelioid Sarcoma, Recurrent Kidney Medullary Carcinoma, Recurrent Malignant Solid Neoplasm, Recurrent Rhabdoid Tumor, Refractory Atypical Teratoid/Rhabdoid Tumor, Refractory Chordoma, Refractory Epithelioid Sarcoma, Refractory Kidney Medullary Carcinoma, Refractory Malignant Solid Neoplasm, Refractory Rhabdoid Tumor, Rhabdoid Tumor
  • Age: 12 Months
  • Gender: All

Inclusion Criteria:
  • Patients must be >= 12 months of age at the time of study enrollment. For part A,ust 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 butwill only enroll patients at least 18 years of age. Patients <18 years of agewill be included in the part B cohorts only after the tiragolumab monotherapydose 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 pathologicumor bi-allelic SMARCB1 (INI1) or SMARCA4 loss or mutation from a Clinical Laboratoryvement 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
    • Note: Documentation of the institutional IHC or molecular testing must beuploaded via the RAVE system
  • 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 responseCNS tumors
  • Patients must have relapsed, refractory disease or newly diagnosed disease for whichhere is no known curative therapy or therapy proven to prolong survival with anble quality of life
  • Patients must have a performance status corresponding to Eastern Cooperative OncologyGroup (ECOG) scores of 0, 1 or 2 (Karnofsky/Lansky score of > 50). Use Karnofsky for> 16 years of age and Lansky for patients =< 16 years of age. Note:urologic deficits in patients with CNS tumors must have been stable for at least 7days 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 ofg the performance score
  • Patients must have fully recovered from the acute toxic effects of all priorherapy and must meet the following minimum duration from priordirected therapy prior to enrollment. If after the required timeframe, theumerical eligibility criteria are met, e.g., blood count criteria, the patient isdered to have recovered adequately
    • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:Developmental Therapeutics (DVL) homepage on the Children's Oncology Group(COG) Members site for commercial and investigational agent classifications. Forgents not listed, the duration of this interval must be discussed with the studyhair and the study-assigned Research Coordinator prior to enrollment
    • Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
      reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after thedose of agent. See the DVL homepage on the COG Members site for commerciald investigational agent classifications. For agents not listed, the duration ofhis interval must be discussed with the study chair and the study-assignedResearch Coordinator prior to enrollment
    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,d toxicity related to prior antibody therapy must be recovered to grade =< 1
    • Hematopoietic growth factors: >= 14 days after the last dose of a long-actinggrowth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. Forgents that have known adverse events occurring beyond 7 days afterdministration, this period must be extended beyond the time during which adversevents are known to occur
    • Interleukins, interferons and cytokines (other than hematopoietic growth): >= 21 days after the completion of interleukins, interferon orytokines (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>= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM)diation
    • Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131dobenzylguanidine [131I MIBG]): >= 42 days after systemically administereddiopharmaceutical 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,PD-L2, or anti-CTLA4 agent or with an agent directed to another stimulatoryhibitory T cell receptor (i.e. OX-40, CD137)
    • Patients must not have received live/attenuated vaccine within 30 days of firstdose of treatment
    • Patients must not be receiving concomitant systemic steroid medications and > 14days must have elapsed since last dose of systemic corticosteroid with thewing exceptions:
      • The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10g/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 aulse dose of systemic immunosuppressant medication (e.g., 48 hoursds for a contrast allergy) are acceptable
    • Treatment with systemic immunosuppressive medication (including, but not limited
      to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumorha [TNF-alpha] agents) must have concluded >= 14 days prior toudy enrollment
  • For patients with solid tumors without known bone marrow involvement
    • Peripheral absolute neutrophil count (ANC) >= 1000/uL (must be performed within 7days prior to enrollment)
  • For patients with solid tumors without known bone marrow involvement
    • Platelet count >= 100,000/uL (transfusion independent, defined as not receivingusions for at least 7 days prior to enrollment) (must be performedwithin 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 knownbe refractory to red cell or platelet transfusions). These patients will not bevaluable for hematologic toxicity
  • A creatinine based on age/gender as follows (must be performed within 7 days prior to):
    • 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)R- a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must bed using direct measurement with a nuclear blood sampling method ORdirect small molecule clearance method (iothalamate or other molecule perutional standard) (must be performed within 7 days prior to)
    • 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,he 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 welld as evidenced by no increase in seizure frequency in the prior 7 days
  • Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v5)ulting from prior therapy must be =< grade 2, with the exception of decreaseddon reflex (DTR). Any grade of DTR is eligible
  • International normalized ratio (INR) =< 1.5 (must be performed within 7 days prior to)
  • 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 ofd teratogenic adverse events as seen in animal/human studies, OR because thereyet no available information regarding human fetal or teratogenic toxicities.Pregnancy tests must be obtained in girls who are post-menarchal. Males or females ofductive potential may not participate unless they have agreed to use twove methods of birth control, including a medically accepted barrier orve method (e.g., male or female condom) for the duration of therapy and at90 days after final dose of tiragolumab and 150 days after final dose ofzolizumab, 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 seriousdverse reactions in the breastfed infant, breastfeeding is not recommendedduring therapy and for at least 150 days after the last dose of atezolizumab and90 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 withhe following exceptions:
        • The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10g/day of prednisone equivalent) is acceptable
        • The use of topical, inhaled, or ophthalmic corticosteroids areble
        • The use of acute, low-dose systemic immunosuppressant medication or aulse dose of systemic immunosuppressant medication (e.g. 48hours 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 agentsgible
    • Systemic immunosuppressive medications (including, but not limited to,yclophosphamide, azathioprine, methotrexate, and thalidomide) during studybecause these agents could potentially alter the efficacy and safety ofudy 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 antibodiesusion proteins
  • Known hypersensitivity to Chinese hamster ovary cell products or to any component ofhe atezolizumab or tiragolumab formulation
  • Patients who have undergone allogeneic bone marrow or stem cell transplant are notgible
  • Patients with known, untreated CNS metastases will be excluded with the following
    • Patients with a history of CNS metastases that have been previously treated mayquential 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 autoimmunedisease, or a syndrome that requires systemic steroids or immunosuppressive agents.ubjects with vitiligo or resolved childhood asthma/atopy are not excluded.Replacement therapy (e.g. thyroxine, insulin, physiologic corticosteroid replacementherapy for adrenal or pituitary insufficiency, etc.) is not considered a form ofystemic 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 quantitativehepatitis 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 isquired to determine eligibility. The HBV DNA test is required only for patientswho have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb. For adults (>= 18 years old at enrollment), hepatitis C serology testing isquired to determine eligibility. The HCV RNA test is required only for patientswho 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 notgible 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 HeartAssociation class III or IV congestive heart failure, myocardial infarction, orbrovascular accident) within 3 months prior to study enrollment, unstablehythmia, or unstable angina are not eligible
  • Patients who have a major surgical procedure, other than for diagnosis, within 4 weeksudy enrollment, or the anticipation of the need for a major surgicaldure 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 notgible. History of radiation pneumonitis in the radiation field is permitted
  • Patients who have uncontrolled pleural effusion, pericardial effusion, or ascitesquiring recurrent drainage procedures (once monthly or more frequently) are notgible. 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 they monitoring requirements of the study are not eligible

Updated on 14 Sep 2024. Study ID: NCI-2022-01992, PHO-COG-PEPN2121, 17227
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