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

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ClinicalTrials.gov Identifier: NCT05286801
Recruitment Status : Not yet recruiting
First Posted : March 18, 2022
Last Update Posted : July 5, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase 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, which is related to having more aggressive cancers that are harder 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.

Condition or disease Intervention/treatment Phase
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 Rhabdoid Tumor Refractory Atypical Teratoid/Rhabdoid Tumor Refractory Chordoma Refractory Epithelioid Sarcoma Refractory Kidney Medullary Carcinoma Refractory Rhabdoid Tumor Rhabdoid Tumor Biological: Atezolizumab Biological: Tiragolumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. 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 Response Assessment in Neuro-Oncology Criteria (RANO) (for CNS tumors).

II. 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 and atezolizumab 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 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.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 60 minutes on day 1 and tiragolumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Tiragolumab (NSC# 827799) and Atezolizumab (NSC# 783608) in Patients With Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors
Estimated Study Start Date : September 9, 2022
Estimated Primary Completion Date : July 31, 2025
Estimated Study Completion Date : July 31, 2025


Arm Intervention/treatment
Experimental: Treatment (atezolizumab, tiragolumab)
Patients receive atezolizumab IV over 60 minutes on day 1 and tiragolumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Biological: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

Biological: Tiragolumab
Given IV
Other Names:
  • MTIG7192A
  • RG6058




Primary Outcome Measures :
  1. Objective response rate [ Time Frame: Up to 5 years ]
    A responder is defined as a patient who achieves a best confirmed response of partial response (PR) or complete response (CR) on the study. Response is defined relative to baseline disease. The true proportion of responders will be estimated by the uniform minimum variance unbiased estimate (UMVUE) with one-sided 93% confidence intervals. A separate analysis will be conducted for each by disease cohort without adjusting for multiple hypothesis testing.

  2. Incidence of adverse events [ Time Frame: Up to 5 years ]
    Toxicities for patients will be described separately. Summary statistics will be stratified by age group. For strata not appropriately filled, descriptive statistics will be employed to describe outcomes.


Secondary Outcome Measures :
  1. Pharmacokinetics (PK) of tiragolumab and atezolizumab [ Time Frame: Cycle 1 days 1 & 15; Cycles 2, 3, 4, 8, 12, & 16 day 1 ]
    Serum concentrations of atezolizumab and tiragolumab over time will be reported as individual values and group statistics by age groups and cohorts, when appropriate and as data allow. Exposure data from subjects >= 18 years old will be compared with that attained in previous studies. Atezolizumab and tiragolumab concentration-time profile in Cycle 1 and beyond from Study PEPN2121 will be estimated using a population PK model, as appropriate. Atezolizumab and tiragolumab concentration data may be pooled with data from other studies with adult data using an established population-PK model to derive PK parameters such as clearance, volume of distribution, and area under the curve (AUC), as warranted by the data. Potential correlations of relevant PK parameters with safety or efficacy may be explored.

  2. Immunogenicity [ Time Frame: Up to cycle 16, day 1 ]
    Will be summarized by age groups and cohorts, when appropriate and as data allow. Demographics and relationship between treatment-emergent anti-drug antibody (ADA) status and safety, efficacy, and PK endpoints may be explored if deemed appropriate.



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be >= 12 months of age at the time of study enrollment
  • 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
  • Patients must have either measurable disease per RECIST v1.1 for non-CNS tumors or RANO 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]):

      • Prior allogeneic (non-autologous) bone marrow or stem cell transplant are not allowed
      • 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 initiation of study treatment
  • 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
  • Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 or 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
  • 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 5 months 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 5 months after the last dose of atezolizumab and 90 days after the last dose of tiragolumab, whichever is later
  • Concomitant medications:

    • Corticosteroids
    • 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
    • Anti-graft-versus-host-disease (GVHD) agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
    • 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 initiation of study treatment, unstable arrhythmia, or unstable angina are not eligible
  • Patients who have a major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05286801


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mary F Wedekind Malone Pediatric Early Phase Clinical Trial Network
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT05286801    
Other Study ID Numbers: NCI-2022-01992
NCI-2022-01992 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PEPN2121 ( Other Identifier: Pediatric Early Phase Clinical Trial Network )
PEPN2121 ( Other Identifier: CTEP )
UM1CA228823 ( U.S. NIH Grant/Contract )
First Posted: March 18, 2022    Key Record Dates
Last Update Posted: July 5, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Carcinoma
Neoplasms
Sarcoma
Rhabdoid Tumor
Chordoma
Carcinoma, Medullary
Thyroid Neoplasms
Recurrence
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Disease Attributes
Pathologic Processes
Neoplasms, Connective and Soft Tissue
Neoplasms, Complex and Mixed
Neoplasms, Germ Cell and Embryonal
Neuroectodermal Tumors
Adenocarcinoma
Neoplasms, Ductal, Lobular, and Medullary
Neoplasms, Nerve Tissue
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Endocrine System Diseases
Thyroid Diseases
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors