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

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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.

Study Overview

Start Date
November 17, 2022
Completion Date
September 30, 2025
Enrollment
86
Date Posted
March 18, 2022
Accepts Healthy Volunteers?
No
Gender
All

Locations

Full Address
Children's Hospital of Alabama
Birmingham, Alabama 35233, United States

Children's Hospital Los Angeles
Los Angeles, California 90027, United States

Children's Hospital of Orange County
Orange, California 92868, United States

Lucile Packard Children's Hospital Stanford University
Palo Alto, California 94304, United States

UCSF Medical Center-Mission Bay
San Francisco, California 94158, United States

Children's Hospital Colorado
Aurora, Colorado 80045, United States

Children's National Medical Center
Washington, District of Columbia 20010, United States

Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia 30322, United States

Lurie Children's Hospital-Chicago
Chicago, Illinois 60611, United States

Riley Hospital for Children
Indianapolis, Indiana 46202, United States

Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland 21287, United States

National Institutes of Health Clinical Center
Bethesda, Maryland 20892, United States

C S Mott Children's Hospital
Ann Arbor, Michigan 48109, United States

University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota 55455, United States

Children's Mercy Hospitals and Clinics
Kansas City, Missouri 64108, United States

Washington University School of Medicine
Saint Louis, Missouri 63110, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York 10032, United States

Memorial Sloan Kettering Cancer Center
New York, New York 10065, United States

New York Medical College
Valhalla, New York 10595, United States

Duke University Medical Center
Durham, North Carolina 27710, United States

Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio 45229, United States

Nationwide Children's Hospital
Columbus, Ohio 43205, United States

Children's Hospital of Philadelphia
Philadelphia, Pennsylvania 19104, United States

Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania 15224, United States

Saint Jude Children's Research Hospital
Memphis, Tennessee 38105, United States

Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee 37232, United States

UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas 75390, United States

Cook Children's Medical Center
Fort Worth, Texas 76104, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas 77030, United States

Primary Children's Hospital
Salt Lake City, Utah 84113, United States

Seattle Children's Hospital
Seattle, Washington 98105, United States

Children's Hospital of Wisconsin
Milwaukee, Wisconsin 53226, United States

Queensland Children's Hospital
South Brisbane, Queensland 4101, Australia

Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec H3T 1C5, Canada

Eligibility

Minimum Age (years)
1
Eligibility Criteria
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
Note: Documentation of the institutional IHC or molecular testing must be uploaded 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 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

Study Contact Info

Study Contact Name
Site Public Contact; Girish Dhall; Fariba Navid; Josephine H. Haduong; Lianna J. Marks; Kieuhoa T. Vo; Margaret E. Macy; AeRang Kim; Jason R. Fangusaro; Elizabeth A. Sokol; Melissa K. Bear; Christine A. Pratilas; Mary F. Wedekind Malone; Steven G. DuBois; Rajen Mody; Emily G. Greengard; Kevin F. Ginn; Shalini Shenoy; Luca Szalontay; Julia L. Glade Bender; Mitchell S. Cairo; Lars M. Wagner; Joseph G. Pressey; Bhuvana A. Setty; Theodore W. Laetsch; Andrew Bukowinski; Jessica Gartrell; Scott C. Borinstein; Laura J. Klesse; Kelly L. Vallance; Jennifer H. Foster; Matthew Dietz; Katherine G. Tarlock; Sarah Rumler; Christopher J. Fraser; Monia Marzouki

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Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors 0 reviews

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Other Details

FDA Regulated Drug?
Yes
FDA Regulated Device?
No
Detailed Description
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, 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 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.
NCTid (if applicable)
NCT05286801