Advanced Rare Malignant Solid NeoplasmPhase 2NCT05715281
Testing the Combination of Anti-cancer Drugs Atezolizumab and Tiragolumab in People With Advanced Stage Rare Cancers, RARE3 Trial
A Phase 2 study testing Atezolizumab, Biopsy Procedure and Biospecimen Collection in people with Advanced Rare Malignant Solid Neoplasm and Rare Malignant Solid Neoplasm, run by National Cancer Institute (NCI) at 3 sites in United States.
Trial summary
This phase II trial tests how well atezolizumab works in combination with tiragolumab in treating patients with rare solid tumors that may have spread from where they first started to nearby tissue, lymph nodes, or distant parts of the body (advanced stage). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Rare Malignant Solid Neoplasm, Rare Malignant Solid Neoplasm, Refractory Rare Malignant Solid Neoplasm
- What is being tested?
- Atezolizumab, Biopsy Procedure and Biospecimen Collection
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 3 sitesUnited States
- Study dates
- 26 Sep 2023to 21 Nov 2026
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have histologically confirmed rare solid tumors that have progressed on standard therapy or for whom there is no standard of care therapy
- Patients must not be eligible for a higher priority study that would be feasible for them to enroll in, such as a disease specific study of phase 2 or higher or a randomized study. Specifically, patients who are eligible for the Pediatric Early Phase-Clinical Trial Network (PEP-CTN) pediatric trial of atezolizumab and tiragolumab in children, adolescents, and young adults with SWItch/Sucrose Non-Fermentable (SWI/SNF) related BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit B1 (SMARCB1) or SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4 (SMARCA4) deficient tumors should be excluded.
- Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, with at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam)
- Patients must have a tumor site amenable to biopsy
- Age >= 18 years. Because biopsies are mandatory on this trial, patients < 18 years of age are excluded
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
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- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- International normalized ratio (INR) or activated partial thromboplastin time (aPTT) =< 1.5 institutional upper limit of normal (ULN)
- Patients who receive therapeutic anticoagulation therapy should be on a stable dose
- Total bilirubin =< 1.5 x institutional ULN (however, patients with known Gilbert disease who have serum bilirubin level of up to 3 mg/dl may be enrolled)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)
- Creatinine =< 1.5 x institutional ULN OR creatinine clearance levels >= 30 mL/min/1.73 m^2 are permitted as the study agents are not secreted by the kidney
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for more than >= 1 month after treatment of the brain metastases
- Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
- Willingness to provide biopsy samples for research purposes
- Administration of atezolizumab and tiragolumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Female patients of child-bearing potential and male patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of study agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
Who cannot join
- Patients who have had prior monoclonal antibody therapy must have completed that therapy >= 5 weeks (or 3 half-lives of the antibody, whichever is shorter) prior to start of treatment (minimum of 1 week between prior therapy and study enrollment)
- Patients must have recovered from clinically significant adverse events of their most recent cancer immunotherapy to grade 1 or less, (with the exception of alopecia and lymphopenia)
- Patients who are receiving any other investigational agents
- Prior anti-T-cell immunoreceptor with Immunoglobulin (Ig) and Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) domains (TIGIT) therapy is not allowed. However, other prior immune checkpoint inhibitor therapy is permitted
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies (i.e., antibodies with generic names ending in "ximab" or "zumab", respectively) or fusion proteins, not resolved by pre-medication or steroids, leading to subsequent treatment cessation. Patients with a history of allergic reaction to chimeric or humanized antibodies for which symptoms never recurred after subsequent re-challenge may be considered after careful medical history review
- Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone [> 10 mg/day], cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1
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- Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
- The use of inhaled corticosteroids and systemic mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
- Patients with uncontrolled intercurrent illness, that would limit compliance with study requirements
- Pregnant women are excluded from this study because atezolizumab and tiragolumab are investigational agents with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, and because it is not known if tiragolumab can be excreted in human milk, breastfeeding should be discontinued if the mother is treated with atezolizumab
- History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
- Patients with autoimmune hyperthyroid disease not requiring immunosuppressive treatment may be eligible
- Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
- Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
- No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
- Patients with active tuberculosis (TB) are excluded
- Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
- Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
- Patients who have undergone major surgical procedures prior to Cycle 1, Day 1 who have not recovered to ECOG performance status =< 2 (Karnofsky >= 60%)
- Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab
- Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at any time during the study
Trial locations and contacts
3 sites in 1 country.
United States3 sites
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, 20892
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
About this study
Official title: Rapid Analysis and Response Evaluation of Combination Anti-Neoplastic Agents in Rare Tumors (RARE CANCER) Trial: RARE 3 Tiragolumab + Atezolizumab
This phase II trial tests how well atezolizumab works in combination with tiragolumab in treating patients with rare solid tumors that may have spread from where they first started to nearby tissue, lymph nodes, or distant parts of the body (advanced stage). Immunotherapy with monoclonal antibodies, such as atezolizumab and tiragolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The study biopsy takes small pieces of cancer tissue from a tumor. The purpose of these biopsies is to compare the body's immune response against the tumor before and after treatment with the study drugs. Blood samples will also be collected for the study. The researchers will use the samples to learn more about how atezolizumab and tiragolumab work and which patients in the future might be most likely to respond to atezolizumab and tiragolumab. Using atezolizumab in combination with tiragolumab may help to shrink tumors in patients diagnosed with advanced stage rare solid-tumor cancers.
Read the detailed description
PRIMARY OBJECTIVE:
- Determine the proportion of activated cluster of differentiation 8 (CD8+) T cells at baseline and after treatment with atezolizumab and tiragolumab.
SECONDARY OBJECTIVES:
- Determine the objective response rate (ORR) of patients with advanced rare cancers to the combination of atezolizumab and tiragolumab using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 and Immune-Modified (i)RECIST guidelines.
II. Measure progression-free survival (PFS) time (time frame: baseline until disease progression, death, loss to follow-up, initiation of another anti-cancer treatment, withdrawal of consent, or study termination).
III. Measure the proportion of patients with a clinically promising increase in CD8+ T cell infiltration following treatment with atezolizumab and tiragolumab.
EXPLORATORY OBJECTIVES:
- Investigate immune activation markers and the immune composition (regulatory T [Treg], natural killer [NK], B-cells, macrophages, myeloid-derived suppressor cells [MDSC], tumor mutation burden [TMB], microsatellite instability [MSI]) in tumor microenvironment (TME) before and after study treatment.
II. Measure T cell receptor (TCR) signaling in tumor-infiltrating T cells in the TME as well as in circulating T cells in blood before and after study treatment using multiplex immunofluorescence assays (IFAs)-developed by the National Cancer Institute (NCI)-Frederick Pharmacodynamic Assay Development \& Implementation Section (PADIS)-and use these measurements to evaluate the relationship between TCR signaling in circulating T cells and TME.
III. Evaluate potential associations between atezolizumab and tiragolumab activity and tumor genomic alterations, genomic expression, or TMB as determined from genomic analysis of biopsy samples.
IV. Evaluate genomic alterations in cell free deoxyribonucleic acid (DNA) (cfDNA) and their potential association with therapy response or resistance.
- Evaluate the pharmacodynamic effects of the treatment on biomarkers of cell death and epithelial-to-mesenchymal transition (EMT) in tumor tissue and circulating tumor cells (CTCs).
VI. Evaluate markers of immune response and the presence of tertiary lymphoid structures (TLS) in TME at baseline and following atezolizumab plus tiragolumab therapy.
OUTLINE:
Patients receive atezolizumab intravenously (IV) over 60 minutes and tiragolumab IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) at baseline, undergo biopsy at baseline and on study, and undergo computed tomography (CT) and collection of blood samples throughout the study.
After completion of study treatment, patients are followed up for 30 days.
- Conditions
- Advanced Rare Malignant Solid Neoplasm, Rare Malignant Solid Neoplasm, Refractory Rare Malignant Solid Neoplasm
- Being tested
- Atezolizumab, Biopsy Procedure, Biospecimen Collection, Computed Tomography, Echocardiography Test
- Keywords
- Rare Cancers, Solid Tumors, Antineoplastic Agents, Immunological: Immune Checkpoint Inhibitors, PD-L1 Inhibitor, TIGIT Inhibitor, Atezolizumab and Tiragolumab Combination
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtezolizumabBiological
Also called MPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A
Given intravenous (IV)
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo tumor biopsy
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection
Undergo blood sample collection
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo computed tomography (CT) scan
Echocardiography TestProcedure or surgery
Also called EC, Echocardiography, Echocardiogram
Undergo echocardiogram (ECHO)
TiragolumabDrug
Also called RG6058, RO7092284, MTIG-7192A
Given intravenous (IV)
| Study group | Role | What they receive |
|---|---|---|
| Treatment (Atezolizumab, Tiragolumab) | Experimental | Participants receive atezolizumab intravenous (IV) over 60 minutes and tiragolumab IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants also undergo echocardiogram (ECHO) at baseline, undergo biopsy at baseline and on study, and undergo computed tomography (CT) and collection of blood samples throughout the study. Receives: Biological: Atezolizumab; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Drug: Tiragolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent Change of Active Cluster of Differentiation 8 (CD8+) T Cells Infiltrating the Tumor at Baseline and After Treatment With Atezolizumab and Tiragolumab
Activated CD8+ T cells will be detected by multiplex immunofluorescence assays and will be defined by the expression of T cell receptor (TCR) activation (Zeta chain phosphorylation) or phosphorylated Zeta-chain-associated protein kinase 70 (Zap70) Tyrosine at position 493 (pY493); CD8+ cells present within the tumor section that are positive for these markers will be quantified. The change in the active CD8+ T cells density inside the tumor after treatment compared to baseline will be reported.
Measured: At baseline within 28 days before start of treatment and beginning cycle 3 (each cycle is 21 days), an average of 45 days
Secondary outcomes (3)
Objective Tumor Response Rate
Objective response rate (ORR) was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, which involves the following response definitions. Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive Disease (PD): at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progression.
Measured: Baseline until confirmation of progressive disease or response (complete or partial) as defined by RECIST v1.1, up to 11 months
Progression-free Survival (PFS)
PFS is time interval from start of treatment to time of disease progression, death, loss to follow-up, initiation of another anti-cancer treatment, withdrawal of consent, or study termination whichever occurs first. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progression.
Measured: Time from start of treatment to time of disease progression, death, loss to follow-up, initiation of another anti-cancer treatment, withdrawal of consent, or study termination whichever occurs first, assessed up to 1 year
Proportion of Participants With a Clinically Promising Change in Cluster of Differentiation 8 (CD8+) T Cell Infiltration in Tumor Biopsies Following Treatment With Atezolizumab and Tiragolumab
The proportion of participants with a clinically promising change in CD8+ T cell infiltration, defined as more than 1.5 standard deviations (SD) (as measured at baseline) in tumor biopsies following treatment with atezolizumab and tiragolumab, as quantified by multiplex immunofluorescence assay.
Measured: At baseline within 28 days before start of treatment and beginning cycle 3, day 1 (each cycle is 21 days), an average of 45 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Feb 2023
- Study start26 Sep 2023
- Primary completion6 Oct 2025
- Study completion21 Nov 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Advanced Rare Malignant Solid NeoplasmStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Jibran Ahmed, Principal investigator, National Cancer Institute LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05715281
- Sponsor's protocol ID
- NCI-2023-00705
- Other IDs
- NCI-2023-00705, IRB001590, 10561, 10561
- Status last verified
- Sep 2026
- First submitted
- 4 Feb 2023
- Last updated
- 14 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: "National Cancer Institute (NCI) is committed to sharing data in accordance with National Institutes of Health (NIH) policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."