Sponsor: H. Lee Moffitt Cancer Center and Research Institute (other)
Phase: 1/2
Start date: Dec. 19, 2024
Planned enrollment: 31
Zimberelimab (also known as AB122, GLS-010, WBP-3055) is a fully human IgG4 monoclonal antibody targeting PD-1, developed using the OmniRat transgenic platform. It has been evaluated as monotherapy and in combinations across multiple solid tumors and hematologic malignancies. In China, zimberelimab is approved for relapsed/refractory classical Hodgkin lymphoma (r/r cHL; 2021) and for PD-L1–positive recurrent/metastatic cervical cancer (2023); development continues globally where it remains investigational. (pubmed.ncbi.nlm.nih.gov)
Zimberelimab binds PD-1 with high affinity (KD ≈ 1.75×10⁻¹⁰ M), blocking PD‑L1/PD‑L2 interactions and restoring T‑cell activity. Preclinical studies demonstrated effective checkpoint blockade and antitumor activity in PD‑1 humanized mouse models. (pubmed.ncbi.nlm.nih.gov)
Classical Hodgkin lymphoma (r/r cHL; phase II, single arm, n=85): Objective response rate (ORR) 90.6% (95% CI 82.3–95.9); complete response (CR) 32.9%. Twelve‑month PFS and OS were 78% and 99%, respectively. (pubmed.ncbi.nlm.nih.gov)
Cervical cancer (recurrent/metastatic, PD‑L1–positive; phase II, single arm, n=105): ORR 27.6%; disease control rate 55.2%; median PFS 3.7 months; median OS 16.8 months; duration of response not reached at 16.9‑month median follow‑up. Results supported approval in China. (pubmed.ncbi.nlm.nih.gov)
Gastric cancer (AFP‑elevated; phase I, combination with lenvatinib + XELOX; n=9): ORR 33.3%; all patients achieved disease control; median PFS 7.67 months and OS 13.17 months in a small dose‑escalation cohort. (pmc.ncbi.nlm.nih.gov)
Esophageal cancer (first‑line; phase 1a/b, zimberelimab + futibatinib + FP chemotherapy; ASCO 2025 abstract): Confirmed ORR 58.5% (overall ORR 70.7%); disease control rate 92.7%; median PFS 4.9 months; data are preliminary. (ascopubs.org)
Non–small cell lung cancer (NSCLC; PD‑L1‑high): In randomized studies, adding domvanalimab (anti‑TIGIT) to zimberelimab improved outcomes versus zimberelimab alone (e.g., PFS improvement in ARC‑7; OS improvement in ARC‑10 Part 1), though detailed peer‑reviewed data are pending. A phase 3 ARC‑10 design comparing domvanalimab+zimberelimab to pembrolizumab has been described. (investors.gilead.com)
Across studies, zimberelimab’s safety profile is consistent with PD‑1 inhibitors. In r/r cHL, treatment‑related adverse events (TRAEs) occurred in 92.9%; grade ≥3 TRAEs in 28.2% (most common: hepatic lab abnormalities, hyperuricemia, neutropenia); one grade 5 AE (GI infection). (pubmed.ncbi.nlm.nih.gov)
In PD‑L1–positive recurrent/metastatic cervical cancer, any‑grade TRAEs occurred in 78.1% (most common: hypothyroidism 26.7%, anemia 19.0%); grade ≥3 TRAEs in 22.9% in a related analysis. (pubmed.ncbi.nlm.nih.gov)
In combinations, early‑phase studies reported manageable safety without new signals (e.g., lenvatinib+chemotherapy in AFP‑elevated gastric cancer; futibatinib+chemotherapy in esophageal cancer). (pmc.ncbi.nlm.nih.gov)
China approvals: r/r cHL (August 2021) and PD‑L1–positive recurrent/metastatic cervical cancer (September 2023). Outside China, zimberelimab is investigational. (gilead.com)
Partnerships: The antibody (GLS‑010) originated with Gloria Biosciences/WuXi Biologics and was licensed to Arcus Biosciences for development ex‑China. Ongoing programs include combinations with domvanalimab (anti‑TIGIT) and etrumadenant (A2a/A2b antagonist). (wuxibiologics.com)
Notes: Reported combination benefits in NSCLC (ARC‑7/ARC‑10) are from company communications and conference disclosures; peer‑reviewed publications are awaited for full details. (investors.gilead.com)
Last updated: Oct 2025
Goal: Evaluate safety and preliminary efficacy of combining stereotactic radiosurgery (SRS) with sacituzumab govitecan (SG) and the PD-1 inhibitor zimberelimab versus SG alone in metastatic triple-negative breast cancer (mTNBC) patients with brain metastases.
Patients: Adults ≥18 years with biopsy-proven triple-negative breast cancer (ER/PR ≤10% by IHC) and MRI-confirmed brain metastases, ECOG 0–2, eligible for SRS to intact metastases or postoperative cavities, with measurable intracranial disease per RANO-BM. Prior taxane and anthracycline required. Stable or no steroids (≤8 mg/day dexamethasone) allowed; prior SRS/FSRT permitted if current measurable lesions were not previously irradiated. Key exclusions include leptomeningeal disease, active autoimmune disease requiring systemic therapy, prior pneumonitis/ILD requiring steroids, significant cardiac disease, active infections (including uncontrolled HBV/HCV, HIV with detectable viral load), active IBD, need for supplemental oxygen, pregnancy or breastfeeding, recent major surgery without recovery, recent anticancer therapy without recovery, and prior topoisomerase I inhibitors in the setting of brain metastases.
Design: Phase I/II, non-randomized study assessing safety (dose-limiting neurologic toxicity) followed by efficacy. Allocation is not applicable; comparison to SG alone is planned contextually but not as a randomized parallel arm within this protocol.
Treatments: Experimental regimen: SRS to brain lesions or postoperative bed, followed one week later by sacituzumab govitecan 10 mg/kg IV on days 1 and 8 plus zimberelimab 360 mg IV on day 1 of each 21-day cycle; imaging every 9 weeks. Sacituzumab govitecan is an antibody–drug conjugate targeting Trop-2 linked to the topoisomerase I inhibitor SN-38; it is standard in pretreated mTNBC with demonstrated improvements in response rate and survival versus chemotherapy. Zimberelimab is a fully human IgG4 monoclonal antibody against PD-1 that blocks PD-1/PD-L1/PD-L2 interactions to restore antitumor T-cell activity. Across phase I/II studies in solid tumors and lymphoma, zimberelimab has shown objective responses in the 20–30% range depending on indication with a safety profile consistent with PD-1 inhibitors, including mostly grade 1–2 immune-related toxicities (e.g., hypothyroidism, anemia).
Outcomes: Primary endpoints: Phase I—rate of grade ≥3 neurologic toxicity during the DLT window, including symptomatic radionecrosis, grade ≥3 headaches, memory impairment, or new-onset grade ≥3 seizures; Phase II—progression-free survival (PFS) up to 12 months. Secondary endpoints: intracranial PFS (RANO), extracranial PFS (irRECIST), overall survival, local brain control of irradiated lesions, and distant brain control (new lesions outside irradiated fields), assessed up to 33 months.
Burden on patient: Moderate to high. Patients undergo SRS, IV infusions on days 1 and 8 every 21 days, and zimberelimab on day 1, necessitating frequent clinic visits. Imaging every 9 weeks and neurological assessments add visit time, and close monitoring for immune-related events and SG-related toxicities (e.g., neutropenia, diarrhea) may require additional labs and potential supportive care visits. No noted serial pharmacokinetic blood draws or mandatory biopsies reduce intensity compared with some phase I studies, but the combination of radiation, dual IV therapies, and frequent assessments remains more burdensome than standard single-agent therapy.
Last updated: Oct 2025
Inclusion Criteria:
* Provision of signed and dated Informed Consent Form (ICF).
* Stated willingness to comply with all study procedures and availability for the duration of the study.
* Age ≥ 18.
* Triple negative breast cancer; to fulfill the requirement of triple negative disease, a breast cancer must express (≤ 10%), by immunohistochemistry (IHC), of the hormone receptors (estrogen receptor \[ER\] and progesterone receptor \[PR\]).
* Breast cancer as documented by extracranial tumor biopsy with brain metastases documented from MRI brain imaging or intracranial surgical pathology.
* Eligible for Stereotactic radiosurgery (SRS) to brain metastases or to the post-operative bed.
* Measurable brain disease per RANO-BM criteria1 that can be measured in at least one dimension as ≥ 0.5 cm for both intact brain metastases and post-operative cavities.
* Maximum diameter of the largest intact brain metastases ≤ 4 cm.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
* Symptomatic patients having undergone surgery or on stable doses of steroids ≤ 8 mg/day dexamethasone will be enrolled.
* Prior treatment with taxane based chemotherapy with anthracyclines.
* Individuals with prior SRS/fractioned stereotactic radiotherapy (FSRT) treatment will be allowed if active measurable disease has not previously been treated with radiation therapy.
* Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the administration of each dose of study agent.
* Male and female patients of childbearing potential who engage in heterosexual intercourse must agree to use specified method(s) of contraception.
Exclusion Criteria:
* Presence of leptomeningeal disease.
* Women who are pregnant or breastfeeding.
* Known history of HIV-1 or 2 with detectable viral load.
* Active, known, or suspected autoimmune disease. Patients with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded. Exceptions are patients with type I diabetes mellitus, hypothyroidism only requiring thyroid replacement therapy, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
* History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Met any of the following criteria for cardiac disease:
1. Myocardial infarction or unstable angina pectoris within 6 months of enrollment
2. History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation
3. New York Heart Association (NYHA) Class III or greater congestive heart failure or left ventricular ejection fraction of \< 40%
* Any patient requiring supplemental oxygen therapy.
* Have an active serious infection requiring antibiotics.
* Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or GI perforation within 6 months of enrollment.
* Patients with prior history of non-breast cancer malignancies are excluded except in the case of adequately treated basal cell cancer, squamous cell skin cancer, chronic lymphocytic leukemia, or other cancers in remission not receiving active therapy for ≥ 2 years.
* Known medical condition that, in the investigator's opinion, would increase the risk associated with study participation or study drug(s) administration or that would interfere with the interpretation of safety results.
* Major surgery or significant traumatic injury that has not been recovered from by 14 days before the initiation of study drug.
* Have had a prior anticancer biologic agent within 4 weeks prior to enrollment or have had prior chemotherapy, targeted small molecule therapy within 2 weeks prior to enrollment and have not recovered.
* Have previously received topoisomerase 1 inhibitors in the setting of brain metastases.
* Use of other investigational drugs (drugs not marketed for any indication) within 28 days or 5 half-lives (whichever is longer) of first dose of study drug.
* Have active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). In patients with a history of HBV or HCV, patients with detectable viral loads will be excluded.
* History of allergy or hypersensitivity to any of the study drugs or study drug components.
* Prisoners or individuals who are involuntarily incarcerated.
* Individuals who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
Tampa, Florida, 33612, United States
[email protected] / 813-745-6911
Status: Recruiting