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 WBP-3055, GLS-010, or AB122, is a fully human anti-PD-1 monoclonal antibody developed for the treatment of various cancers. It has been evaluated in multiple clinical trials, demonstrating efficacy and safety across different malignancies.
Zimberelimab targets the programmed death-1 (PD-1) receptor, a checkpoint protein on T cells that, when engaged by its ligands, inhibits T-cell activation. By blocking PD-1, zimberelimab enhances the immune system's ability to detect and destroy cancer cells.
Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL):
In the Phase II YH-S001-04 trial, 75 patients with R/R cHL received zimberelimab 240 mg every two weeks. With a median follow-up of 38 months, the objective response rate (ORR) was 91.6% (95% CI, 83.8-95.9). The median progression-free survival (PFS) was 23.6 months, and the 3-year overall survival (OS) rate was 94.0% (95% CI, 85.9-97.4). (pubmed.ncbi.nlm.nih.gov)
Recurrent or Metastatic Cervical Cancer (R/M CC):
A pivotal Phase II study (YH-S001-05) evaluated zimberelimab monotherapy in 90 patients with R/M CC. The ORR was 27.8%, with 5.6% achieving complete remission and 22.2% partial remission. The median PFS was 3.7 months, and the median OS was 16.8 months. (pipelinereview.com)
Advanced Cervical Cancer Post-ICI Therapy:
In a Phase II trial, 30 patients with advanced cervical cancer who had progressed after prior immune checkpoint inhibitor (ICI) therapy received zimberelimab combined with lenvatinib. The ORR was 33.3%, with a disease control rate of 96.7%. The median PFS was 7.1 months. (trial.medpath.com)
Third-Line Metastatic Colorectal Cancer (mCRC):
The ARC-9 Phase 1b/2 study assessed the combination of etrumadenant, zimberelimab, FOLFOX chemotherapy, and bevacizumab (EZFB) in 75 patients with third-line mCRC. The median OS was 19.7 months, compared to 9.5 months for the control group receiving regorafenib. The median PFS was 6.2 months versus 2.1 months, respectively. The confirmed ORR was 17.3% for EZFB, compared to 2.7% for regorafenib. (stocktitan.net)
Across clinical trials, zimberelimab has demonstrated a favorable safety profile. In the YH-S001-04 trial for R/R cHL, no serious adverse events with an incidence greater than 5% were reported. (pubmed.ncbi.nlm.nih.gov) In the ARC-9 study for third-line mCRC, the EZFB regimen had a safety profile consistent with the known profiles of each individual component, without unexpected toxicities. A higher percentage of patients treated with regorafenib (17%) had treatment-emergent adverse events leading to discontinuation compared to those treated with EZFB (5%). (stocktitan.net)
Last updated: Apr 2025
Goal: To evaluate the safety and efficacy of sacituzumab govitecan and zimberelimab in combination with stereotactic radiosurgery (SRS) for patients with metastatic triple-negative breast cancer (TNBC) with brain metastases, compared to sacituzumab govitecan alone.
Patients: Adult patients (≥18 years) with metastatic triple-negative breast cancer and measurable brain metastases, ECOG 0-2, who are eligible for SRS. Patients may have prior taxane and anthracycline treatment and prior SRS/FSRT if lesions included in the trial have not previously been irradiated. Excludes those with leptomeningeal disease, significant uncontrolled comorbidities, active autoimmune disease requiring immunosuppressive therapy, and prior topoisomerase I inhibitor exposure for brain metastases.
Design: Single-arm, open-label, non-randomized phase I/II trial with a dose-escalation (safety) phase followed by an expansion (efficacy) phase. All patients receive the experimental combination therapy. Participants are closely monitored for toxicity, response, and progression.
Treatments: All patients receive stereotactic radiosurgery to brain metastases, followed by sacituzumab govitecan (10mg/kg IV on days 1 and 8 of a 21-day cycle) and zimberelimab (360 mg IV on day 1 every 3 weeks). Zimberelimab is a fully human anti-PD-1 monoclonal antibody that blocks PD-1/PD-L1 interaction, reactivating anti-tumor immune responses. In prior trials for cervical cancer and other tumors, zimberelimab has demonstrated objective response rates in the 20–28% range and a safety profile consistent with other PD-1 inhibitors, the most common adverse events being grade 1-2 hypothyroidism and anemia. Sacituzumab govitecan is an antibody-drug conjugate targeting Trop-2, already approved for metastatic TNBC.
Outcomes: Primary endpoints include safety (phase I: neurologic toxicity graded by CTCAE v5, focusing on grade 3 or higher events) and progression-free survival (PFS, phase II). Secondary outcomes are intracranial and extracranial PFS, overall survival (OS), local and distant brain control, all tracked up to 33 months. Neurologic adverse events of interest include symptomatic radionecrosis, grade ≥3 headache, memory impairment, and new-onset seizures.
Burden on patient: Patients will undergo SRS, receive intravenous therapies every three weeks, and have follow-up with brain imaging at nine-week intervals. Standard laboratory monitoring and clinical assessments will be required, and neurologic assessments will be emphasized early in the trial. There is no mention of extra mandatory biopsies or intensive pharmacokinetic blood draws, but patients will require regular visits for imaging and infusion therapy. The overall burden is moderate, similar to other early-phase combination trials for brain metastases, primarily due to the need for frequent clinical, imaging, and neurologic monitoring.
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