Ivonescimab for Brain Tumors
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must not be taking: Anticoagulants, Dexamethasone
Disqualifiers: Pregnancy, Hypertension, Cardiac disease, others
No Placebo Group
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?The goal of Phase 1 of this clinical research study is to find the highest tolerable dose and the recommended Phase 2 dose of ivonescimab that can be given to patients who have recurrent glioblastoma.
The goal of Phase 2 of this clinical research study is to learn if the recommended Phase 2 dose of ivonescimab found in Phase 1 can help to control the disease.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you are taking dexamethasone at more than 2mg daily or need therapeutic anticoagulant therapy, you may not be eligible to participate.
What data supports the effectiveness of the drug Ivonescimab for brain tumors?
Ivonescimab, which targets proteins involved in tumor growth, has shown promise in treating advanced lung cancer, and similar treatments targeting these proteins have been effective in other cancers, suggesting potential benefits for brain tumors.
12345What safety data exists for Ivonescimab (AK-112, Evoximab, PD-1/VEGF bi-specific antibody) in humans?
In a Phase 1b study, Ivonescimab was tested for safety in patients with advanced lung cancer, and the study aimed to evaluate its safety and effectiveness. While specific safety outcomes are not detailed in the abstract, the study's focus on safety suggests that it was a primary consideration in the research.
13678What makes the drug Ivonescimab unique for treating brain tumors?
Ivonescimab is unique because it is a bi-specific antibody that targets both PD-1 (a protein that helps keep the immune system in check) and VEGF (a protein that promotes blood vessel growth), potentially offering a dual mechanism to fight brain tumors by enhancing immune response and inhibiting tumor blood supply.
59101112Eligibility Criteria
This trial is for individuals with recurrent glioblastoma, a type of brain tumor. Participants should have experienced the return of their cancer after previous treatments. Specific eligibility criteria are not provided, but typically include factors like age, overall health status, and the absence of certain medical conditions.Inclusion Criteria
I am 18 years old or older.
I can care for myself but may need occasional assistance.
Recurrent supratentorial Glioblastoma that has progressed following standard therapy; patients must have previously been treated with radiation with or without temozolomide. Patients will be eligible at first or second recurrence. Patients must be greater than 12 weeks from completion of initial chemoradiation at the time of progression, with exceptions for patients with biopsy-confirmed recurrent disease prior to this time window. Diagnosis of Glioblastoma IDH-wildtype, WHO Grade 4 consistent with WHO CNS 2021 criteria. Measurable or evaluable disease per RANO criteria. A baseline MRI Brain no more than 14 days prior to study enrollment. Adequate Organ Function as per specified criteria. Female patients of childbearing age must have negative serum pregnancy test results before randomization or per region-specific guidance documented in the informed consent and a negative urine pregnancy test on the day of first dose prior to dosing. Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 120 days after the last dose of the ivonescimab. Male patients of childbearing potential having sex with a female partner of childbearing potential must agree to use an effective method of contraception from the beginning of screening until Day 120 after the last dose of ivonescimab. Ability to understand and willingness to sign informed consent form prior to the initiation of study and any study procedures.
Exclusion Criteria
Major surgical procedures or serious trauma within 4 weeks prior to randomization, or plans for major surgical procedures within 4 weeks after the first dose. Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to randomization. Currently pregnant or breastfeeding. History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomization. Current hypertension with specified blood pressure values. Is receiving dexamethasone >2mg daily, or the corticosteroid equivalent thereof. History of major diseases before randomization as specified. History of other malignancy diagnosed or requiring treatment within the past 3 years prior to enrolment, with exceptions. History of prior treatment with specified agents or therapies. Has known leptomeningeal disease, gliomatosis cerebri, extracranial disease, or multicentric disease. Uncontrolled seizures after best medical therapy or other neurological conditions. History of clinically significant autoimmune disease including but not limited to specified conditions. Has contraindication for undergoing MRI scans or receiving MRI contrast. History of stroke or TIA within 6 months prior to study enrolment. Imaging during the screening period shows that the patient has radiologically documented evidence of major blood vessel invasion or encasement by cancer, or radiographic evidence of intratumor cavitation.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1 Treatment
Participants receive ivonescimab to determine the highest tolerable dose and recommended Phase 2 dose
12 weeks
Phase 2 Treatment
Participants receive the recommended Phase 2 dose of ivonescimab to assess disease control
24 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study is testing ivonescimab to determine the highest dose patients can tolerate without severe side effects (Phase I) and to see if this dose can help control recurrent glioblastoma (Phase II).
1Treatment groups
Experimental Treatment
Group I: Treatment with IvonescimabExperimental Treatment1 Intervention
Participants will be enrolled in either Phase 1 or Phase 2 depending on when they join the study.
Ivonescimab is already approved in China for the following indications:
🇨🇳 Approved in China as Ivonescimab for:
- Locally advanced or metastatic non-squamous NSCLC
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The University of Texas M. D. Anderson Cancer CenterHouston, TX
The University of Texas MD Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
Summit Therapeutics Sub, IncCollaborator
References
A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC. [2023]This study (HARMONi-5) aimed to evaluate the safety and efficacy of ivonescimab (a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor) as first- or second-line monotherapy in patients with advanced immunotherapy-naive NSCLC.
Ipilimumab plus nivolumab in patients with symptomatic melanoma brain metastasis requiring corticosteroids. [2023]To investigate the efficacy of PD-1-directed antibody-based therapy in patients with symptomatic melanoma brain metastases (MBM) and concurrent treatment with corticosteroids.
First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1). [2023]The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.
Icrucumab, a fully human monoclonal antibody against the vascular endothelial growth factor receptor-1, in the treatment of patients with advanced solid malignancies: a Phase 1 study. [2021]IMC-18F1 (icrucumab), a human monoclonal antibody against vascular endothelial growth factor receptor-1 (VEGFR-1), potently inhibits ligand-dependent phosphorylation of VEGFR-1 and downstream signaling, making icrucumab an attractive candidate for antitumor activity.
Phase II study of single-agent bevacizumab in Japanese patients with recurrent malignant glioma. [2022]This single-arm, open-label, Phase II study evaluated the efficacy and safety of single-agent bevacizumab, a monoclonal antibody against vascular endothelial growth factor, in Japanese patients with recurrent malignant glioma.
First-in-human, phase I study of AK109, an anti-VEGFR2 antibody in patients with advanced or metastatic solid tumors. [2023]Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in antiangiogenesis which has been an essential strategy for cancer treatment. We report the first-in-human study of AK109, a novel anti-VEGFR2 monoclonal antibody, to characterize the safety profile and pharmacokinetics/pharmacodynamics (PK/PD) properties, and explore the preliminary antitumor efficacy in patients with solid tumors.
Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. [2022]We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer.
Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma. [2021]Evofosfamide (Evo or TH302) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard, which has shown safety and signals of efficacy in a prior phase 1 study in recurrent glioblastoma. We performed a dual center single-arm Phase II study to expand on the safety and efficacy of Evo plus bevacizumab in bevacizumab refractory glioblastoma. 33 patients with bevacizumab refractory GBM received Evo 670 mg/m2 in combination with Bevacizumab 10 mg/kg IV every 2 weeks. Assessments included adverse events, response, and survival. Median age of patients was 47 (range 19-76) and 24 (69%) were male. At the time of study entry, 9 (26%) had ongoing corticosteroid use. ECOG performance status was 0 or 1 in 83% of patients. Patients were mostly heavily pretreated with 77% have three or more prior regimens. A total of 12 patients (36%) suffered grade 3-4 drug associated adverse event (AE); no grade 5 AE were reported. Of the 33 evaluable patients, best response was PR in 3 (9%), SD in 14 (43%), and PD in 16 (48%) with responses confirmed by a second reviewer. Median time to progression of disease was 53 days (95% CI 42-113) and Median time to death was 129 days (95% CI 86-199 days). Progression free survival at 4 months (PFS-4) on Evo-Bev was 31%, which was a statistically significant improvement over the historical rate of 3%. The median overall survival of patients receiving Evo-Bevacizumab was 4.6 months (95% CI 2.9-6.6). The progression free survival of patients on Evo-Bevacizumab met the primary endpoint of progression free survival at 4 months of 31%, although the clinical significance of this may be limited. Given the patient population and Phase II design, these clinical outcomes will need further validation.
Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity. [2018]Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27(KIP1) and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.
Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases. [2018]Endothelial proliferation has been recognized as a marker of high-grade or aggressive glioma. Bevacizumab is a humanized immunoglobulin G1 monoclonal antibody to vascular endothelial growth factor that has been shown to have activity in malignant gliomas when combined with irinotecan. The authors report on a case series of 13 patients with recurrent heavily pretreated malignant glioma that was treated with the combination of bevacizumab and irinotecan.
Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study. [2019]Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM.
Inhibition of glioblastoma growth in a highly invasive nude mouse model can be achieved by targeting epidermal growth factor receptor but not vascular endothelial growth factor receptor-2. [2020]Major shortcomings of traditional mouse models based on xenografted human glioblastoma cell lines are that tumor cells do not invade and that genetic alterations, such as amplification of the epidermal growth factor receptor (EGFR) gene, are not maintained. Such models are thus of limited value for preclinical studies. We established a highly invasive model to evaluate the effect of antibodies against EGFR (cetuximab) and vascular endothelial growth factor receptor-2 (antibody DC101).