REGN5668 + Cemiplimab/REGN4018 for Ovarian Cancer
Recruiting in Palo Alto (17 mi)
+35 other locations
Age: 18+
Sex: Female
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Regeneron Pharmaceuticals
Must not be taking: Immunotherapy, Corticosteroids
Disqualifiers: Recent cancer, Autoimmune, Brain tumor, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study is researching an investigational drug called REGN5668. Participants will receive additional investigational drugs in combination with REGN5668. These additional drugs include cemiplimab or REGN4018 (with or without sarilumab).
The main purposes of this study are to:
* Learn about the safety and profile of any side effects from the study drugs and to determine the highest, safe dose that can be given to participants with ovarian cancer or cancer of the uterus
* Look for signs that the study drugs can treat ovarian cancer or cancer of the uterus
This study has 2 parts. The purpose of Part 1 (Escalation) to find the highest, safe dose of the study drug(s). The purpose of Part 2 (Expansion) is to use the doses chosen in Part 1. Participants with cancer of the uterus will only participate in Part 2.
The study is looking at several other research questions, including:
* Side effects that may be experienced by participants taking REGN5668 alone and/or in combination with cemiplimab or REGN4018
* How REGN5668 works in the body either alone and/or in combination with cemiplimab or REGN4018
* How much of the study drugs (REGN5668, cemiplimab, REGN4018) are in the blood
* To see if REGN5668 in combination with cemiplimab or REGN4018 works to treat cancer
* To find out how safe, tolerable, and effective in mitigating Cytokine Release Syndrome (CRS) sarilumab pretreatment is when given before REGN4018
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on continuous corticosteroid therapy, you may need to stop it at least one week before starting the study drugs.
What data supports the effectiveness of the drug REGN5668 + Cemiplimab/REGN4018 for ovarian cancer?
The bispecific antibody REGN4018, which is part of the treatment, has shown promising results in preclinical studies by activating immune cells to target ovarian cancer cells, leading to tumor growth inhibition. Additionally, combining REGN4018 with an anti-PD-1 antibody, similar to Cemiplimab, enhanced its effectiveness in these studies.
12345What makes the drug REGN5668 + Cemiplimab/REGN4018 unique for ovarian cancer?
This drug is unique because it uses bispecific antibodies, like REGN4018, to target MUC16, a protein highly expressed on ovarian cancer cells, and CD3 on T cells, effectively bridging and activating the immune system to attack the cancer cells. This approach is innovative compared to traditional chemotherapy, offering a new immunotherapy strategy for treating ovarian cancer.
13678Eligibility Criteria
This trial is for adult women with advanced ovarian, fallopian tube, or peritoneal cancer who've had at least one platinum-based therapy. They should have a life expectancy of over 3 months, good organ and bone marrow function, and higher than normal CA-125 levels. Exclusions include ongoing steroid use, recent anti-cancer immunotherapy or MUC16-targeted therapy, more than three prior chemo treatments for certain conditions (expansion phase), significant autoimmune disease requiring treatment within the last 5 years, active brain tumors/CNS metastases/spinal cord compression, or serious heart disease.Inclusion Criteria
My organs and bone marrow are functioning well.
I am fully active or restricted in physically strenuous activity but can do light work.
You are expected to live for at least 3 more months.
+2 more
Exclusion Criteria
I have had another cancer in the last 5 years that is getting worse or might come back.
I have an untreated brain tumor or cancer that has spread to my brain or spinal cord.
I am on continuous corticosteroid therapy as per my treatment plan.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
The purpose of Part 1 (Escalation) is to find the highest, safe dose of the study drug(s).
6 weeks
Multiple visits for dose escalation and monitoring
Dose Expansion
The purpose of Part 2 (Expansion) is to use the doses chosen in Part 1.
Up to 5 years
Regular visits for treatment and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests REGN5668 alone and in combination with either cemiplimab or REGN4018 to find safe dosages (Dose Escalation Phase) and to evaluate preliminary effectiveness based on tumor response rates (Dose Expansion Phase). It also examines safety profiles, pharmacokinetics (how the body processes the drugs), changes in CA-125 levels after treatment with these combinations.
2Treatment groups
Experimental Treatment
Group I: Module 2Experimental Treatment3 Interventions
REGN5668 and REGN4018
Group II: Module 1Experimental Treatment2 Interventions
REGN5668 and cemiplimab
Cemiplimab is already approved in European Union, United States, Canada, Brazil for the following indications:
🇪🇺 Approved in European Union as Libtayo for:
- Cutaneous squamous cell carcinoma (CSCC)
- Non-small cell lung cancer (NSCLC)
🇺🇸 Approved in United States as Libtayo for:
- Cutaneous squamous cell carcinoma (CSCC)
- Basal cell carcinoma (BCC)
- Non-small cell lung cancer (NSCLC)
🇨🇦 Approved in Canada as Libtayo for:
- Cutaneous squamous cell carcinoma (CSCC)
- Non-small cell lung cancer (NSCLC)
🇧🇷 Approved in Brazil as Libtayo for:
- Cutaneous squamous cell carcinoma (CSCC)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Regeneron Research SiteChicago, IL
Regeneron Research SiteBoston, MA
University of PennsylvaniaPhiladelphia, PA
City of Hope Comprehensive Cancer CenterDuarte, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Regeneron PharmaceuticalsLead Sponsor
References
Overcoming the challenges of drug development in platinum-resistant ovarian cancer. [2023]The definition of "platinum-resistant ovarian cancer" has evolved; it now also reflects cancers for which platinum treatment is no longer an option. Standard of care for platinum-resistant ovarian cancer is single-agent, non-platinum chemotherapy with or without bevacizumab, which produces modest response rates, with the greatest benefits achieved using weekly paclitaxel. Several recent phase 3 trials of pretreated patients with prior bevacizumab exposure failed to meet their primary efficacy endpoints, highlighting the challenge in improving clinical outcomes among these patients. Combination treatment with antiangiogenics has improved outcomes, whereas combination strategies with immune checkpoint inhibitors have yielded modest results. Despite extensive translational research, there has been a lack of reliable and established biomarkers that predict treatment response in platinum-resistant ovarian cancer. Additionally, in the platinum-resistant setting, implications for the time between the penultimate dose of platinum therapy and platinum retreatment remain an area of debate. Addressing the unmet need for an effective treatment in the platinum-resistant setting requires thoughtful clinical trial design based on a growing understanding of the disease. Recent cancer drug approvals highlight the value of incorporating molecular phenotypes to better define patients who are more likely to respond to novel therapies. Clinical trials designed per the Gynecologic Cancer InterGroup recommendations-which advocate against relying solely upon the platinum-free interval-will help advance our understanding of recurrent ovarian cancer response where platinum rechallenge in the platinum-resistant setting may be considered. The inclusion of biomarkers in clinical trials will improve patient stratification and potentially demonstrate correlations with biomarker expression and duration of response. With the efficacy of antibody-drug conjugates shown for the treatment of some solid and hematologic cancers, current trials are evaluating the use of various novel conjugates in the setting of platinum-resistant ovarian cancer. Emerging novel treatments coupled with combination trials and biomarker explorations offer encouraging results for potential strategies to improve response rates and prolong progression-free survival in this population with high unmet need. This review outlines existing data from contemporary clinical trials of patients with platinum-resistant ovarian cancer and suggests historical synthetic benchmarks for non-randomized trials.
Atezolizumab and Bevacizumab Attenuate Cisplatin Resistant Ovarian Cancer Cells Progression Synergistically via Suppressing Epithelial-Mesenchymal Transition. [2020]The AURELIA trial demonstrated that adding Bevacizumab to chemotherapy significantly improved progression-free survival (PFS) for platinum resistant recurrent ovarian cancer. Recently, immunotherapy also presented potential anti-tumor effects in several malignant solid tumors. This study aimed to investigate whether combining anti-PD-L1 Atezolizumab with BEV may have a synergistic effect and enhance the efficacy of both treatments in cisplatin resistant epithelial ovarian cancer (CREOC). We retrospectively analyzed 124 epithelial ovarian cancer (EOC) patients from Gynecologic Oncology Department of Tianjin Cancer Hospital between January 2013 and June 2018, who all were diagnosed with cisplatin resistance due to progressing <6 months after completing platinum-based therapy. Based on responding to at least 2 cycles of Bevacizumab-containing chemotherapy (BC), these Patients were divided into BC response group and BC non-response group. Immunohistochemistry was used to detect that PD-L1 expression and tumor angiogenesis-related proteins (VEGF and Semaphorin4D) in tissues from 124 patients with CREOC. The positive expressions of PD-L1, VEGF, and Semaphorin4D (SEMA4D) were found in 58.73, 50.79, and 71.43% of the 63 cases CREOC tissues with BC response, respectively, which were significantly higher than that in the 61 cases BC non-response group (P < 0.05). PD-L1 expression correlated with SEMA4D and VEGF positively (r = 0.344 and 0.363, P < 0.001). Over-expressions of PD-L1, VEGF and SEMA4D are associated with more malignant clinicopathologic characteristics of CREOC Patients. In survival analysis, patients' response to BC was the independent factor for evaluation of PFS and overall survival (OS). Cell functional assays showed that Atezolizumab in combination with Bevacizumab inhibited the proliferation, migration, and invasion of cisplatin resistant ovarian cancer cell line A2780cis in vitro synergistically, which maybe associate with Bevacizumab suppressing the epithelial-mesenchymal transition (EMT) and PD-L1 expression by targeting STAT3. Furthermore, Bevacizumab and Atezolizumab induced synergistic anti-tumor effect in vivo. These findings suggest a novel therapeutic strategy for cisplatin resistant recurrent EOC and its mechanism warrants further study.
A Mucin 16 bispecific T cell-engaging antibody for the treatment of ovarian cancer. [2020]Advanced ovarian cancer is frequently treated with combination chemotherapy, but high recurrence rates show the need for therapies that can produce durable responses and extend overall survival. Bispecific antibodies that interact with tumor antigens on cancer cells and activating receptors on immune cells offer an innovative immunotherapy approach. Here, we describe a human bispecific antibody (REGN4018) that binds both Mucin 16 (MUC16), a glycoprotein that is highly expressed on ovarian cancer cells, and CD3, thus bridging MUC16-expressing cells with CD3+ T cells. REGN4018 induced T cell activation and killing of MUC16-expressing tumor cells in vitro. Binding and cytotoxicity of REGN4018 in vitro were minimally affected by high concentrations of CA-125, the shed form of MUC16, which is present in patients. In preclinical studies with human ovarian cancer cells and human T cells in immunodeficient mice, REGN4018 potently inhibited growth of intraperitoneal ovarian tumors. Moreover, in a genetically engineered immunocompetent mouse expressing human CD3 and human MUC16 [humanized target (HuT) mice], REGN4018 inhibited growth of murine tumors expressing human MUC16, and combination with an anti-PD-1 antibody enhanced this efficacy. Immuno-PET imaging demonstrated localization of REGN4018 in MUC16-expressing tumors and in T cell-rich organs such as the spleen and lymph nodes. Toxicology studies in cynomolgus monkeys showed minimal and transient increases in serum cytokines and C-reactive protein after REGN4018 administration, with no overt toxicity. Collectively, these data demonstrate potent antitumor activity and good tolerability of REGN4018, supporting clinical evaluation of REGN4018 in patients with MUC16-expressing advanced ovarian cancer.
Patient selection and targeted treatment in the management of platinum-resistant ovarian cancer. [2021]Ovarian cancer (OC) has the highest mortality rate of any gynecologic cancer, and patients generally have a poor prognosis due to high chemotherapy resistance and late stage disease diagnosis. Platinum-resistant OC can be treated with cytotoxic chemotherapy such as paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine, but many patients eventually relapse upon treatment. Fortunately, there are currently a number of targeted therapies in development for these patients who have shown promising results in recent clinical trials. These treatments often target the vascular endothelial growth factor pathway (eg, bevacizumab and aflibercept), DNA repair mechanisms (eg, iniparib and olaparib), or they are directed against folate related pathways (eg, pemetrexed, farletuzumab, and vintafolide). As many targeted therapies are only effective in a subset of patients, there is an increasing need for the identification of response predictive biomarkers. Selecting the right patients through biomarker screening will help tailor therapy to patients and decrease superfluous treatment to those who are biomarker negative; this approach should lead to improved clinical results and decreased toxicities. In this review the current targeted therapies used for treating platinum-resistant OC are discussed. Furthermore, use of prognostic and response predictive biomarkers to define OC patient populations that may benefit from specific targeted therapies is also highlighted.
Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO--the MIMOSA study. [2021]To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission.
PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer. [2023]High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.
A Bispecific Antibody to Link a TRAIL-Based Antitumor Approach to Immunotherapy. [2020]T-cell-based immunotherapy strategies have profoundly improved the clinical management of several solid tumors and hematological malignancies. A recently developed and promising immunotherapy approach is to redirect polyclonal MHC-unrestricted T lymphocytes toward cancer cells by bispecific antibodies (bsAbs) that engage the CD3 complex and a tumor-associated antigen (TAA). The TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) is an attractive immunotherapy target, frequently expressed by neoplastic cells, that we decided to exploit as a TAA. We found that a TRAIL-R2xCD3 bsAb efficiently activates T cells and specifically redirect their cytotoxicity against cancer cells of different origins in vitro, thereby demonstrating its potential as a pan-carcinoma reagent. Moreover, to mimic in vivo conditions, we assessed its ability to retarget T-cell activity in an ex vivo model of ovarian cancer patients' ascitic fluids containing both effector and target cells-albeit with a suboptimal effector-to-target ratio-with remarkable results.
Carboplatin and programmed death-ligand 1 blockade synergistically produce a similar antitumor effect to carboplatin alone in murine ID8 ovarian cancer model. [2018]In advanced, platinum resistant or refractory ovarian cancer (OC), the therapeutic efficacy of carboplatin is controversial. Although anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway blockages show great potential in cancer treatment, the antitumor effect of single anti-PD-L1 pathway monoclonal antibody (mAb) is not obvious in advanced or some poorly immunogenic tumors, including OC. We compared the effects of single or combined carboplatin and anti-PD-L1 mAb treatments and explored the possible antitumor mechanisms in a murine ID8 OC model.