REGN5678 Before Surgery for High-Risk Prostate Cancer
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Male
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must not be taking: Hormone therapy, Corticosteroids
Disqualifiers: Autoimmune disease, Cardiovascular disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?To learn about the safety and effects of a drug called REGN5678 when it is given to patients with high-risk prostate cancer.
Do I need to stop taking my current medications to join the trial?
The trial does not specify if you need to stop taking your current medications, but you cannot be on certain treatments like systemic corticosteroids or other immunosuppressive drugs within 14 days before starting the trial. It's best to discuss your current medications with the trial team to see if they are allowed.
What data supports the effectiveness of the drug REGN5678 for high-risk prostate cancer?
Research on similar treatments shows that bispecific antibodies, like those targeting PSMA and CD28, can enhance the body's immune response against prostate cancer cells. These antibodies have shown promise in early trials by activating immune cells to attack cancer cells, potentially improving outcomes for patients with prostate cancer.
12345Is REGN5678 safe for humans?
REGN5678, a type of bispecific antibody, has shown little or no toxicity in preclinical studies with mice and primates, suggesting it may be well-tolerated in humans.
12456What makes the drug REGN5678 unique for treating high-risk prostate cancer?
REGN5678 is unique because it is a bispecific antibody that targets both the prostate-specific membrane antigen (PSMA) on cancer cells and the CD28 receptor on T cells, enhancing the immune system's ability to attack the cancer. This dual targeting approach is different from traditional treatments and aims to improve the immune response against prostate cancer.
12457Eligibility Criteria
Men over 18 with high-risk, localized prostate cancer that hasn't spread and is operable. They must have a specific Gleason score from recent biopsies, good organ function, no prior prostate cancer treatments, and an ECOG performance status of 0 or 1. Participants need to agree to use condoms during the study and for three months after.Inclusion Criteria
Platelet count ≥100 x 109 /L
ALT ≤2.5 x ULN
Alkaline Phosphatase (ALP) ≤2.5 x ULN
+20 more
Exclusion Criteria
I have myocarditis.
I have inflammation or significant fluid around my heart.
I have not had major surgery within the last 14 days.
+21 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive REGN5678 weekly for 6 weeks, with initial administration over 2 hours and subsequent doses over 30-90 minutes
6 weeks
6 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial tests REGN5678 (an experimental drug) in combination with Piflufolastat F18 before patients undergo surgery for prostate cancer. The goal is to assess the safety and effects of REGN5678 on men preparing for radical prostatectomy.
1Treatment groups
Experimental Treatment
Group I: REGN5678 (anti-PSMAxCD28)Experimental Treatment2 Interventions
Participants will receive REGN5678 by vein over about 2 hours the first time you receive it.
Participants will be admitted to the hospital, where participants will be monitored for side effects. Other doses may be given over 30-90 minutes depending on how you handle the dose.
Participants will receive REGN5678 weekly for 6 weeks.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
MD Anderson Cancer CenterHouston, TX
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
References
Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. [2021]Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti-PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA). The class of TSAxCD3 bispecific antibodies have generated exciting results in early clinical trials. We have recently described another class of "costimulatory bispecifics" that cross-link a TSA to CD28 (TSAxCD28) and cooperate with TSAxCD3 bispecifics. Here, we demonstrate that these TSAxCD28 bispecifics (one specific for prostate cancer and the other for epithelial tumors) can also synergize with the broader anti-PD-1 approach and endow responsiveness-as well as long-term immune memory-against tumors that otherwise do not respond to anti-PD-1 alone. Unlike CD28 superagonists, which broadly activate T cells and induce cytokine storm, TSAxCD28 bispecifics display little or no toxicity when used alone or in combination with a PD-1 blocker in genetically humanized immunocompetent mouse models or in primates and thus may provide a well-tolerated and "off the shelf" combination approach with PD-1 immunotherapy that can markedly enhance antitumor efficacy.
Bispecific Antibodies in Prostate Cancer Therapy: Current Status and Perspectives. [2021]Prostate carcinoma (PC) is the second most common cancer in men. When the disease becomes unresponsive to androgen deprivation therapy, the remaining treatment options are of limited benefit. Despite intense efforts, none of the T cell-based immunotherapeutic strategies that meanwhile have become a cornerstone for treatment of other malignancies is established in PC. This refers to immune checkpoint inhibition (CI), which generally reinforces T cell immunity as well as chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) that stimulate the T cell receptor/CD3-complex and mobilize T cells in a targeted manner. In general, compared to CAR-T cells, bsAb would have the advantage of being an "off the shelf" reagent associated with less preparative effort, but at present, despite enormous efforts, neither CAR-T cells nor bsAbs are successful in solid tumors. Here, we focus on the various bispecific constructs that are presently in development for treatment of PC, and discuss underlying concepts and the state of clinical evaluation as well as future perspectives.
A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand. [2022]Despite the development of next-generation antiandrogens, metastatic castration-resistant prostate cancer (mCRPC) remains incurable. Here, we describe a unique semisynthetic bispecific antibody that uses site-specific unnatural amino acid conjugation to combine the potency of a T cell-recruiting anti-CD3 antibody with the specificity of an imaging ligand (DUPA) for prostate-specific membrane antigen. This format enabled optimization of structure and function to produce a candidate (CCW702) with specific, potent in vitro cytotoxicity and improved stability compared with a bispecific single-chain variable fragment format. In vivo, CCW702 eliminated C4-2 xenografts with as few as three weekly subcutaneous doses and prevented growth of PCSD1 patient-derived xenograft tumors in mice. In cynomolgus monkeys, CCW702 was well tolerated up to 34.1 mg/kg per dose, with near-complete subcutaneous bioavailability and a PK profile supporting testing of a weekly dosing regimen in patients. CCW702 is being evaluated in a first in-human clinical trial for men with mCRPC who had progressed on prior therapies (NCT04077021).
A PSMA-Targeting CD3 Bispecific Antibody Induces Antitumor Responses that Are Enhanced by 4-1BB Costimulation. [2021]Patients with hematologic cancers have improved outcomes after treatment with bispecific antibodies that bind to CD3 on T cells and that redirect T cells toward cancer cells. However, clinical benefit against solid tumors remains to be shown. We made a bispecific antibody that targets both the common prostate tumor-specific antigen PSMA and CD3 (PMSAxCD3) and provide evidence for tumor inhibition in several preclinical solid tumor models. Mice expressing the human extracellular regions of CD3 and PSMA were generated to examine antitumor efficacy in the presence of an intact immune system and PSMA expression in normal tissues. PSMAxCD3 accumulated in PSMA-expressing tissues and tumors as detected by immuno-PET imaging. Although PSMAxCD3 induced T-cell activation and showed antitumor efficacy in mice with low tumor burden, PSMAxCD3 lost efficacy against larger solid tumors, mirroring the difficulty of treating solid tumors in the clinic. Costimulatory receptors can enhance T-cell responses. We show here that costimulation can enhance the antitumor efficacy of PSMAxCD3. In particular, 4-1BB stimulation in combination with PSMAxCD3 enhanced T-cell activation and proliferation, boosted efficacy against larger tumors, and induced T-cell memory, leading to durable antitumor responses. The combination of CD3 bispecific antibodies and anti-4-1BB costimulation represents a therapeutic approach for the treatment of solid tumors.
Protocol of a prospective, multicentre phase I study to evaluate the safety, tolerability and preliminary efficacy of the bispecific PSMAxCD3 antibody CC-1 in patients with castration-resistant prostate carcinoma. [2021]Prostate cancer is the second most common cancer in men worldwide. When the disease becomes resistant to androgen-deprivation therapy, treatment options are sparse. To address the high medical need in castration-resistant prostate cancer (CRPC), we generated a novel PSMAxCD3 bispecific antibody termed CC-1. CC-1 binds to prostate-specific membrane antigen that is expressed on prostate cancer cells and tumour vessels, thereby allowing a dual anticancer effect.
Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer. [2021]The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).
Refining Immuno-Oncology Approaches in Metastatic Prostate Cancer: Transcending Current Limitations. [2022]Due to its immunosuppressive tumor microenvironment, prostate cancer has historically been difficult to treat with immuno-oncology approaches. Other than pembrolizumab, which is now regulatory-approved for all microsatellite instability (MSI)-high and tumor mutational burden (TMB)-high advanced solid tumors, sipuleucel-T is the only immunotherapeutic agent approved by the US Food and Drug Administration (FDA) for prostate cancer. However, sipuleucel-T efficacy is optimal for select patients with indolent metastatic castration-resistant prostate cancer. Although manipulation of immune regulation by blocking immune checkpoints has led to substantial benefit in many cancers, experience with single-agent CTLA-4 and PD-1 or PD-L1 antibodies has shown limited effect for the majority of patients with prostate cancer, especially when administered as monotherapy. Combination therapies are now being attempted, in addition to enrichment strategies employing patient clinicopathologic and biologic characteristics that may heighten responses to immuno-oncology treatment, such as PD-L1 expression, TMB, MSI status, and alterations in CDK12. More work is needed to overcome the immune-exclusive barriers in prostate cancer, such as relatively low TMB, increased activity of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, and defects in major histocompatibility complex (MHC) class I expression and interferon (IFN)-1 signaling. A promising approach and the likely next step in immuno-oncology for prostate cancer involves forced direction to markers expressed by prostate cancer tumor cells, such as prostate-specific membrane antigen (PSMA), that bypass the typical requirements for MHC class I interaction. The future will incorporate bispecific antibodies and chimeric antigen receptor (CAR)-T cells, potentially targeted towards phenotypic markers identified by next-generation PET imaging as part of the next wave of "precision medicine" in prostate cancer. Ultimately, we believe that the immune-exclusive prostate cancer tumor microenvironment can be overcome, and that patient outcomes can be enhanced through these more refined immuno-oncology approaches.