Vudalimab + Chemotherapy/Targeted Therapy for Prostate Cancer
Recruiting in Palo Alto (17 mi)
+27 other locations
Age: 18+
Sex: Male
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Xencor, Inc.
Must be taking: Androgen suppression
Must not be taking: Immunotherapy, Chemotherapy
Disqualifiers: CNS metastases, Autoimmune disease, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This Phase 2 study will investigate the safety and clinical activity of vudalimab (XmAb20717) alone or in combination with standard of care anticancer therapies in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on prior therapy.
Will I have to stop taking my current medications?
The trial requires that you stop taking any anticancer therapies other than androgen deprivation therapy at least 2 weeks before starting the study drug. If you are currently taking prednisone for prostate cancer, you can continue it during the study.
What data supports the effectiveness of the drug Vudalimab + Chemotherapy/Targeted Therapy for Prostate Cancer?
The research indicates that while immune checkpoint inhibitors like those in Vudalimab have shown limited benefits in prostate cancer, certain subgroups of patients with specific genetic markers may respond better. For example, patients with DNA mismatch repair deficiency (dMMR) or high PD-L1 expression might experience improved outcomes with these treatments.
12345What safety data exists for Vudalimab and related therapies in humans?
The safety data for therapies similar to Vudalimab, such as anti-PD-1 and anti-CTLA-4 antibodies, indicate that they can cause immune-related side effects, which may include muscle inflammation (myositis) and thyroid issues (hypothyroidism). These side effects can be serious if not managed properly.
26789What makes the drug Vudalimab unique for prostate cancer treatment?
Vudalimab is a novel bispecific antibody that targets both PD-1 and CTLA-4, which are proteins that help cancer cells evade the immune system. This dual-targeting approach is unique compared to traditional treatments that typically focus on a single target, potentially enhancing the immune response against prostate cancer.
1231011Eligibility Criteria
This trial is for adults with metastatic castration-resistant prostate cancer who've had at least two prior anticancer treatments. Participants must have a confirmed diagnosis, documented disease progression, and be on or willing to continue androgen suppression if not surgically castrated. They should have specific genetic profiles based on the cohort they fit into and must not be receiving other anticancer therapies.Inclusion Criteria
Able to provide written informed consent
I am on hormone therapy to lower testosterone and willing to continue it.
I am willing and able to follow the study's schedule.
+7 more
Exclusion Criteria
I have not received a live-virus vaccine in the last 30 days.
I have recovered from previous cancer treatment side effects to a mild level.
I do not have HIV or hepatitis B/C, or it is under control.
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive XmAb20717 alone or in combination with chemotherapy or targeted therapies
12 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Open-label extension (optional)
Participants may opt into continuation of treatment long-term
Long-term
Participant Groups
The study tests vudalimab (XmAb20717) alone or combined with chemotherapy or targeted therapy in patients with advanced prostate cancer. It aims to assess safety and effectiveness after previous treatments failed. The combinations include vudalimab with olaparib, cabazitaxel or docetaxel, carboplatin plus one of the taxanes, or as monotherapy.
5Treatment groups
Experimental Treatment
Group I: Cohort E - No Targetable MutationsExperimental Treatment2 Interventions
XmAb20717 + carboplatin + cabazitaxel
Group II: Cohort D - MSI-H, MMRD or TMB-HExperimental Treatment1 Intervention
Group III: Cohort C - HRD/CDK12 PARP NaïveExperimental Treatment1 Intervention
XmAb20717 + olaparib
Group IV: Cohort B - HRD/CDK12 PARP - ProgressorsExperimental Treatment1 Intervention
XmAb20717 + carboplatin + cabazitaxel
Group V: Cohort A - AVPCaExperimental Treatment1 Intervention
XmAb20717 + carboplatin + cabazitaxel
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Alaska Oncology and HematologyAnchorage, AK
Palo Verde Hematology OncologyGlendale, AZ
Rocky Mountain Cancer CentersLone Tree, CO
Northwest Cancer SpecialistsTigard, OR
More Trial Locations
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Who Is Running the Clinical Trial?
Xencor, Inc.Lead Sponsor
References
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).
Re-sensitization to pembrolizumab following PSMA-CD3 T-cell redirection therapy with JNJ-081 in a patient with mismatch repair-deficient metastatic castration-resistant prostate cancer: a case report. [2023]While checkpoint inhibitor therapy has revolutionized the treatment landscape of some solid tumors, it has shown limited efficacy in metastatic castration-resistant prostate cancers (mCRPC). A small (~3-5%) but clinically distinct subset of mCRPC tumors have a DNA mismatch repair deficiency (dMMR) and develop a hypermutation phenotype with elevated tumor mutational burden and high microsatellite instability (MSI-H). Retrospective analyses have shown dMMR/MSI-H status to be a predictive biomarker for response to pembrolizumab in prostate tumors. Here, in this report, we present a case of a patient with mCRPC harboring a somatic dMMR who had progressed on pembrolizumab after an initial response. He enrolled on a clinical trial with JNJ-081, a prostate-specific membrane antigen-CD3 bispecific T-cell engager antibody and experienced a partial response with course complicated by cytokine release syndrome. On progression, he was reinitiated on pembrolizumab and experienced an exceptional second response, with his prostate-specific antigen falling from a high of 20.01 to undetectable after 6 weeks and remaining undetectable for >11 months. To our knowledge, this represents the first reported case of bispecific T-cell engager-mediated re-sensitization to checkpoint inhibitor therapy in any cancer.
Recent Advances in Prostate Cancer Treatment and Drug Discovery. [2022]Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.
Phase II Study of Ipilimumab in Men With Metastatic Prostate Cancer With an Incomplete Response to Androgen Deprivation Therapy. [2020]Background: Phase 3 studies of immune checkpoint inhibitors have not shown a survival benefit in prostate cancer, but some patients have a profound anticancer response. Patients and Methods: We evaluated the efficacy of the CTLA-4 targeted agent, ipilimumab, in metastatic prostate cancer patients who had an incomplete biochemical response to initial androgen deprivation therapy (ADT) alone. Ten patients were enrolled, each treated with ipilimumab 10 mg/kg (every 3 weeks for up to 4 doses) with maintenance ipilimumab every 12 weeks for non-progressing patients. The primary endpoint was proportion of patients with an undetectable PSA. The total sample size was 30 patients, but there was an interim analysis planned at 10 for futility. If none of the 10 patients achieved an undetectable PSA, the study would be halted. Results: The study was halted at the interim analysis as none of the 10 patients achieved the primary endpoint, but 30% of patients demonstrated a >50% reduction in PSA, with one patient achieving a >90% reduction in PSA. Peripheral blood mononuclear cells (PBMC) examined by mass cytometry showed that patients with clinical responses had an increase in effector memory T-cell subsets as well as an increase in T-cell expression of T-bet, suggesting induction of a Th1 response. Conclusions: This study provides further evidence that ipilimumab has activity in some patients with prostate cancer and provides further rationale for the development of future studies aimed at identifying a subset of patients with CPRC that are more likely to derive a benefit from treatment with ipilimumab. Implications for Practice: There is insufficient evidence to use ipilimumab in prostate cancer in routine practice. Trial Registration: ClinicalTrials.gov, NCT01498978. Registered 26 December 2011. https://www.clinicaltrials.gov/ct2/show/NCT01498978?term=julie+graff&rank=3.
Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. [2023]Early clinical data indicate that some patients with castration-resistant prostate cancer may benefit from program death ligand-1 (PD-L1) inhibition, especially with enzalutamide. The IMbassador250 trial (no. NCT03016312) enrolled 759 men with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The addition of atezolizumab to enzalutamide in an open-label randomized trial did not meet the primary endpoint of improved overall survival in unselected patients (stratified hazard ratio 1.12, 95% confidence interval (0.91, 1.37), P = 0.28), despite an acceptable safety profile. In archival tumor samples, prostate tumors showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, phosphatase and tensin homolog status and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant prostate cancers. In planned biomarker analysis, longer progression-free survival was seen with atezolizumab in patients with high PD-L1 IC2/3, CD8 expression and established immune gene signatures. Exploratory analysis linked progression-free survival in the atezolizumab arm with immune genes such as CXCL9 and TAP1, together with other potentially relevant biomarkers including phosphatase and tensin homolog alterations. Together these data indicate that the expected biology associated with response to immune checkpoint inhibitors is present in prostate cancer, albeit in fewer patients. Careful patient selection may be required for immune checkpoint inhibitors to identify subgroups of patients who may benefit from this treatment approach.
A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. [2017]Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) augments and prolongs T-cell responses and is a strategy to elicit antitumor immunity. The objectives of this pilot study were to establish the pharmacokinetic and safety profile for a single dose of 3 mg/kg of the anti-CTLA-4 antibody Ipilimumab (MDX-010, BMS-734016) and to assess if this therapy resulted in prostate-specific antigen (PSA) modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in patients with hormone-refractory prostate cancer treated with Ipilimumab.
[Adverse effects of immune checkpoint inhibitors used to treat melanoma and other cancer]. [2017]Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers and metastatic renal cancer. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events that may be life threatening if not anticipated and managed appropriately. This new family of dysimmune toxicities remains largely unknown to the broad oncology community. We propose here some practical guidelines for the oncologist to help in the clinical care of patients under immune checkpoint molecules.
Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. [2022]The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown.
Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. [2022]While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.
Pasotuxizumab, a BiTE® immune therapy for castration-resistant prostate cancer: Phase I, dose-escalation study findings. [2023]Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE®) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 μg/d; cIV: n = 16, 5-80 μg/d). The SC maximum tolerated dose was 172.0 μg/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration: NCT01723475 (ClinicalTrials.gov).
A Phase Ib/II study of IGF-neutralising antibody xentuzumab with enzalutamide in metastatic castration-resistant prostate cancer. [2023]This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC).