Cancer Vaccine + Pembrolizumab for Advanced Cancers
(PNeoVCA Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Mayo Clinic
Must be taking: Pembrolizumab
Must not be taking: Systemic corticosteroids
Disqualifiers: Pregnancy, Autoimmune diseases, Heart failure, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase I trial tests the safety and tolerability of an experimental personalized vaccine when given by itself and with pembrolizumab in treating patients with solid tumor cancers that have spread to other places in the body (advanced). The experimental vaccine is designed target certain proteins (neoantigens) on individuals' tumor cells. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving the personalized neoantigen peptide-based vaccine with pembrolizumab may be safe and effective in treating patients with advanced solid tumors.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, it mentions that certain therapies, like chemotherapy or experimental drugs, should not be taken within a few weeks before registration. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of this treatment for advanced cancers?
Research shows that combining personalized vaccines with drugs like pembrolizumab can boost the body's immune response against cancer cells. In studies, this approach has been well tolerated and has shown promise in enhancing the body's ability to fight tumors.
12345Is the cancer vaccine with Pembrolizumab safe for humans?
The cancer vaccine, when tested in various forms and combinations, has generally been found to be safe in humans. Most side effects were mild, such as fatigue or skin reactions at the injection site, and serious side effects were rare and self-limiting.
46789How is the cancer vaccine with pembrolizumab treatment different from other cancer treatments?
This treatment combines a cancer vaccine with pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells more effectively. Unlike traditional chemotherapy, pembrolizumab specifically targets the PD-1 pathway to enhance the body's immune response against tumors, potentially offering a more targeted and less toxic approach.
1011121314Eligibility Criteria
Adults with advanced solid tumors that have spread and are not treatable by surgery. Participants must have a life expectancy over 6 months, adequate organ function, and agree to use effective contraception. They should be willing to provide tissue samples for research and not have other active cancers or severe diseases.Inclusion Criteria
My cancer has worsened after receiving standard treatment.
I am fully active or restricted in physically strenuous activity but can do light work.
I have recovered from side effects of my previous cancer treatments.
+51 more
Exclusion Criteria
REGISTRATION: Nursing persons
I had a severe reaction to previous immunotherapy that needed steroids or stopped treatment.
I haven't taken steroids or immunosuppressants in the last 14 days.
+20 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive cyclophosphamide, personalized neoantigen vaccine, and pembrolizumab in 21-day cycles
Up to 2 years
Multiple visits per cycle (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 2 years
Every 3 months (in-person)
Participant Groups
The trial is testing the safety of a new personalized cancer vaccine combined with Pembrolizumab (an existing immunotherapy drug) in patients with various types of advanced solid tumors. The vaccine targets specific proteins on tumor cells to help the immune system fight cancer.
1Treatment groups
Experimental Treatment
Group I: Treatment (cyclophosphamide, vaccine, pembrolizumab)Experimental Treatment4 Interventions
Patients receive cyclophosphamide IV on day -3. Patients then receive personalized neoantigen vaccine with sargramostim SC on days 1, 4, 8, and 15 of cycle 1 and day 1 of cycles thereafter. Patients also receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Patients may undergo blood sample collection during screening, cycle 1 days -3, 1, 8, 15, 22, cycles 2, 3, 4, 5, 7, 8 and 9+ day 1 and 30 days after last dose of GM-CSF or pembrolizumab and may undergo tissue biopsy during screening, week 25 or at the time of disease progression. Patients also undergo CT or MRI during screening, week 9 then every 9 weeks, and 30 days after last dose of GM-CSF or pembrolizumab.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo Clinic in FloridaJacksonville, FL
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Who Is Running the Clinical Trial?
Mayo ClinicLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Immunogenicity and antitumor efficacy of a novel human PD-1 B-cell vaccine (PD1-Vaxx) and combination immunotherapy with dual trastuzumab/pertuzumab-like HER-2 B-cell epitope vaccines (B-Vaxx) in a syngeneic mouse model. [2021]Therapeutic blockade of PD-1/PD-L1 signaling with monoclonal antibodies (mAbs) has shown clinical success and activity across a broad set of cancer subtypes. However, monotherapy with PD-1/PD-L1 inhibitors are only effective in a subset of patients and ongoing studies show efficacy of treatment depends on a combinatorial approach. Contrary to mAbs chimeric B-cell cancer vaccines incorporating a "promiscuous" T-cell epitope have the advantage of producing a polyclonal B-cell antibody that can potentially induce memory B- and T-cell responses, while reducing immune evasion and suppression. Here, we describe a novel PD-1 B-cell peptide epitope vaccine (amino acid 92-110; PD1-Vaxx) linked to a measles virus fusion peptide (MVF) amino acid 288-302 via a four amino acid residue (GPSL) emulsified in Montanide ISA 720VG that aims to induce the production of polyclonal antibodies that block PD-1 signaling and thus trigger anticancer effects similar to nivolumab. In preclinical studies, the PD1-Vaxx outperformed the standard anti-mouse PD-1 antibody (mAb 29F.1A12) in a mouse model of human HER-2 expressing colon carcinoma. Furthermore, the combination of PD1-Vaxx with combo HER-2 peptide vaccine (B-Vaxx) showed enhanced inhibition of tumor growth in colon carcinoma BALB/c model challenged with CT26/HER-2 cells. The PD-1 or combined vaccines were safe with no evidence of toxicity or autoimmunity.
Combining personalized neoantigen vaccination with chemotherapy and anti-PD-1 to treat NSCLC. [2022]In this issue of Cancer Cell, Awad et al. report a phase 1b clinical trial combining a personalized vaccine NEO-PV-01 with chemotherapy and anti-PD-1 pembrolizumab in first-line metastatic non-squamous NSCLC. They demonstrate that this treatment regimen was well tolerated and induced neoantigen-specific CD4+ T cell responses with effector phenotype.
Can Personalized Neoantigens Raise the T Cell Bar? [2022]Ott et al. report the results of a phase 1B study in which a personalized neoantigen vaccine was combined with programmed death receptor-1 blockade in patients with advanced cancers. The study provides a framework for combinatorial vaccine therapies that could mount robust T cell responses, enhance tumor killing, and provide clinical benefit.
A phase I study of personalized peptide vaccination using 14 kinds of vaccine in combination with low-dose estramustine in HLA-A24-positive patients with castration-resistant prostate cancer. [2013]To evaluate the safety, tolerability, immune response, and antitumor activity of a combination of personalized peptide vaccination (PPV) and estramustine phosphate (EMP) in patients with castration-resistant prostate cancer (CRPC).
Dexamethasone did not suppress immune boosting by personalized peptide vaccination for advanced prostate cancer patients. [2013]To evaluate the immunological responses of personalized peptide vaccination combined with low-dose glucocorticoids for advanced hormone refractory prostate cancer (HRPC) patients (pts).
Immunological evaluation of individualized peptide vaccination with a low dose of estramustine for HLA-A24+ HRPC patients. [2020]The safety, toxicity, and immunological response of individualized peptide vaccination or human leukocyte antigen (HLA)-A24+ hormone refractory prostate cancer (HRPC) patients in combination with a low dose of estramustine were evaluated.
Phase I trial of a cancer vaccine consisting of 20 mixed peptides in patients with castration-resistant prostate cancer: dose-related immune boosting and suppression. [2015]The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once a week for 6 weeks. KRM-20 was applicable for patients with positive human leukocyte antigen (HLA) A2, A3, A11, A24, A26, A31 or A33 alleles, which cover the majority of the global population. To evaluate the minimum immunological effective dose (MIED), peptide-specific CTL and immunoglobulin G (IgG) responses, and immune suppressive subsets were evaluated during the vaccination. Total of 17 patients was enrolled. No serious adverse drug reactions were encountered. The MIED of KRM-20 in CTL or IgG response calculated by logistic regression model was set as 16 or 1.6 mg, respectively. The frequency of immune suppressive subsets was fewer in the 20 mg cohort than that in 6 or 60 mg cohort. Clinical responses determined by prostate-specific antigen levels were two partial responses (from the 20 mg cohort), five no changes and ten progressive diseases. Twenty milligrams of KRM-20 could be recommended for further studies because of the safety and ability to augment CTL activity.
A pilot trial of vaccination with Carcinoembryonic antigen and Her2/neu peptides in advanced colorectal cancer. [2021]Checkpoint-blockade therapy (CBT) is approved for select colorectal cancer (CRC) patents, but additional immunotherapeutic options are needed. We hypothesized that vaccination with carcinoembryonic antigen (CEA) and Her2/neu (Her2) peptides would be immunogenic and well tolerated by participants with advanced CRC. A pilot clinical trial (NCT00091286) was conducted in HLA-A2+ or -A3+ Stage IIIC-IV CRC patients. Participants were vaccinated weekly with CEA and Her2 peptides plus tetanus peptide and GM-CSF emulsified in Montanide ISA-51 adjuvant for 3 weeks. Adverse events (AEs) were recorded per NIH Common Terminology Criteria for Adverse Events version 3. Immunogenicity was evaluated by interferon-gamma ELISpot assay of in vitro sensitized peripheral blood mononuclear cells and lymphocytes from the sentinel immunized node. Eleven participants were enrolled and treated; one was retrospectively found to be ineligible due to HLA type. All 11 participants were included in AEs and survival analyses, and the 10 eligible participants were evaluated for immunogenicity. All participants reported AEs: 82% were Grade 1-2, most commonly fatigue or injection site reactions. Two participants (18%) experienced treatment-related dose-limiting Grade 3 AEs; both were self-limiting. Immune responses to Her2 or CEA peptides were detected in 70% of participants. Median overall survival (OS) was 16 months; among those enrolled with no evidence of disease (n = 3), median OS was not reached after 10 years of follow-up. These data demonstrate that vaccination with CEA or Her2 peptides is well tolerated and immunogenic. Further study is warranted to assess potential clinical benefits of vaccination in advanced CRC either alone or in combination with CBT.
Phase I trial of patient-oriented vaccination in HLA-A2-positive patients with metastatic hormone-refractory prostate cancer. [2020]To evaluate the safety and toxicity of peptide vaccination for patients with metastatic hormone-refractory prostate cancer (HRPC) based on pre-existing peptide-specific cytotoxic T-lymphocyte (CTL) precursors in the circulation, 10 patients positive for human leukocyte antigen (HLA)-A2 with metastatic HRPC were enrolled in a phase I study. Peptide-specific CTL-precursors reactive to 16 kinds of vaccine candidates in the pre-vaccination peripheral blood mononuclear cells (PBMCs) were measured, and patients were followed by vaccination with only positive peptides (up to 4 kinds of peptides). Serum prostate-specific antigen (PSA) levels were monitored regularly. The peptide vaccination was safe and well tolerated with no major adverse effects. The most common toxicities were dermatologic reactions at the injection site. Increased CTL response to peptides was observed in 4 of 10 patients. Anti-peptide IgG was also detected in post-vaccination sera of 7 of 10 patients. One patient showed the disappearance of a pelvic bone metastasis after five vaccinations. Three patients showed a decrease of serum PSA level from the baseline after the vaccination, but no patients showed a serum PSA level decrease of >/= 50%. The median survival duration of study patients was 22 months with follow-up from 3 to 27 months. We consider that the increase in cellular and humoral immune responses, and decrease in PSA level in some patients justify further development of peptide vaccination for metastatic HRPC patients.
Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.
Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).
Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.
FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.
Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1-mediated immune suppression in T-cell cultures by enhancing IL2 production following staphylococcal enterotoxin B stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture. Ex vivo and in vitro studies with human and primate T cells show that pembrolizumab enhances antigen-specific T-cell IFNγ and IL2 production. Pembrolizumab does not mediate FcR or complement-driven effector function against PD-1-expressing cells. Pembrolizumab displays dose-dependent clearance and half-life in cynomolgus monkey pharmacokinetic and toxicokinetic studies typical for human IgG4 antibodies. In nonhuman primate toxicology studies, no findings of toxicologic significance were observed. The preclinical data for pembrolizumab are consistent with the clinical anticancer activity and safety that has been demonstrated in human clinical trials.