Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Seagen Inc.
Must not be taking: Anti-PD-L1, MMAE
Disqualifiers: Recent malignancy, CNS metastases, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial is testing a new drug, SGN-PDL1V, alone and with pembrolizumab, in patients with advanced solid tumors. The goal is to see if these treatments are safe and effective. SGN-PDL1V targets cancer cells directly, while pembrolizumab helps the immune system fight the cancer.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot have taken an anti-PD-L1 agent recently. It's best to discuss your current medications with the study team to see if they might affect your eligibility.
What data supports the effectiveness of the drug SGN-PDL1V for cancer?
Research shows that drugs targeting PD-L1, like SGN-PDL1V, have been effective in improving survival in lung cancer patients by helping the immune system better recognize and attack cancer cells. Additionally, high levels of PD-L1 expression in tumors have been linked to better responses to these types of treatments.
12345What safety information is available for SGN-PDL1V (also known as PF-08046054) in humans?
While specific safety data for SGN-PDL1V in humans is not available, similar PD-L1 inhibitors have been shown to be generally safe, though they can cause side effects like lung inflammation, liver inflammation, and inflammation of the colon. It's important to discuss potential risks with your healthcare provider.
678910What makes the drug SGN-PDL1V unique for cancer treatment?
SGN-PDL1V is unique because it targets the PD-L1 protein, which helps cancer cells evade the immune system, potentially enhancing the body's ability to fight cancer. This approach is different from traditional chemotherapy, which directly targets and kills cancer cells.
1471112Eligibility Criteria
This trial is for adults with certain advanced solid tumors like lung, breast, esophageal cancer or melanoma that have spread and can't be surgically removed. Participants must have tried standard treatments without success or cannot tolerate them. They should be relatively active and well (ECOG score of 0 or 1) and not have had specific recent cancers, brain metastases, severe neuropathy, or treatment with similar drugs.Inclusion Criteria
Parts A and B: Participants must have one of the following histologically- or cytologically-confirmed metastatic or unresectable solid tumor types: Non-small cell lung cancer (NSCLC), Head and neck squamous cell carcinoma (HNSCC), Esophageal squamous cell carcinoma (SCC), Triple negative breast cancer (TNBC). Participants must have disease that is relapsed or refractory, that has progressed on approved therapies, be intolerant to or refused such therapies, or such and therapies are contraindicated and in the judgement of the investigator, should have no appropriate SoC therapeutic option. Participants must have PD-L1 expression based on historical testing. Parts C: Participants must have disease that is relapsed or refractory or be intolerant to SoC therapies and must have one of the following tumor types: HNSCC, NSCLC, Esophageal SCC, Ovarian cancer, Melanoma, TNBC, Gastric cancer. Participants must have been previously tested for PD-L1 expression and should have PD-L1 expression ≥1 or <1 by CPS or TPS based on historical testing. Parts D: Participants must have histologically or cytologically-confirmed disease of the HNSCC. Participants must have PD-L1 expression based on historical testing. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Measurable disease per RECIST v1.1 at baseline.
Exclusion Criteria
History of another malignancy within 3 years of first dose of study treatment or any evidence of residual disease from a previously diagnosed malignancy. Known active central nervous system metastases. Participants with previously-treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry after brain metastasis treatment, have no new or enlarging brain metastases, and are off of corticosteroids prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study treatment. Lepto-meningeal disease. Prior treatment with an anti-PD-L1 agent within less than 5 half-lives. Previous receipt of a monomethylauristatin E (MMAE)-containing agent. Pre-existing neuropathy ≥Grade 2 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Finding (Parts A and B)
Determine the appropriate dose of PF-08046054/SGN-PDL1V for participants
8-12 weeks
Safety and Efficacy Evaluation (Part C)
Evaluate the safety and efficacy of PF-08046054/SGN-PDL1V at the determined dose
12-24 weeks
Combination Therapy Evaluation (Parts D and E)
Assess the safety and efficacy of PF-08046054/SGN-PDL1V with pembrolizumab
12-24 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 3 years
Participant Groups
SGN-PDL1V is being tested to determine its safety and effectiveness in treating various types of advanced solid tumors. The study has three parts: Parts A and B will decide the right dose; Part C will test this dose further for safety outcomes and how well it works against the cancer.
2Treatment groups
Experimental Treatment
Group I: PF-08046054 MonotherapyExperimental Treatment1 Intervention
PF-08046054 monotherapy
Group II: PF-08046054 Combination TherapyExperimental Treatment2 Interventions
PF-08046054 + pembrolizumab
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Chao Family Comprehensive Cancer Center University of California IrvineOrange, CA
Case Western Reserve University / University Hospitals Cleveland Medical CenterCleveland, OH
University of California Davis Comprehensive Cancer CenterSacramento, CA
University of California, Davis Medical CenterSacramento, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Seagen Inc.Lead Sponsor
References
Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy. [2022]Programmed death-ligand 1 (PD-L1) expression in tumor tissue is under investigation as a candidate biomarker in immuno-oncology dug development. The soluble form of PD-L1 (sPDL1) is suggested to have immunosuppressive activity. In this study, we measured the serum level of sPDL1 and evaluated its prognostic implication in biliary tract cancer (BTC). Blood was collected from 158 advanced BTC patients (68 intrahepatic cholangiocarcinoma, 56 gallbladder cancer, 22 extrahepatic cholangiocarcinoma and 12 ampulla of vater cancer) before initiation of palliative chemotherapy. Serum sPDL1 was measured using an enzyme-linked immunosorbent assay. Clinical data included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). The patients were assigned to two cohorts (training and validation cohort) using a simple random sampling method to validate the cut-off value of each marker. Validation was performed using a twofold cross-validation method. Overall survival (OS) of all patients was 9.07 months (95% CI: 8.20-11.33). Median sPDL1 was 1.20 ng/mL (range 0.03-7.28, mean 1.50, SD 1.22). Median NLR, PLR and SII were 2.60, 142.85 and 584.93, respectively. Patients with high sPDL1 (≥0.94 ng/mL) showed worse OS than patients with low sPDL1 (7.93 vs. 14.10 months, HR 1.891 (1.35-2.65), p
Programmed cell death ligand 1 expression in osteosarcoma. [2022]Programmed cell death ligand 1 (PDL1, also known as B7H1) is a cell-surface protein that suppresses the cytotoxic CD8(+) T-cell-mediated immune response. PDL1 expression and its clinical relevance in sarcomas are not well understood. Therefore, we sought to measure RNA expression levels for PDL1 in 38 clinically annotated osteosarcoma tumor samples and aimed to determine if PDL1 expression correlates with clinical features and tumor-infiltrating lymphocytes (TIL). Quantitative real-time RT-PCR for PDL1 was optimized in 18 cell lines, of which 5 were osteosarcoma derived. qRT-PCR results were validated via flow cytometry and immunohistochemistry (IHC) in select cell lines. Total RNA was isolated from 38 human osteosarcoma samples for qRT-PCR analysis. Clinical data were sorted, and significance was determined by the Student t test. TILs were examined in patient samples by tissue microarray hematoxylin-eosin staining. We confirmed the constitutive PDL1 mRNA expression in cell lines by qRT-PCR, flow cytometry, and IHC. Across human osteosarcoma samples, PDL1 mRNA gene expression ranged over 4 log (>5,000-fold difference). Relative expression levels were evaluated against clinical factors such as age/gender, metastasis, recurrence, chemotherapy, percentage of necrosis, and survival; no significant associations were identified. The presence of TILs was associated with high PDL1 expression (R(2) = 0.37; P = 0.01). In summary, we developed an RNA-based assay to determine PDL1 expression levels, and we show, for the first time, that high levels of PDL1 are expressed in a subset of osteosarcoma, and PDL1 expression is positively correlated with TILs. Multiple agents targeting PD1/PDL1 are in clinical development, and this may be a novel immunotherapeutic strategy for osteosarcoma clinical trials.
The Era of Checkpoint Blockade in Lung Cancer: Taking the Brakes Off the Immune System. [2019]Despite recent advances with targeted kinase inhibitors and better-tolerated chemotherapy, the treatment of metastatic non-small-cell lung cancer remains suboptimal. One recent advance that holds great promise is immunotherapy-an approach that enhances a patient's immune system to better recognize and react to abnormal cells. The most successful immunotherapeutic strategy to date uses antibodies to block inhibitory receptors (also called "checkpoints") that are up-regulated on the T cells that infiltrate the tumor. Two examples of such molecules are programmed cell death-1 (PD1) and cytotoxic T lymphocyte-associated protein-4. With more than a dozen clinical trials in non-small-cell lung cancer completed, checkpoint blockade targeting PD1 has demonstrated durable responses and superior survival compared with traditional chemotherapy agents when used as first-line therapy in individuals with more than 50% PD1 ligand (PDL1) expression by immunohistochemical staining and as second-line therapy independent of PDL1 status. Antibodies to PDL1 have shown similar activity. Combinations of anti-PD1 and anti-PDL1 with anti-cytotoxic T lymphocyte-associated protein-4 and chemotherapy are being actively tested. These agents have generally tolerable safety profiles; pneumonitis, although rare, remains the most feared adverse effect. PDL1 expression on tumors has been identified as a biomarker predictive of response. Although PDL1 expression has traditionally been measured on resected tumor specimens, the pulmonologist has a growing role in obtaining samples for testing via minimally invasive means.
The real-world experience with nivolumab in previously treated patients with advanced non-small cell lung cancer from a cancer center in India. [2022]PDL-1 inhibitors have emerged as the new standard of care for second line treatment of NSCLC.
Soluble PD-L1 as a predictive biomarker in lung cancer: a systematic review and meta-analysis. [2022]Background: We performed a meta-analysis to evaluate the association between soluble PD-L1 (sPD-L1) and survival outcomes and treatment response in lung cancer. Methods & methods: Eligible studies were obtained by searching PubMed, EMBASE and Web of Science. Pooled effect estimates were calculated for overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twelve eligible studies with 1188 lung cancer patients were included. High sPD-L1 was significantly associated with worse OS (hazard ratio [HR] = 2.20; 95% CI: 1.59-3.05; p < 0.001) and PFS (HR = 2.42; 95% CI: 1.72-3.42; p < 0.001) in patients treated with immune checkpoint inhibitors (ICIs). Meanwhile, high sPD-L1 predicted worse OS (HR = 1.60; 95% CI: 1.31-1.96; p < 0.001) and lower ORR (odds ratio = 0.52; 95% CI: 0.35-0.80; p = 0.002) in patients treated with non-ICI therapies. Conclusion: sPD-L1 is a potential predictive biomarker of lung cancer.
Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy. [2021]PD-1/PD-L1 inhibitors are a group of immune checkpoint inhibitors as front-line treatment of multiple types of cancer. However, the serious immune-related adverse reactions limited the clinical application of PD-1/PD-L1 monoclonal antibodies, despite the promising curative effects. Therefore, it is urgent to develop novel inhibitors, such as small molecules, peptides or macrocycles, targeting the PD-1/PD-L1 axis to meet the increasing clinical demands. Our review discussed the mechanism of action of PD-1/PD-L1 inhibitors and presented clinical trials of currently approved PD-1/PD-L1 targeted drugs and the incidence of related adverse reactions, helping clinicians pay more attention to them, better formulate their intervention and resolution strategies. At last, some new inhibitors whose patent have been published are listed, which provide development ideas and judgment basis for the efficacy and safety of novel PD-1/PD-L1 inhibitors.
Design and selection of anti-PD-L1 single-domain antibody and tumor necrosis factor superfamily ligands for an optimal vectorization in an oncolytic virus. [2023]Arming oncolytic viruses with transgenes encoding immunomodulators improves their therapeutic efficacy by enhancing and/or sustaining the innate and adaptive anti-tumoral immune responses. We report here the isolation, selection, and vectorization of a blocking anti-human PDL1 single-domain antibody (sdAb) isolated from PDL1-immunized alpacas. Several formats of this sdAb were vectorized into the vaccinia virus (VV) and evaluated for their programmed cell death protein 1 (PD1)/PD1 ligand (PDL1) blocking activity in the culture medium of tumor cells infected in vitro. In those conditions, VV-encoded homodimeric sdAb generated superior PDL1 blocking activity compared to a benchmark virus encoding full-length avelumab. The sdAb was further used to design simple, secreted, and small tumor necrosis factor superfamily (TNFSF) fusions with the ability to engage their cognate receptors (TNFRSF) only in the presence of PDL1-positive cells. Finally, PDL1-independent alternatives of TNFRSF agonists were also constructed by fusing different variants of surfactant protein-D (SP-D) oligomerization domains with TNFSF ectodomains. An optimal SP-D-CD40L fusion with an SP-D collagen domain reduced by 80% was identified by screening with a transfection/infection method where poxvirus transfer plasmids and vaccinia virus were successively introduced into the same cell. However, once vectorized in VV, this construct had a much lower CD40 agonist activity compared to the SP-D-CD40L construct, which is completely devoid of the collagen domain that was finally selected. This latest result highlights the importance of working with recombinant viruses early in the payload selection process. Altogether, these results bring several complementary solutions to arm oncolytic vectors with powerful immunomodulators to improve their immune-based anti-tumoral activity.
Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. [2023]Immune checkpoint antibodies that augment the programmed cell death protein 1 (PD-1)/PD-L1 pathway have demonstrated antitumor activity across multiple malignancies, and gained recent regulatory approval as single-agent therapy for the treatment of metastatic malignant melanoma and nonsmall-cell lung cancer. Knowledge of toxicities associated with PD-1/PD-L1 blockade, as well as effective management algorithms for these toxicities, is pivotal in order to optimize clinical efficacy and safety. In this article, we review selected published and presented clinical studies investigating single-agent anti-PD-1/PD-L1 therapy and trials of combination approaches with other standard anticancer therapies, in multiple tumor types. We summarize the key adverse events reported in these studies and their management algorithms.
A newly discovered PD-L1 B-cell epitope peptide vaccine (PDL1-Vaxx) exhibits potent immune responses and effective anti-tumor immunity in multiple syngeneic mice models and (synergizes) in combination with a dual HER-2 B-cell vaccine (B-Vaxx). [2022]Blockade of checkpoint receptors with monoclonal antibodies against CTLA-4, PD-1 and PD-L1 has shown great clinical success in several cancer subtypes, yielding unprecedented responses albeit a significant number of patients develop resistance and remain refractory. Both PD-1/PD-L1 and HER-2 signaling pathway inhibitors have limited efficacy and exhibits significant toxicities that limit their use. Ongoing clinical studies support the need for rationale combination of immuno-oncology agents to make a significant impact in the lives of cancer patients. We introduce the development of a novel chimeric PD-L1 B-cell peptide epitope vaccine (amino acid 130-147) linked to a "promiscuous" T cell measles virus fusion (MVF) peptide (MVF-PD-L1(130); PDL1-Vaxx) or linked to tetanus toxoid (TT3) TT3-PD-L1 (130) via a linker (GPSL). These vaccine constructs are highly immunogenic and antigenic in several syngeneic animal models. The PD-L1 vaccines elicited high titers of polyclonal antibodies that inhibit tumor growth in multiple syngeneic cancer models, eliciting antibodies of different subtypes IgG1, IgG2a, IgG2b and IgG3, induced PD-1/PD-L1 blockade, decreased proliferation, induced apoptosis and caused ADCC of tumor cells. The PDL1-Vaxx induces similar inhibition of tumor growth versus the standard anti-mouse PD-L1 antibody in both syngeneic BALB/c and C57BL/6J mouse models. The combination of PDL1-Vaxx with HER-2 vaccine B-Vaxx demonstrated synergistic tumor inhibition in D2F2/E2 carcinoma cell line. The anti-PDL1-Vaxx block PD-1/PD-L1 interaction and significantly prolonged anti-tumor responses in multiple syngeneic tumor models. The combination of HER-2 vaccine (B-Vaxx) with either PDL1-Vaxx or PD1-Vaxx demonstrated synergistic tumor inhibition. PDL1-Vaxx is a promising novel safe checkpoint inhibitor vaccine.
The Clinical Safety and Efficacy of Targeted PD-L1 Therapy with Durvalumab in Solid Tumors. [2023]Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint inhibitors have been on the front line of clinical revolution in which, the targeted PD-L1 therapy has obtained some success in patients with solid tumors. A large number of clinical trials revealed that both monotherapy and combination therapy of PD-L1 antibody significantly suppress some tumor growth and promote the survival of patients. At present, anti-PD-L1 treatment has been used as a portion of standard treatment for lung cancer, breast cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. Although much evidence has demonstrated that PD-L1 antibody is safe in most patients, there are still some adverse reactions, such as pneumonitis, hepatitis, colitis, neurologic events and myocarditis. In this review, the clinical information, including the efficacy and safety of durvalumab in solid tumors, was enumerated and summarized at this stage to grasp the current application of targeted PD-L1 therapy and provide guidance for clinical application.
Nanobody against PDL1. [2020]Programmed death ligand 1 (PDL1, CD274, B7-H1) has been identified as the ligand for the immune inhibitory receptor programmed death 1 protein (PD1/PDCD1). PDL1 is a member of B7 family of immune molecules and this protein together with PDL2, are two ligands for PD1 expressed on activated lymphoid cells. By binding to PD1 on activated T cells, PDL1 may inhibit T cell responses by inducing apoptosis. Accordingly, it leads to the immune evasion of cancers and contribute to tumor growth, thus PDL1 is regarded as therapeutic target for malignant cancers. We selected PDL1 specific nanobodies from a high quality dromedary camel immune library by phage display technology, three anti-PDL1-VHHs were developed.
Evaluation on the Distribution of EGFR, KRAS and BRAF Genes and the Expression of PD-L1 in Different Types of Lung Cancer. [2022]To evaluate the distribution of high frequency mutant genes and the expression of PDL1 in different types of lung cancer.