Brief Summary
This study is being done to learn more about a new medicine called PF-08634404. It is for adults with a type of bladder cancer called locally advanced or metastatic urothelial cancer (LA/mUC), meaning the cancer has spread to nearby tissues or other parts of the body.
The purpose of the study is to see if PF-08634404 is safe, how well it works, how it moves through the body, and how it affects the cancer. The study will also look at how the medicine may change certain markers in the body that are linked to cancer.
To join the study, participants must:
* Be adults (18 years or older) and
* Have locally advanced or metastatic urothelial cancer,
The study has two groups:
* Cohort A: People who have already received treatment for their cancer will get the study medicine ( PF-08634404) alone.
* Cohort B: People who have not had treatment before will get the study medicine along with another cancer medicine called enfortumab vedotin.
Everyone in the study will get the study medicine through a vein (IV infusion) with or without enfortumab vedotin. Treatment will continue as long as it helps and side effects are manageable.
Before starting, participants will go through a screening period to check if they are eligible. During the study, they will have regular visits for treatment, health checks, and tests to see how the cancer is responding. Scans will be done regularly to monitor the cancer.
If the cancer gets worse but the treatment is still helping and side effects are manageable, participants may be allowed to continue treatment with their doctor’s and the sponsor’s agreement.
Protocol Interventions
Biological: PF-08634404, Biological: Enfortumab Vedotin
Brief Summary
This phase III trial compares the effectiveness of pembrolizumab and sacituzumab govitecan-hziy to standard of care in treating patients with urothelial cancer that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread to other places in the body (metastatic). 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. Sacituzumab govitecan-hziy is a monoclonal antibody, called sacituzumab, linked to a chemotherapy drug called govitecan-hziy. Sacituzumab attaches to TROP2 positive tumor cells in a targeted way and delivers govitecan-hziy to kill them. The usual treatment approach is treatment with chemotherapy such as cisplatin, carboplatin, gemcitabine, docetaxel or paclitaxel. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid and may kill tumor cells. Docetaxel is in a class of medications called taxanes. It stops tumor cells from growing and dividing and may kill them. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Giving pembrolizumab and sacituzumab govitecan-hziy may be more effective than usual care of carboplatin or cisplatin with gemcitabine, docetaxel or paclitaxel in treating patients with locally advanced or metastatic urothelial cancer.
Protocol Interventions
Procedure: Biospecimen Collection, Procedure: Computed Tomography, Procedure: Magnetic Resonance Imaging, Biological: Pembrolizumab, Other: Questionnaire Administration, Biological: Sacituzumab Govitecan
Brief Summary
The purpose of this study is to test a new medicine, vepugratinib, in comparison with placebo, to see if it is safe and can help people with a bladder cancer that is advanced or has spread.
Vepugratinib or placebo will be administered in combination with enfortumab vedotin and pembrolizumab.
Study participation could last up to approximately 6 years.
Protocol Interventions
Other: Placebo, Drug: EV, Drug: Pembrolizumab
Brief Summary
This is a global, multicenter, randomized, open-label, Phase 2/3 study of Dato-DXd plus carboplatin or cisplatin versus gemcitabine plus carboplatin or cisplatin in participants with la/mUC who progressed during or after EV plus pembrolizumab combination treatment.
This trial will start with part A, Phase 2. During part A, Phase 2, preliminary efficacy and safety will be assessed, and the recommended Phase 3 dose (RP3D) will be identified when the data allow sufficient assessment of activity, safety, and tolerability. The Phase 3 part will start contingent upon the assessment in the Phase 2 part, taking into consideration the totality of information.
Protocol Interventions
Drug: Carboplatin, Drug: Cisplatin, Drug: Gemcitabine
Brief Summary
This is a phase 1 clinical trial to evaluate the safety, feasibility and immunogenicity of a personalized cancer vaccine strategy in patients with solid tumors and molecular residual disease. The hypothesis of the trial is that synthetic long peptide personalized cancer vaccines will be safe and capable of generating measurable neoantigen-specific T-cell responses enabling ctDNA clearance. The personalized cancer vaccines are composed of synthetic long peptides corresponding to prioritized cancer neoantigens and will be co-administered with poly-ICLC.
Protocol Interventions
Biological: Synthetic long peptide personalized cancer vaccine, Drug: Poly ICLC, Device: Signatera assay
Brief Summary
This phase II/III trial examines whether patients who have undergone surgical removal of bladder, kidney, ureter or urethra, but require an additional treatment called immunotherapy to help prevent their urinary tract (urothelial) cancer from coming back, can be identified by a blood test. Many types of tumors tend to lose cells or release different types of cellular products including their DNA which is referred to as circulating tumor DNA (ctDNA) into the bloodstream before changes can be seen on scans. Health care providers can measure the level of ctDNA in blood or other bodily fluids to determine which patients are at higher risk for disease progression or relapse. In this study, a blood test is used to measure ctDNA and see if there is still cancer somewhere in the body after surgery and if giving a treatment will help eliminate the cancer. Immunotherapy with monoclonal antibodies, such as nivolumab and relatlimab, can help the body’s immune system to attack the cancer, and can interfere with the ability of tumor cells to grow and spread. This trial may help doctors determine if ctDNA measurement in blood can better identify patients that need additional treatment, if treatment with nivolumab prolongs patients’ life and whether the additional immunotherapy treatment with relatlimab extends time without disease progression or prolongs life of urothelial cancer patients who have undergone surgical removal of their bladder, kidney, ureter or urethra.
Protocol Interventions
Procedure: Biospecimen Collection, Other: cfDNA or ctDNA Measurement, Procedure: Computed Tomography, Procedure: Cystoscopy, Procedure: Magnetic Resonance Imaging, Biological: Nivolumab, Other: Questionnaire Administration
Brief Summary
This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the safety and preliminary efficacy of sacituzumab tirumotecan plus enfortumab vedotin (EV). Part 2 will be based on Part 1 results and will evaluate the efficacy, pharmacokinetics, and safety of sacituzumab tirumotecan plus EV in combination with pembrolizumab in participants with advanced urothelial carcinoma.
Protocol Interventions
Biological: Sacituzumab tirumotecan, Biological: Enfortumab Vedotin, Biological: Pembrolizumab, Drug: Supportive care measures
Brief Summary
The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435 by itself or when it is combined with other standard medicines that treat cancer. LOXO-435 may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as the FGFR3 gene). Participation could last up to 30 months (2.5 years) and possibly longer if the disease does not get worse.
Protocol Interventions
Drug: LOXO-435, Drug: Pembrolizumab, Drug: enfortumab vedotin
Brief Summary
Upon successful screening and registration, enrollment to a cohort will begin. If DLT criteria are exceeded in a cohort, that cohort will close and will not proceed to Phase 2 of the study. Provided the safety of a cohort is established, enrollment will continue. Within BCG-containing cohorts, treatment will begin at full-dose BCG. If DLT criteria are exceeded with full-dose BCG, a one level dose reduction of BCG will be implemented. If DLT criteria are exceeded with reduced-dose BCG, the BCG-containing cohort will not proceed to Phase 2 of the study
Phase 1 Cohorts:
* Durvalumab Monotherapy (cohort 1); ENROLLMENT COMPLETE
* Durvalumab plus BCG (cohort 2); ENROLLMENT COMPLETE
* Durvalumab plus External Beam Radiotherapy (EBRT) (cohort 3); ENROLLMENT COMPLETE
* Durvalumab plus Intravesical Gemcitabine plus Intravesical Docetaxel (cohort 4); ENROLLMENT COMPLETE
* Durvalumab plus Tremelimumab plus Intravesical Gemcitabine plus Intravesical Docetaxel (cohort 5); ENROLLMENT DID NOT OCCUR
* Intravesical N-803NAI plus Intravesical Gemcitabine (cohort 6)
* Intravesical N-803NAI plus Intravesical Gemcitabine plus Intravesical Docetaxel (cohort 7)
* Subcutaneous N-803NAI plus Intravesical N-803NAI plus Intravesical Gemcitabine plus Intravesical Docetaxel (cohort 8)
If any of the combination regimen cohorts establishes a RP2D in Phase 1 of the study, enrollment to Phase 2 of the study may proceed within the individual phase 2 expansion cohorts defined by patient BCG exposure history. Upon successful screening and registration, Phase 2 subjects will be assigned to one of the treatment arms. Assignment will occur amongst the arms that are open to accrual at the time of subject registration. Phase 2 subjects will be administered treatment at the RP2D’s established for each regimen within Phase 1 of the study.
However, within BCG-containing cohorts, the BCG dose will be reduced to Dose level -1 (1/3rd-dose BCG) even if the RP2D established in the Phase 1 of the study was full-dose BCG. The rationale for this stems from ongoing global BCG supply shortages that have arisen since the launch of the trial and multiple prior clinical trials demonstrating similar efficacy with decreased toxicity when reduced-dose BCG regimens are utilized compared to full-dose BCG therapy. This modification was deemed necessary to facilitate continued enrollment to the study while not sacrificing clinical efficacy or safety. This modification also aligns with recent AUA consensus guidelines on BCG dosing during BCG shortages.
It is anticipated that individual treatment cohorts will be closed and added during the conduct of the study as cohorts complete accrual, individual cohort safety data is analyzed, and new cohorts are added. Enrollment to Phase 2 cohorts will not begin until at least one cohort has successfully established a RP2D in the Phase 1 portion of the study and deemed safe to proceed to the Phase 2 portion of the trial.
Protocol Interventions
Other: To be determined
