Marshall

Researchers are investigating the effectiveness and safety of a combination treatment involving inavolisib, ribociclib, and fulvestrant compared to a placebo combined with ribociclib and fulvestrant. This study focuses on people with advanced breast cancer that is hormone receptor-positive, HER2-negative, resistant to endocrine therapy, and has chromosome 8p loss but no PIK3CA mutation. The trial is a Phase II, randomized, double-blind study designed to assess how well these treatments work in this specific group of patients. Participants will receive either the triplet combination of inavolisib plus ribociclib and fulvestrant or a placebo plus ribociclib and fulvestrant. All medications will be given according to the schedules outlined in the study protocol. The study evaluates the treatments in the first-line setting for patients with locally advanced or metastatic breast cancer not suitable for surgery or radiation with curative intent. During the study, participants will undergo evaluations to confirm tumor response and measure disease progression using established criteria. Researchers will monitor safety and effectiveness outcomes, including the percentage of participants with a confirmed objective response over approximately two years. The study includes central laboratory testing to confirm biomarker eligibility, and participants will be followed closely to assess treatment impact and side effects throughout the trial period.

Researchers are evaluating the effectiveness of pembrolizumab combined with sacituzumab govitecan-hziy compared to the standard chemotherapy treatments in patients with locally advanced or metastatic urothelial cancer. This Phase III trial focuses on cancers that have spread to nearby tissues, lymph nodes, or other parts of the body. The study aims to compare overall survival and other outcomes such as progression-free survival, response rates, clinical benefits, duration of response, and treatment toxicity between the two treatment approaches. Quality of life and fatigue are also assessed as secondary measures. Participants are randomly assigned to one of two treatment groups. One group receives standard of care chemotherapy, which may include carboplatin or cisplatin combined with gemcitabine, or alternatively docetaxel or paclitaxel, administered intravenously in cycles every 21 days for up to six cycles, unless the disease progresses or side effects become unacceptable. The other group receives sacituzumab govitecan-hziy intravenously on days 1 and 8, along with pembrolizumab intravenously on day 1 of each 21-day cycle, continuing for up to 35 cycles or two years, unless there is disease progression or unacceptable toxicity. Throughout the study, participants undergo regular blood sample collections and imaging scans using computed tomography or magnetic resonance imaging to monitor their condition. Quality of life questionnaires are also completed to assess symptoms and fatigue over time. After treatment ends, patients are followed up 30 days later and then annually for up to five years to evaluate long-term outcomes and safety. The main outcome measured is overall survival from the time of randomization up to five years.

Researchers are studying the wide range of molecular features found in people receiving care within a large community-based healthcare system. They aim to understand the genetic causes of premalignant and malignant conditions across different cancer types and stages by using comprehensive genomic profiling. This includes tumor testing with next-generation sequencing, and some samples may undergo advanced sequencing methods for research. Pharmacogenomic testing will also be done to explore how individuals respond differently to medications. Participants may optionally provide microbiome samples to add more information. Participants will have their tumor tissue or blood tested for genetic information, which will be linked to their electronic health records that include past and future health data. This detailed clinical information will be carefully collected and connected to the genetic data from the study. Participants can also choose to store their biological samples in a biobank and allow their anonymous data to be used in future research. This combination of genetic and clinical data will help researchers better understand cancer biology and discover markers related to patient outcomes. During the study, researchers will monitor how many participants complete the full molecular profiling, how many are referred for genetic testing in their family members, and how many get referred to clinical trials targeting specific molecular features, all over a five-year period. This long-term participation will support collaborative research efforts and promote new advances in cancer research. Participants will contribute valuable information through genetic testing, health record review, and optional sample storage to help improve future cancer care.

Researchers are evaluating a new medicine called PF-08634404 to see how well it works in adults with colorectal cancer that has spread or returned after previous treatments. This study focuses on whether PF-08634404 combined with approved chemotherapy can help patients compared to another approved medicine called Bevacizumab combined with chemotherapy. The study is a Phase 3, double-blind, randomized trial involving participants who have metastatic colorectal cancer and have not received prior systemic therapy for metastatic disease. Participants will be randomly assigned to one of two groups: one receiving PF-08634404 plus chemotherapy, and the other receiving Bevacizumab plus chemotherapy. Both treatments are given by intravenous infusion in cycles. Participants may continue treatment if it is beneficial and side effects are manageable. Treatments are administered at clinical sites with medical staff monitoring participants during and after each infusion. During the approximately 33-month study, participants will visit the study site regularly for treatment, health checks, and tests. After stopping treatment, there will be a follow-up visit about 30 to 37 days later to assess health and side effects. Participants will also have follow-up every 12 weeks by phone, in person, or through health record reviews to monitor their health status and any new treatments. The main outcomes measured include progression-free survival and overall survival over about 4 years.

PRIMARY OBJECTIVE: I. To determine investigator assessed progression-free survival using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (non-inferiority) for one versus (vs.) two years of maintenance olaparib. SECONDARY OBJECTIVES: I. To evaluate overall survival (OS360) in the modified intent to treat (ITT) population, with time at risk for progression/death starting 360 days after randomization. II. To evaluate progression-free survival (PFS), PFS2 and overall survival (OS) in the ITT population. III. To evaluate PFS, PFS2, and OS in the as-treated population. IV. To evaluate toxicity, including rates of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and other secondary malignancies, in the safety population. EXPLORATORY OBJECTIVE: I. To evaluate the moderating effect of physician-choice bevacizumab (as stratified) on randomized treatment effect estimates. TRANSLATIONAL OBJECTIVES: I. To assess BRCA reversion mutations in circulating tumor deoxyribonucleic acid (ctDNA) as a predictor of poor response in the BRCA mutated (BRCAm) population. II. To correlate a combined assay assessing quantitative BRCA1 and RAD51C promoter methylation and pathogenic variants in core homologous recombination repair (HRR) genes with clinical homologous recombination deficiency (HRD) testing and outcomes in the BRCA wildtype (BRCAwt) population. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (REFERENCE): Patients receive olaparib orally (PO) twice daily (BID) on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the study. ARM II (EXPERIMENTAL): Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.

PRIMARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) and pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive endometrial cancer. SECONDARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) and pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive endometrial cancer. II. To evaluate the overall response rate (ORR) in patients with measurable disease. III. To evaluate the duration of objective response in patients with measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. IV. To determine the nature, frequency and degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0 for each treatment arm. V. To compare quality of life (QOL), as measured by Functional Assessment of Cancer Therapy - Endometrial Trial Outcome Index (FACT-En-TOI), in the experimental versus control arms. VI. To compare patient-reported treatment-associated symptoms (diarrhea and rash) as measured with the Patient Reported Outcomes (PRO) - CTCAE, patient-reported fatigue as measured with the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue short form, and worry concerning side effects of treatment as measured by the item 'bothered by side effect', in the FACT-En TOI, respectively, in the experimental and control arms. VII. To assess the correlation of HER2 immunohistochemistry (IHC) expression and in situ hybridization (ISH) amplification with clinical outcome and response to HER2 targeted therapies. EXPLORATORY OBJECTIVE: I. To explore time to sustained deterioration in quality of life, as measured by a drop in the FACT-En-TOI by 6 or more points lasting for more than one PRO time point, in the experimental and control arms. OUTLINE: Patients are randomized to 1 of 3 arms. ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with stable disease (SD) or partial response (PR) who still have measurable disease after completion of cycle 6 may receive 4 additional cycles of this treatment at the discretion of the treating physician. ARM II: Patients receive paclitaxel IV over 3 hours, carboplatin IV over 30-60 minutes, and trastuzumab/hyaluronidase-oysk subcutaneously (SC) over 2-5 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease after completion of cycle 6 may receive 4 additional cycles of this treatment at the discretion of the treating physician. MAINTENANCE: Patients receive trastuzumab/hyaluronidase-oysk SC over 2-5 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients with SD or PR may continue maintenance therapy for up to 3 years from the start of treatment. ARM III: Patients receive paclitaxel IV over 3 hours, carboplatin IV over 30-60 minutes, and pertuzumab/trastuzumab/hyaluronidase-zzxf SC over 5-8 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease after completion of cycle 6 may receive 4 additional cycles of this treatment at the discretion of the treating physician. MAINTENANCE: Patients receive pertuzumab/trastuzumab/ hyaluronidase-zzxf SC over 5 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for up to 1 year in absence of disease progression or unacceptable toxicity. Patients with SD or PR may continue maintenance for up to 3 years from the start of treatment. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and computed tomography (CT) throughout the study. Additionally, patients may optionally undergo blood sample collection throughout the study, vaginal brachytherapy on study, and urine sample collection prior to treatment. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.