Metastatic Cancer

Peptide receptor radionuclide therapy (PRRT) may be recommended in G1- G2 GEP-NET patients with disease progression on somatostatine analogues therapy (LUTATHERA®). However, there are several diseases, including neuroendocrine neoplasia not originating from the digestive tract, for which the efficacy of PRRT has already been demonstrated, but which are not currently within the indications of LUTATHERA and therefore cannot benefit from it (i.e. bronchopulmonary, ovarian, renal NETs and neuroendocrine carcinomas). Moreover, the role of PRRT is also accepted in Pheochromocytomas and paragangliomas (PPGLs), Meningiomas, but also as a salvage therapy in pre-treated NET pts, and other SSTR-positive malignancies (Lymphomas, Gliomas…). Least explored among radiopharmaceuticals for SSTR-positive tumors is 177Lu-DOTATOC. This study aims to investigate the efficacy and safety of lutetium (177Lu) edotreotide (Lu-Dotatoc) on all the above-mentioned diseases that could benefit from receptor radionuclide therapy. We believe that this study, which will involve only patients outside the indication of LUTATHERA, will expand the current knowledge of radionuclide receptor therapy with 177Lu- DOTATOC, particularly with regard to objective response and safety parameters, and may consolidate its in the management of these diseases.

Assuming the following hypotheses: H0: The mPFS of the test group minus the mPFS of the control group equals 0 H1: The mPFS of the test group minus the mPFS of the control group does not equal 0 Assuming an mPFS of 5.0 months for the test group and 1.8 months for the control group, with a two-sided alpha level of 0.05 and 80% power, at least 32 events need to be observed. Within a 9-month enrollment period and a total study duration of 15 months, 44 subjects need to be enrolled to achieve this. Considering an additional dropout rate of 15%, 26 subjects per group are required, totaling 52 subjects (using PASS 2023 Log-rank procedure). Enrollment sites: Beijing Friendship Hospital, Capital Medical University, Peking Union Medical College Hospital, Peking University People's Hospital. Allocation of enrollment across sites: Each site will compete for enrollment, with each site enrolling no less than 14 subjects. 1. Regorafenib: Start at 80 mg once daily, orally, taken at a fixed time for 2 consecutive weeks and then stopped for 1 week. If the patient tolerates it well, increase to 120 mg/d in Cycle 2. 2. Tislelizumab: 200 mg, iv.gtt, single infusion, 21 days as a cycle, Day 1. 3. Thymalfasin: 4.8 mg, administered subcutaneously twice weekly. Treatment will continue until disease progression or until an intolerable adverse reaction occurs that does not resolve despite dose modification.

This study is a phase II non-randomised, multi-centre, single arm trial of image-guided (IG)-SABR for patients with high-risk centrally located T1-T4 lung tumours (NSCLC) or a single pulmonary oligometastatic lesions. Treatment will consist of IG-SABR using a total of 8 fractions of 7.5 Gy per fraction adhering to organ at risk dose-volume histogram constraints allowing a minimum dose coverage of 75% to 95% of the planning target volume (PTV) coverage, and a minimum dose of 87% to 99% of the gross tumour volume (GTV), using dose intensity modulation. The primary aim of the study is to determine the safety of the 8 x 7.5 Gy treatment regimen on the basis of the rate of ≥ Grade 3 treatment related toxicity using NCI CTCAE V5, in patients with medically inoperable early stage, ultracentrally located lung tumours. This is defined by central tumours which are not fulfilling the conservative hybrid DVCs of the LungTech (Adebahr et al., 2015), RTOG 0813 (Bezjak et al., 2015) studies and current UK consortium guidelines with full dose coverage, but which subsequently meet SOURCE DVC's with potentially reduced dose coverage. To remain in line with international practice, the SOURCE Lung protocol was amended to reduce near maximum dose constraints to 0.1cc for OARs (Diez et al. 2022). Toxicities occurring between start of treatment and one-year from the end of treatment, which are possibly, probably or definitely related to radiotherapy will be assessed. A total of 60 evaluable patients will be required for the study. The sample size was calculated using continuous monitoring for toxicity, up to one year post RT, using a Pocock-type boundary. Accrual will be halted if excessive numbers of ≥ Grade 3 TxR-AEs are seen. The regime will not be considered to be safe if \>25% of evaluable patients experience a ≥ Grade 3 treatment-related adverse event (TxR-AE) by the end of 1-year post-RT. This study will be considered adequately safe if ≤ 25% of evaluable patients experience ≥ Grade 3 TxR-AE by the end of 1 year post-RT. The enrolment period is expected to be 6 years. Toxicity assessments will be carried out weekly during radiotherapy (RT), at 2, 4 and 8-weeks post-treatment and at 3, 6, 9, 12, 18, 24 months post treatment and annually thereafter to 5 years post treatment. Translational Sub-Study 1 (Raman spectroscopic analysis) - Primary aim is to undertake biomarker discovery using label-free Raman spectroscopy coupled with multivariate statistical methods to identify spectral biomarkers that could: 1. Predict response based on individual radiation sensitivity 2. Monitor response based on individual radiation sensitivity Translational Sub-Study 2 (Proteomic analysis) - Primary aim is to use proteomic analysis of sequential blood samples before, during and after treatment to detect changes in protein expression profiles that may predict outcome and identify prognostic biochemical markers of early toxicity.

Patients with cancer receiving systemic anti-cancer treatments have been generally assumed by many to be at a higher risk from the disease than their counterparts are who are not receiving anticancer treatment. However, their risk of morbidity and mortality from COVID-19 as a consequence of severe acute respiratory syndrome coronavirus 2 infection is not uniform across the world. The evidence to support this claim is scarce and limited to retrospective series arising from China, the epicenter of the COVID-19 pandemic, and involving small numbers of patients. However, despite these severe limitations, the promulgation of this hypothesis has led to widespread global changes to patterns of prescribing chemotherapy and anticancer treatment. In a global health emergency, oncologists, must secure evidence from a large datasets, which can then inform their risk-benefit analyses for individual patients in terms of the use of anticancer treatments. On March 18, 2020, the investigators launched the UK Coronavirus Cancer Monitoring Project (UKCCMP), with widespread support across our national cancer network. 8 Within 5 weeks, the UKCCMP had generated the largest prospective database of COVID-19 in patients with cancer that had been generated to date. the investigators aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in this cohort of patients with cancer and symptomatic COVID-19, and attempted to assess how the presence of cancer and the receipt of cytotoxic chemotherapy and other anticancer treatments affects the COVID-19 disease phenotype. New Taipei City Municipal Hospital has established a special infectious pneumonia ward in May 2021 to treat patients infected with symptomatic severe acute respiratory syndrome coronavirus 2 patients. During the period, 97 patients were admitted and treated with 10 infection-related deaths. In light of the current timing of the pandemic, most published serological studies are predominantly cross-sectional, or at most, include a longitudinal follow-up of few months. Severe acute respiratory syndrome coronavirus 2 has spread globally over the past year, infecting an immunologically naive population and causing significant morbidity and mortality. Immunity to severe acute respiratory syndrome coronavirus 2 induced either through natural infection or vaccination has been shown to afford a degree of protection against reinfection and/or reduce the risk of clinically significant outcomes. Seropositive recovered subjects have been estimated to have 89% protection from reinfection, and vaccine efficacies from 50 to 95% have been reported. However, the duration of protective immunity is presently unclear, primary immune responses are inevitably waning, and there is ongoing transmission of increasingly concerning viral variants that may escape control by both vaccine-induced and convalescent immune responses. Age is considered one of the most crucial covariates that affect phenotypes. However, aging rate may vary among different populations due to genetic variation or miscellaneous environmental exposures. Chronological age is not a perfect proxy for the true biological aging status of the body. A new biological aging measure, phenotypic age (PhenoAge), has been shown to capture morbidity and mortality risk in the general US population and diverse subpopulations. However, how the phenotypic age affect host immunity is not well investigated. There are currently no effective therapies for severe acute respiratory syndrome coronavirus 2, which causes severe respiratory illness or death. Serum neutralizing antibodies rapidly appear after severe acute respiratory syndrome coronavirus 2 infection and vaccination. However, little was known about the change of protective antibody titers both to nature infection and post vaccination. And there is ongoing transmission of increasingly concerning viral variants that may escape control by both vaccine-induced and convalescent immune responses. Defining the antibody response to severe acute respiratory syndrome coronavirus 2 in patients with cancer receiving anti-cancer therapy, (including chemotherapy, targeted therapy and immunotherapy) will be essential for understanding infection progression, long-term immunity, vaccine efficacy and how phenotypic age affect associated antibodies.

This open-label research study is studying (Z)-endoxifen as a possible treatment for pre-menopausal women with ER+/HER2- breast cancer. (Z)-endoxifen belongs to a group of drugs called selective estrogen receptor modulators or "SERM", which help block estrogen from attaching to cancer cells. This study has two parts: a pharmacokinetic part and a treatment part. The PK part (how the body processes the drug) will enroll about 18 participants. All participants will take (Z)-endoxifen capsules daily. Twelve participants will be randomly assigned (50/50 chance) to take (Z)-endoxifen alone or (Z)-endoxifen with a monthly injection of goserelin a drug that temporarily stops the ovaries from making estrogen. This part will help determine the best dose of (Z)-endoxifen by measuring the drug levels in the blood and how long the body takes to remove it. The Treatment Cohort has been simplified to a single study arm (Z)-endoxifen + goserelin. Up to 20 participants will be enrolled that have a baseline Ki-67 ≤ 10% and 45 participants will be enrolled that have a baseline Ki-67\>10%. A key goal of the study is to see if (Z)-endoxifen can slow down or stop tumor growth as measured by a reduction in Ki-67 levels. Tumor tissue samples will be taken by breast biopsy after about 4 weeks of treatment to check levels of this biomarker. If the tumor shows signs of response, participants can continue treatment for up to 24 weeks or until they have surgery. Study participation is up to 6 months (24 weeks of treatment) followed by surgery and a one-month follow up visit.

Participants eligible for this trial will be randomized 1:1 into one of the two arms (Arm A and Arm B) stratified by: I) -Previous anti-angiogenic therapy (yes vs. no), II) BRAF/RAS mutation status (wildtype vs. mutation) or III) History of liver metastases (never vs. prior but treated). Patients in Arm A (experimental arm) will receive Fruquintinib (orally, 5 mg once a day, at day 1-21 of each 28-day cycle \[Q4W\]) plus Tislelizumab (i.v., 400 mg, at day 1 of each 42-day cycle \[Q6W\]). Patients in Arm B (control arm) will receive Trifluridine/tipiracil (orally, 35 mg/m2 twice a day, day 1-5 and day 8-12 of each 28-day cycle \[Q4W\]) plus Bevacizumab (i.v., 5 mg/kg, at day 1 of each 14-day cycle \[Q2W\]). The treatment will be performed until disease progression, unacceptable toxicity, patients' request, or end of protocol-defined treatment time (maximum of 15 months). All patients will be followed up for a maximum of 18 months after last patient in or until death, withdrawal of consent or loss to follow-up, whatever occurs first.

PRIMARY OBJECTIVE: I. To evaluate the immune response induced by the combination of lutetium Lu 177 vipivotide tetraxetan (177\^Lu-PSMA-617) and sipuleucel-T, using changes in anti-prostatic acid phosphatase (PAP) immunoglobulin G (IgG) antibody titers. SECONDARY OBJECTIVES: I. To evaluate anti-PA2024 antibody titers in patients receiving 177\^Lu-PSMA-617 alone versus in combination with sipuleucel-T. II. To assess the safety and tolerability of 177\^Lu-PSMA-617 plus sipuleucel-T. III. To evaluate the clinical efficacy of 177\^Lu-PSMA-617 alone versus in combination with sipuleucel-T. EXPLORATORY OBJECTIVES: I. To characterize the pharmacokinetics (PK) of 177\^Lu-PSMA-617 plus sipuleucel-T in the blood. II. To determine the impact of 177\^Lu-PSMA-617 in combination with sipuleucel-T on systemic immunomodulation. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A (CONTROL GROUP): Patients receive 177\^Lu-PSMA-617 intravenously (IV). Treatment repeats every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, PSMA positron emission tomography (PET)/computed tomography (CT), bone scan, and magnetic resonance imaging (MRI) throughout the study. Additionally, patients may undergo MRI or CT of the brain throughout the study. ARM B (EXPERIMENTAL GROUP): Patients receive 177\^Lu-PSMA-617 IV. Treatment repeats every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Starting during week 8 of treatment, patients receive sipuleucel-T IV over 1 hour. Treatment repeat every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo leukapheresis, blood sample collection, PSMA PET/CT, bone scan, and MRI throughout the study. Additionally, patients may undergo MRI or CT of the brain throughout the study. After completion of study treatment, patients are followed up at 30 days, every 3 months for up to 1 year then every 6 months until progression followed by survival follow until death or withdrawal of consent.

Integrin αvβ3 is highly expressed in some tumor cells and neovascularization, which is an ideal target for diagnosis and treatment of Integrin αVβ3 positive tumors. 177Lu-AB-3PRGD2, is a kind of new drug based on independent research and development in China, provide an effective target for the treatment of Integrin αVβ3 positive tumors. All patients underwent whole-body 68Ga-RGD PET/CT for selection and accepted intravenous injection with single dose 1.48 GBq (40 mCi) of 177Lu-AB-3PRGD2 within one week. 1-2 ml venous blood was collected at 5min, 3h, 24h, 72h and 168h after administration to detect radioactivity count, respectively. Then monitored at 3, 24, 48, 72, 96, 120 and 168 h after 177Lu-AB-3PRGD2 administration with serial whole body planar and SPECT/CT imaging (72 or 96h). Analyze and calculate the internal radiation dose of 177Lu-AB-3PRGD2 and evaluate its therapeutic efficiency and response.

The purpose of this study is to establish the safety profile, biodistribution, pharmacokinetics (pk), and radiation dosimetry of 177Lu-BetaBart, to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), and to evaluate preliminary anti-tumor activity in select patient populations. The study is divided into 2 phases. Phase 1 is the dose escalation phase to establish the safety profile of 177Lu-BetaBart and to determine the MTD and/or RP2D of 177Lu-BetaBart using a Bayesian Optimal Interval (BOIN) design. Phase 2a is the dose expansion phase at the RP2D to confirm the safety of the MTD and/or RP2D and to evaluate preliminary anti-tumor activity of 177Lu-BetaBart in select patient populations using a probability of success design for the objective response rate (ORR) based on a Bayesian beta-binomial design. Participants ≥ 18 years of age with castration-resistant prostate cancer (CRPC), colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), head and neck squamous cell carcinoma (HNSCC), ovarian cancer, cervical cancer, endometrial cancer, triple negative breast cancer (TNBC), or esophageal squamous cell carcinoma (ESCC) who have documented disease progression during or after their most recent line of anticancer therapy will be eligible to enroll. CRC will be capped at 33% of enrollment per cohort. Each phase consists of a Screening Period, a Treatment and Imaging Period, and a Safety and Long-term Follow-up Period.

Subjects with various types of cancer underwent 18F-FAPI-04 PET/CT and PET/MR imaging either for an initial assessment, recurrence detection or assessment of pathologic response. Tumor uptake was quantified by the maximum standard uptake value (SUVmax) and tumor to background (TBR). Using histopathology and follow-up as gold standard, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 18F-FAPI-04 PET/CT and PET/MR were calculated.