Nasopharyngeal Cancer

This is a first in human, Phase 0/1, open-label study of 177Lu-RAD204 consisting of an Imaging Period with 177Lu-RAD204im (imaging dose) and a Treatment Period with 177Lu-RAD204tr (treatment dose) to determine the recommended dose(s) for future exploration of 177Lu-RAD204 in participants with PDL1+ advanced solid tumors. Screening Period: Screening Period of up to 4 weeks. Phase 0 (Imaging Period): Low dose (10mCi) of 177Lu-RAD204 administered on Imaging Day 1 with a follow-up period of up to 2 weeks to assess imaging, safety and dosimetry. The dose may be increased, if needed, to improve image quality. Phase 1 (treatment Period): 177Lu-RAD204tr dose escalation * Treatment Period with each cycle lasting 6 weeks. Extension of the planned dose intervals are possible following discussion and agreement between the Sponsor and Investigator. * Participants may be treated with multiple cycles, as long as they appear to derive clinical benefit as determined by the Investigator and provided there is adequate clinical safety and organ dosimetry data. * Dose Limiting Toxicity (DLT) observation period for 177Lu-RAD204tr is 6 weeks following the first injection of 177Lu-RAD204tr. * Should an alternative treatment schedule be explored, the DLT observation period for 177Lu-RAD204tr at that dose level will be the proposed cycle duration.

Enrolled patients with complete metabolic response (CMR) and more than 70% partial metabolic response (PMR) according to PERCIST criteria at the 25th fraction will receive intensity modulated radiation therapy (IMRT) of reduced-dose (prescribed dose, 63.6 Gy, 2.12 Gy per fractions, 30 fractions), for those who with ≤70% PMR will receive conventional dose (prescribed dose, 70Gy, 2.12 Gy per fractions, 33 fractions).

It is estimated that 65,000 new cases of head and neck squamous cell carcinoma (HNSCC) were diagnosed in the United States in 2020. The incidence of HNSCC is projected to increase 30% worldwide by 2030. Surgical resection is the preferred treatment for oral cavity cancer and frequently plays a role in the management of oropharyngeal and laryngeal cancer. Approximately 70-80% of patients who undergo primary resection for oropharyngeal HNSCC will receive post-operative radiotherapy. Post-operative radiotherapy is generally indicated for HNSCC with features associated with high risk of locoregional recurrence, such as stage pT3 or pT4 primary tumors, close or positive margins, multiple involved lymph nodes, extranodal extension, or the presence of multiple additional high risk features such as lymphovascular invasion, perineural invasion, deep depth of invasion, or high grade. The delineation of post-operative target volumes for localization and radiation planning can be difficult for the treating radiation oncologist due to post-operative anatomy changes from surgical manipulation of tissues, loss of normal tissue planes, and post-operative fluid collections. Post-operative radiotherapy treatment plans and volumes are usually delineated by the radiation oncologist based on review of a combination of data points including operative reports, pre-operative and post-operative diagnostic images, pathology reports, identification of surgical clips, and discussions with the treating head and neck surgeon and/or pathologists. Generally, the post-operative Clinical Target Volume for the primary tumor (CTVp) should include the primary tumor operative bed with a suitable margin to account for microscopic spread and is generally treated to 60Gy. For tumors with a positive margin, some radiation oncologists may choose to boost the area of positive margin up to 66Gy. The CTV boost (CTVb) can be difficult to visualize, and accurate understanding of the location of the positive margin can influence how small or large the boost volume is and thus dose to adjacent normal tissues, or organs at risk (OARs). Optical 3D scanning technology has been a standard procedure quality control in industrial manufacturing for years. Due to its speed, accuracy, and relative ease of use, 3D scanning has steadily proven its utility in medicine over the past decade. The investigators have developed a protocol for optical 3D scanning of the specimen to improve communication between the OR and pathology lab (Figure 2). The resected specimen is scanned using a structured light 3D scanner. Graphics software is then used to virtually ink and annotate 3D specimen models, indicating and clearly defining the specific anatomic locations of the frozen section margins (Figure 3). In the present study, the investigators aim to use the patient-specific 3D specimen maps to improve communication between surgeons and radiation oncologists for adjuvant radiation therapy treatment planning and determine the impact of these 3D specimen maps on CTVs and OARs. 3D innovations are numerous and have become a well-established avenue of research in otolaryngology and a variety of other fields over the past decade. Optical innovations increasingly represent a new diagnostic modality that has demonstrated potential for intraoperative guidance.The team of investigators has previously published a study on the use of 3D scanning technology and virtual graphics software to bridge the gap between the operating room and pathology lab. The investigators determined this relatively simple, non-invasive technique to be a valuable communication tool for surgeons and pathologists responsible for the care of patients with head and neck cancer. However, the utilization of this technology in post-operative discussions and treatment planning with radiation oncologists has yet to be evaluated. The overarching goal of this research is to improve communication and mutual comprehension between the surgeon, pathologist, and radiation oncologist using commercially available, readily implementable 3D scanning technology and virtual graphics software thus to improve delineation of post-operative radiation therapy target volumes for patients with head and neck cancer. The primary objective of this study is to measure the impact of patient-specific 3D specimen maps on adjuvant radiation treatment volumes and doses to critical organs. All patients will receive standard-of-care post-operative radiotherapy not impacted by the experimental 3D specimen maps. The secondary objective is to demonstrate the feasibility of incorporating 3D specimen mapping tools into post-operative communication, and to determine if utilization of the 3D specimen map improves post-operative communication between surgeons, pathologists, and radiation oncologists. Aim #1 - Measure the impact of patient-specific 3D specimen maps on adjuvant radiation treatment fields The investigators hypothesize that the use of virtual 3D specimen mapping in radiation treatment planning will impact clinical target volumes (CTVs) to the primary tumor bed (CTVp) and/or boost (CTVb) and doses to adjacent organs at risk because of improved understanding of gross and microscopic tumor involvement. The investigators will compare volume measurements between CTVs of two radiation treatment plans: one using standard of care planning techniques and the other with the addition of virtual 3D specimen mapping. The investigators will also compare radiotherapy doses to determine any changes to adjacent organs at risk between the two radiation treatment plans. All patients will be treated with the standard of care radiation plan that does not incorporate the 3D specimen tool. Aim #2 - Investigate the subjective benefit of 3D specimen mapping on postoperative communication with the radiation oncologist. The investigators hypothesize that 3D scanning and specimen mapping will benefit key stakeholders (surgeons, pathologists, radiation oncologists). Surveys will be administered at baseline and at the end of the study to assess the perceived effect of the 3D specimen tool on post-operative communication of pathology relevant to radiation field design (ie, location of positive or close margins, orientation of gross tumor in specimen, volume of resected specimen, etc).

Iodine-125 seeds Implantation (RISI) for the treatment of tumors, mainly with the help of imaging guidance, the radioactive I-125 seeds radioactive source is directly implanted into the tumor tissue, and the purpose of killing tumor cells is achieved through the continuous release of radiation by radionuclide. At present, it has been clinically used in the local treatment of tumors in head and neck, chest, abdomen, pelvis, spine, columns and limbs. The main technical difficulties in implementing RISI lies in the complexity of operation and the control of operation quality.In the era of unarmed puncture, the quality of operation is difficult to guarantee, and the therapeutic effect is quite different.In 2015, our unit carried out RISI technology under the guidance of 3D model plates, which significantly improved the treatment accuracy of RISI. The current 3D printing templates are divided into two types: non-coplanar template (3D-PNCT) and coplanar template (3D-PCT). In clinical practice, due to the complex technical requirements, high production cost and long printing time of non-coplanar mold board, a considerable number of patients can be well treated with coplanar template.Compared with the non-coplanar individualized template, the coplanar template has the advantages of accurate needle path control, rapid needle path adjustment, convenient real-time optimization, batch production without waiting for template printing time, and the operation is easy to process, easy for doctors to grasp quickly, the cost is lower than non-coplanar template, and easy to carry out at the grass-roots level. However, most of the existing clinical application data of the template come from the non-coplanar template, and the dosimetry, needle path error and clinical effect of particle implantation guided by the coplanar template are still lack of research. Therefore, this study intends to explore the coplanar template technology and analyze the safety and effectiveness of 3D printing coplanar template combined with CT-guided I-125 seeds implantation in the treatment of head and neck malignant tumors. The purpose of this study is to verify the accuracy, short-term efficacy and side effects of 3D printing coplanar template combined with CT-guided I-125 seeds implantation in the treatment of malignant tumors of the head and neck.

In this study, 200 patients with resectable head and neck squamous cell carcinoma (T3 or T4, N0) were enrolled and preoperatively combined with pembrolizumab (PD-1 inhibitor), carboplatin, and albumin-binding paclitaxel. The subjects were randomly divided 1:1 into four treatments and two treatments. The imaging and pathological changes of tumor and paracancer tissues before and after treatment were observed. Clinical information, such as pathological grade, stage, treatment, prognosis, serology, imaging, etc., was collected to evaluate the safety and efficacy of 4-course pembrolizumab combined with carboplatin and albumin-binding paclitaxel compared with 2-course neoadjuvant therapy for resectable oral and oropharyngeal squamous cell carcinoma. This is a prospective, one-arm, phase II clinical study. Main purpose By calculating pathological complete response (pCR) in the experimental group, we evaluated the efficacy (optimality) of four courses of pembrolizumab combined with carboplatin and albumin-binding paclitaxel compared with two courses of neoadjuvant therapy for resectable oral and oropharyngeal squamous cell carcinoma (T3 or T4, N0). At the same time, this study evaluated the safety of medication, specifically: The severity of adverse events associated with neoadjuvant therapy will be graded according to NCI CTCAE (version 5.0) during this study and during follow-up, and the occurrence of adverse events in the experimental and control groups will be compared. To evaluate the safety of 4-course Pembrolizumab combined with carboplatin and albumin-binding paclitaxel compared with 2-course neoadjuvant therapy for resectable oral and oropharyngeal squamous cell carcinoma (T3 or T4, N0). Secondary Purpose 1. The event-free survival (EFS) of the two groups were compared; 2. The main pathological response rate (MPR) of the two groups were compared; 3. pTR of the two groups was compared; 4. Overall survival (OS) of the two groups was compared; 5. The radiological responses of the two groups were compared; 6. The operation delay rate of the two groups was compared; Exploratory purpose For the response of enrolled patients after treatment, group treatment was conducted according to the guidelines, and stratified factors influencing the prognosis and treatment plan of immunotherapy were explored according to stratification. The stratification factors taken into consideration are: P16 status, smoking history, TNM stage, tumor reduction (MPR condition), presence of risk factors (according to the guidelines, risk factors are presence of episopercular invasion, positive incisal margin, proximal incisal margin, pT3 or pT4, pN2 or pN3 lymph nodes located in the IV and V regions of the neck, Nerve invasion, vascular invasion, etc.). The purpose of this study was to stratified risk factors for evaluating the efficacy of pembrolizumab combined with carboplatin and albumin-paclitaxel in neoadjuvant therapy for resectable head and neck squamous cell carcinoma. At the same time, hematological, pathological and fecal indicators collected in the design of the experiment were collected. Correlation analysis was conducted to statistically analyze the relationship between these indicators and the therapeutic effect of the program.

This study intends to enroll low-risk intermediate-stage nasopharyngeal carcinoma patients who achieve CR/PR after induction chemotherapy and whose plasma EBV-DNA level has dropped to 0 or below the lower detection limit. These patients will be randomly assigned at a 1:1 ratio to receive either reduced-dose radiotherapy (40.2Gy) or conventional-dose radiotherapy (49.2Gy) to CTV2. Both groups will receive full-course immunotherapy. The study will follow up to observe differences in survival, adverse events, and quality of life between the two groups. It is expected that, on the premise of maintaining treatment efficacy, reducing the dose to CTV2 can decrease acute and chronic toxicities caused by radiotherapy and chemotherapy, thereby improving patients' quality of life.

At present, radiopharmaceuticals targeting FAP have been developed for the diagnosis and treatment of various tumors. Considering the problems of fast tumor tissue clearance and short retention time in small molecule FAP inhibitors based on quinoline rings, this project optimized their ligands and developed a new FAP targeted technetium labeled molecular imaging probe for SPECT/CT imaging research to evaluate its safety in clinical application and its effectiveness in tumor diagnosis.

The goal of this clinical trial is to evaluate the safety and tolerability of increasing doses of \[177Lu\]Lu-AKIR001, both in relation to tolerable activity of lutetium-177 and the absorbed protein mass dose of AKIR-001 in patients with irresectable or metastatic CD44v6-expressing solid malignancies for whom no reasonable systemic treatment options are be available. The main question it aims to answer is: • What is the toxicity profile of the study drug \[177Lu\]Lu-AKIR001 according to the rate of Dose Limiting Toxicities and (Severe) Adverse Events? Participants will receive one \[177Lu\]Lu-AKIR001 infusion followed by a 6-week safety follow-up period, which can be extended up to 12 weeks. Possible additional infusions of the trial drug, up to a maximum number of four, can be given when clinical benefit is noted and toxicity is deemed acceptable.

Background: * Somatostatin receptors (SSTR) have been shown to be over-expressed in a number of human tumors, including gastrointestinal (GI) neuroendocrine tumors (NET), pheochromocytoma/paragangliomas (PPGL), small cell lung cancers (SCLC), kidney cancers (KC), and some head and neck (H\&N) cancers. * Targeted radioligand therapy (TRT) is a class of cancer therapeutic agents formed by attaching a radioactive isotope to a ligand that can target specific surface receptors such as SSTR on a tumor cell membrane. Efficacy is typically determined by the radiation dose deposited onto a tumor, which is determined by the radioactive isotope being used as well as the binding characteristics of the ligand-receptor/transporter pair. * Alpha emitters such as 212Pb emit alpha particles that are more damaging to tumor cells than beta emitters such as 177Lu. Therefore, TRT agents using alpha emitters are considered to be more potent than beta-emitting TRTs. * VMT-Alpha-NET is a peptide that binds to SSTR, which when attached to 212Pb becomes an alpha particle-emitting TRT that can be used to treat tumors that have SSTR surface expression. * \[203Pb\]VMT-Alpha-NET is the chemically identical imaging surrogate for \[212Pb\]VMT-Alpha-NET and has the same mechanism of action via binding to SSTR2. The nuclide 203Pb contained in \[203Pb\]VMT-Alpha-NET emits gamma radiation suitable for single-photon emission computerized tomography (SPECT) imaging. These images can be used to assess drug product biodistribution throughout the body. Objective: -To determine the maximum tolerated dose (MTD) of \[212Pb\]VMT-Alpha-NET (dose escalation cohort) and assess the safety of \[212Pb\]VMT-Alpha-NET at the MTD (dose expansions cohorts). Eligibility: * Age \>= 18 years. * Histopathologically confirmed GI NET, PPGL, SCLC, KC, or H\&N (nasopharyngeal carcinoma \[NPC\], olfactory neuroblastoma \[ONB\], sinonasal neuroendocrine carcinoma \[SNEC\]) cancers that are metastatic or inoperable. * No prior systemic radioligand therapy. * Eastern Cooperative Oncology Group (ECOG) Performance Status \<= 1. Design: * This is an open-label, single-arm, single-center, phase I study evaluating the safety, preliminary efficacy, and pharmacokinetic properties of \[212Pb\]VMT-Alpha-NET in GI NET, PPGL, SCLC, KC, or H\&N cancers. * First, participants will be accrued in Dose Escalation Part with 4 dose levels to estimate MTD of \[212Pb\]VMT-Alpha-NET. Once MTD is estimated, the following participants with GI NET, PPGL, SCLC, KC, or H\&N cancers will be accrued in separate cohorts and treated at MTD of \[212Pb\]VMT-Alpha-NET. * \[212Pb\]VMT-Alpha-NET will be given IV every 8 weeks for a total of 4 administrations. * A subset of participants (Dosimetry Arm 1) will have \[203Pb\]VMT-Alpha-NET administration followed by whole-body gamma scans combined with dosimetry SPECT/ Computed Tomography (CT) scans and collection of blood and urine samples prior to each cycle. * Participants will have timed clinical laboratory evaluations, imaging studies, and research blood, and urine samples while on the study therapy for safety and efficacy evaluations. * Following completion of treatment, participants will be seen at the NIH Clinical Center approximately 30 days later, every 12 weeks for 3 years after that for safety and efficacy assessments. Beyond 3 years, participants will be contacted annually through any NIH-approved platform to assess for overall survival and health status.

This is a Phase 1/2a, open-label, first-in-human study of T3011 given via intratumoral (IT) injection as a single agent and in combination with IV pembrolizumab in participants with advanced or metastatic solid tumors. The Phase 1 portion of the study is a single agent dose escalation which will use a 3+3 design to evaluate escalating doses of T3011. Total enrollment will depend on the toxicities and/or activity observed, with approximately 15 to 30 evaluable participants enrolled. Once the RP2D is established Phase 2a Part 1 will enroll approximately 10 participants with locally recurrent or metastatic melanoma (in Arm A) 23 to 53 participants with HNSCC in Arm B, 40 to 80 participants with sarcoma in Arm C and 10 participants with cSCC in Arm D. During Phase 2a Part 1 the safety, tolerability, and preliminary efficacy of T3011 as a single agent will be evaluated. Phase 2a Part 2 will enroll in parallel to Phase 2a Part 1 once the RP2D is established. The safety, tolerability, and preliminary efficacy of IT T3011 given in combination with IV pembrolizumab will be evaluated in 15 participants with histologically or pathologically confirmed metastatic NSCLC (Arm E). A rollover arm is also included in this study to allow participants who have documented progression on T3011 alone to receive T3011 in combination with pembrolizumab if considered eligible.