Neoplasms

Symptoms and General Pathology

All Conditions

Rare Diseases

Neoplasm Metastasis

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Pembrolizumab

Somatostatin

Liver Extracts

Lutetium Lu 177 dotatate

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Radiopharmaceuticals

Patients will be treated with pembrolizumab and intravenous peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate (177Lu-DOTATATE, Lutathera®) for up to four (4) sessions. Patients with somatostatin receptor positive (SSTR+) tumors with Ki-67 index \> 20% (well-differentiated grade 3) and any number of liver and/or extrahepatic lesions with liver parenchyma replacement by tumor \< 75%. Patients who achieve progressive or stable disease response after cycle 4 may receive an additional 4 cycles of pembrolizumab and lutetium Lu-177 DOTATATE in the absence of disease progression or unacceptable toxicity and pembrolizumab for up to 35 cycles.

Patients receive pembrolizumab as in Group I. Patients with any number of liver lesions, largest being no larger than 5 cm, who have \< 75% liver parenchyma replacement by tumors, undergo Arterial Embolization (TAE) over 2-3 hours, 3-7 days following the first dose of pembrolizumab.

Patients receive pembrolizumab as in Group I. Patients with any number of liver lesions, largest measuring more than 5 cm, who have \< 75% liver parenchyma replacement by tumors, undergo yttrium-90 microsphere Radio Embolization (RE) 3-15 days following the first dose of pembrolizumab.

Arterial Embolization

Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate

Yttrium-90 Microsphere Radioembolization

Nicholas Fidelman, MD

This pilot phase II trial studies how effective pembrolizumab and liver-directed therapy or peptide receptor radionuclide therapy are at treating patients with well-differentiated neuroendocrine tumors and symptomatic and/or progressive tumors that have spread to the liver (liver metastases). 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. Liver-directed therapies such as radiofrequency ablation, transarterial embolization, yttrium-90 microsphere radioembolization, and cryoablation may help activate the immune system in order to shrink tumors that are not being directly targeted. Peptide receptor radionuclide therapy is a form of targeted treatment that is performed by the use of a small molecule, which carries a radioactive component attached to a peptide. Once injected into the body, this small molecule binds to some specific sites on tumor cells called receptors and emit medium energy radiation that can destroy cells. Because this radionuclide is attached to the peptide, which binds receptors on tumor lesions, the radiation can preferably be targeted to the tumor cells in order to destroy them. Giving pembrolizumab in combination with liver-directed therapy or peptide receptor radionuclide therapy may work better than pembrolizumab alone.

PRIMARY OBJECTIVES:

I. To evaluate safety profile of pembrolizumab in combination with Peptide Receptor Radionuclide Therapy (PRRT), transarterial embolization, and radioembolization.

II. To evaluate the best observed overall response rate (ORR) in lesion(s) not targeted for liver-directed therapy (abscopal effect) to pembrolizumab plus liver-directed therapy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for patients with metastatic well-differentiated (WD) neuroendocrine tumors (NET)s (WD-NETs).

III. To evaluate the best observed ORR to pembrolizumab plus peptide receptor radionuclide therapy (PRRT) according to RECIST 1.1 for patients with metastatic grade 2 and 3 WD-NET (Ki-67 \> 10%).

SECONDARY OBJECTIVES:

I. To evaluate duration of response (DOR) in patients receiving pembrolizumab in combination with liver-directed therapies or PRRT.

II. To evaluate progression free survival (PFS) in subjects treated with pembrolizumab in combination with liver-directed therapies or PRRT.

III. Best observed radiographic ORR per modified RECIST (mRECIST) in lesions targeted for liver-directed therapy.

IV. Duration of response in lesions targeted for liver-directed therapy by mRECIST.

EXPLORATORY OBJECTIVES:

I. To compare ORR, DOR, and PFS based on immune-related (ir)RECIST with the same measures assessed by RECIST 1.1.

II. To correlate clinical outcomes (ORR, DOR, PFS) with baseline immune cell infiltration and PD-L1 staining in cycle 1 and cycle 5 tumor biopsies.

III. To assess the level of PD-L1 expression in tumor tissue prior to liver-directed therapy (prior to PRRT) and 5 weeks following liver-directed therapy (following PRRT).

IV. To assess T cell infiltration on the pre-177Lu-DOTATATE (pre-PRRT) and on the on-treatment tumor tissue biopsies.

V. To assess baseline circulating T cell receptor (TCR) repertories and changes in TCR repertories with treatment, and correlate baseline and turnover of repertories to clinical outcomes.

VI. To analyze the relationship between baseline tumor proliferative index (as measured by Ki67) and response to therapy.

OUTLINE: Patients originally assigned to 1 of 3 groups. As of 09/15/2022, Groups 2 and 3 are closed to enrollment.

GROUP I (PRRT): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. PRRT using 177Lu-DOTATATE(Lutathera®) will be offered to patients with somatostatin receptor positive (SSTR+) tumors with Ki-67 index \> 20% (well-differentiated grade 3). Patients may have any number of liver and/or extrahepatic lesions with liver parenchyma replacement by tumor \< 75%. 200±20 millicurie (mCi) of 177Lu-DOTATATE will be administered intravenously per treatment on outpatient basis. Patients will receive a total of four treatments of 177Lu-DOTATATE, administered every 8±1 weeks. Patients with partial response (PR) or stable disease (SD) by RECIST v. 1.1 after cycle 4 of pembrolizumab who were treated with PRRT (group 1) would continue to receive systemic IV administrations of 177Lu-DOTATATE every 8 +/-1 weeks for up to four (4) treatments. After completion of four (4) PRRT treatments, pembrolizumab may be administered alone for up to 35 cycles

CLOSED - GROUP II (TRANSARTERIAL EMBOLIZATION (TAE)): Patients receive pembrolizumab as in Group I. Patients with any number of liver lesions, largest being no larger than 5 cm, who have \< 75% liver parenchyma replacement by tumors, undergo TAE over 2-3 hours, 3-7 days following the first dose of pembrolizumab.

CLOSED - GROUP III (RADIOEMBOLIZATION (RE)): Patients receive pembrolizumab as in Group I. Patients with any number of liver lesions, largest measuring more than 5 cm, who have \< 75% liver parenchyma replacement by tumors, undergo yttrium-90 microsphere RE 3-15 days following the first dose of pembrolizumab.

After completion of study treatment, patients are followed up at 30 days and then every 3-6 months thereafter.

Pembrolizumab With Liver-Directed or Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors and Liver Metastases

A Pilot Study of Pembrolizumab and Liver-Directed Therapy or Peptide Receptor Radionuclide Therapy for Patients With Well-Differentiated Neuroendocrine Tumors and Symptomatic and/or Progressive Metastases

The All Subjects as Treated (ASaT, ITT) population will be used for the analysis of ORR. The primary efficacy endpoint will be best observed Overall Response Rate (ORR) by RECIST 1.1 (investigator reported). ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). The point estimate and 95% confidence interval of overall response rate will be obtained for each of the three groups separately.

Adverse events occurring from the start of treatment until 30 days after the end of treatment will be summarized by maximum toxicity grade. All treatment related adverse events will be graded using NCI CTCAE v5.0. Safety analysis will include a tabulation of all toxicities by grade. The frequency of toxicities will be tabulated separately for each cohort.

Kaplan-Meier method will be used to summarize DOR for participants with a documented complete response or partial response per RECIST v.1.1 criteria. . Median DOR and its 95% confidence interval will be obtained for each of the three liver-directed therapies and PRRT groups separately.

Progression free survival is defined as the time from the first day of study treatment with protocol therapy to the date of documented tumor progression or death due to any cause, whichever occurs first, as determined by RECIST v1.1. Kaplan-Meier methods will be used to estimate PFS with 95% confidence interval for each group separately.

Immune-related progression free survival is defined as the time from the first day of study treatment with protocol therapy to the date of documented tumor progression or death due to any cause, whichever occurs first, as determined by immune-related-RECIST (irRC). Kaplan-Meier methods will be used to estimate irPFS with 95% confidence interval for each group separately.

Merck Sharp & Dohme LLC

BTG International Inc.

Assistant Professor of Clinical Radiology

Digestive System Diseases

Carcinoma

Liver Cirrhosis

Carcinoma, Hepatocellular

Hypoxia

Liver Neoplasms

Neoplasms, Glandular and Epithelial

Fibrosis

Liver Diseases

Gastrointestinal Diseases

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Anti-Infective Agents

Misonidazole

Antiprotozoal Agents

Antiparasitic Agents

Patients undergo transcatheter arterial embolization. Patients also receive 18F-fluoromisonidazole IV and undergo PET/CT scans 4 weeks prior to embolization treatment and in the 20 hours following completion of treatment.

18F-Fluoromisonidazole

Undergo transcatheter arterial embolization

Computed Tomography

Positron Emission Tomography

Rajesh Shah

This clinical trial studies how well 18F-fluoromisonidazole (\[18F\]FMISO) positron emission tomography (PET)/computed tomography (CT) works after transcatheter arterial embolization in imaging tumors in patients with liver cancer. Transcatheter arterial embolization blocks blood flow to tumor cells by inserting tiny foreign particles into an artery near the tumor. \[18F\]FMISO is a type of radioimaging agent that binds to large molecules in tumor cells that have a low level of oxygen, and the radiation given off by \[18F\]FMISO is picked up by a PET scan and this may help researchers learn whether changes occur in the tumors after treatment, which can help decide how well the treatment worked earlier than is currently possible

PRIMARY OBJECTIVES:

I. Determine the variability of 18F FMISO uptake in hepatocellular carcinoma (HCC) tumors compared to normal liver after transcatheter arterial embolization by determining the difference in the mean of the maximum standardized uptake value (SUVmax) and tumor-to-liver ratio (TLR) of a region of normal liver and of up to 5 index tumors.

SECONDARY OBJECTIVES:

I. Determine if areas of tumor recurrence as determined by CT or magnetic resonance imaging (MRI) within a 6 month period after transcatheter arterial embolization show evidence of increased 18F FMISO labeling on the initial post treatment 18F FMISO PET/CT.

II. Determine the variability in SUVmax and TLR of untreated (non embolized) HCC lesions compared to normal liver by determining the difference in the mean of the SUVmax and TLR of normal liver and tumor.

III. Determine any toxicities related to \[18F\]FMISO use for PET/CT.

OUTLINE:

Patients undergo transcatheter arterial embolization. Patients also receive 18F-fluoromisonidazole intravenously (IV) and undergo PET/CT scans within 4 weeks prior to embolization treatment and in the 20 hours following completion of treatment.

After completion of treatment, patients are followed up at 2 and 3 months.

[18F]FMISO PET/CT After Transcatheter Arterial Embolization in Imaging Tumors in Patients With Liver Cancer

Assessment of Treatment-Induced Tissue Hypoxia After Transcatheter Arterial Embolization of Hepatocellular Carcinoma: A Feasibility Study With [18F]FMISO PET/CT

All participants undergo transcatheter arterial embolization (TACE) and 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET)/computed tomography (CT) scans were conducted. Maximum standardized uptake value (SUVmax) were determined at the tumor lesion and in normal tissue, represented by liver. The variability of 18F-FMISO uptake in hepatocellular carcinoma (HCC) tumors post-TACE was assessed as the ratio of the SUVmax as observed in the tumor vs liver (tumor-to-liver ratio, TLR). The outcome is reported as the mean TLR, with standard deviation.

Follow-up 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET)/computed tomography (CT) scans were to be conducted within 6 months or at the time of tumor recurrence. Maximum standardized uptake value (SUVmax) were determined at the tumor lesion and in normal tissue, represented by liver. The variability of 18F-FMISO uptake at the hepatocellular carcinoma (HCC) tumor lesion site post-TACE was assessed as the mean difference in the ratio of the SUVmax as observed in the tumor vs liver (tumor-to-liver ratio, TLR), between lesions that recurred, and those that did not. The outcome is reported as the mean TLR, with standard deviation.

Toxicity to 18F-fluoromisonidazole (18F-FMISO) was assessed by the number of adverse events that occurred within 18 hours of administration (about 10 half-lives), that were also unanticipated and related to 18F-FMISO. The outcome is reported as the number of adverse events that were unanticipated and related to 18F-FMISO, a number without dispersion.

National Cancer Institute (NCI)

Stanford University

Patients undergo transcatheter arterial embolization. Patients also receive 18F-fluoromisonidazole IV and undergo PET/CT scans 4 weeks prior to embolization treatment and in the 20 hours following completion of treatment.

18F-Fluoromisonidazole: Undergo \[18F\] FMISO PET/CT

Arterial Embolization: Undergo transcatheter arterial embolization

Computed Tomography: Undergo \[18F\] FMISO PET/CT

Positron Emission Tomography: Undergo \[18F\] FMISO PET/CT

Diagnostic (18F-fluoromisonidazole, PET/CT, Embolization)

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Before participants undergo transcatheter arterial embolization (TACE), ie, at baseline, 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET)/computed tomography (CT) scans were conducted. Maximum standardized uptake value (SUVmax) were determined at the tumor lesion and in normal tissue, represented by liver. The variability of 18F-FMISO uptake in hepatocellular carcinoma (HCC) tumors before treatment was assessed as the ratio of the SUVmax as observed in the tumor vs liver (tumor-to-liver ratio, TLR). The data is reported as the mean TLR, with standard deviation.

Maximum Standardized Uptake Value (SUVmax) in Tumor vs Normal Tissue

Due to withdrawal, not all participants completed for this outcome.

Post-treatment Maximum Standardized Uptake Value (SUVmax) in Tumor and Normal Tissue

Follow-up 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET) scans at the time of tumor recurrence were not conducted.

Maximum Standardized Uptake Value (SUVmax) at Lesion Sites With and Without Tumor Recurrence

All participants are included for this outcome.

Adverse Events Related to 18F-fluoromisonidazole (18F-FMISO)

Overall Study

Heart and Blood Diseases

Diseases and Abnormalities at or Before Birth

Arteriovenous Malformations

Congenital Abnormalities

Hemangioma

Vascular Malformations

Cardiovascular Abnormalities

Vascular Diseases

Neoplasms, Vascular Tissue

E7040 of optimal particle size (-300 um, 300-500 um, or 500-700 um to fit in a target vessel, target lesion, or embolized area) as transcatheter study device will be administered .

E7040

Shin Maeda

To evaluate the efficacy and safety of transcatheter arterial embolization with E7040 in Japanese subjects with hypervascular tumor or arteriovenous malformation

A Multicenter, Open-label Study for E7040 in Japanese Subjects With Hypervascular Tumor and Subjects With Arteriovenous Malformation

Embolization performance was graded per 1 of 4 levels: (1) complete embolization, 100% disappearance of contrast enhancement in the target vessel as evaluated by post-embolization digital subtraction angiography; (2) intensive embolization, ≥80% disappearance; (3) moderate embolization, ≥50% and \<80% disappearance; (4) mild embolization, \<50% disappearance. Success rate was obtained by calculating the percentage of complete embolization and intensive embolization cases. Embolization performance evaluated by both the Imaging Evaluation Committee and by the Investigator or Subinvestigator.

Operability and usability were evaluated by the Investigator on the basis of the sense of resistance when E7040 was injected, and how smoothly the microspheres could pass through the catheter. The evaluation criteria are very easy to use, easy to use, difficult to use, very difficult to use. Success rate was obtained by calculating the percentage of very easy to use and easy to use cases.

Eisai Co., Ltd.

The analysis was performed using the Safety Analysis Set defined as all participants who received the embolization therapy with E7040 and had at least 1 evaluable safety data after the procedure.

An optimal dose and size (100 to 300 μm, 300 to 500 μm, 500 to 700 μm) of microsphere that best matches the pathology (i.e., vascular target, vessel size, and target lesion) and the extent of embolization were carefully selected.

Device E7040

Imaging Evaluation Committee

Investigator or Subinvestigator

The analysis was performed using Full Analysis Set defined as all participants who received embolization therapy with E7040 and had at least one evaluable efficacy data after the procedure.

Success Rate of Embolization in the Target Vessel

Success Rate for Operability of Embolization

Neoplastic Processes

Giancarlo Facchini, MD

To date, arterial embolization constitutes one of the most popular methods in minimally invasive treatment of bone metastases, allowing good results in terms of pain reduction, local control of disease and reduction of peri-operative bleeding, with low invasiveness.

Arterial Embolization for the Treatment of Bone Metastases: Prospective Observational Study

Embolizzazione Arteriosa Per il Trattamento Delle Metastasi Ossee: Studio Osservazionale Prospettico

Clinical assessment regarding pain by Visual Analogue Scale (VAS) score (0-100 mm), in which 0 represents no pain, and 100 represents maximum pain imaginable.

Clinical assessment regarding quality of life by EORTC QLQ - BM22 questionnaire. The questionnaire consists of several scales, covering different aspects related to palliation. The maximum and minimum scores for each scale of the questionnaire can range from 0 to 100. The interpretation of scores depends on the specific scale in the questionnaire, and a higher value may indicate either greater negative impact (e.g., more symptoms or more suffering) or greater positive impact (e.g., better quality of life or less symptomatology). The overall assessment requires a detailed analysis of individual scores and related scales.

Clinical assessment regarding quality of life by EORTC QLQ-C15-PAL questionnaire. The questionnaire consists of several scales, covering different aspects related to palliation. The maximum and minimum scores for each scale of the questionnaire can range from 0 to 100. The interpretation of scores depends on the specific scale in the questionnaire, and a higher value may indicate either greater negative impact (e.g., more symptoms or more suffering) or greater positive impact (e.g., better quality of life or less symptomatology). The overall assessment requires a detailed analysis of individual scores and related scales.

Reduction of the lesion evaluated with CT scans, measuring the diameter of the lesion in cm.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab With Liver-Directed or Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors and Liver Metastases	NCT03457948	Metastatic Mali... Neuroendocrine ...	Arterial Emboli... Pembrolizumab Peptide Recepto... Yttrium-90 Micr...	18 Years -	University of California, San Francisco
[18F]FMISO PET/CT After Transcatheter Arterial Embolization in Imaging Tumors in Patients With Liver Cancer	NCT02695628	Adult Liver Car... Liver Cirrhosis	18F-Fluoromison... Arterial Emboli... Computed Tomogr... Positron Emissi...	19 Years -	Stanford University
A Multicenter, Open-label Study for E7040 in Japanese Subjects With Hypervascular Tumor and Subjects With Arteriovenous Malformation	NCT01677624	Hypervascular T...	E7040	20 Years - 75 Years	Eisai Inc.
Arterial Embolization for the Treatment of Bone Metastases: Prospective Observational Study	NCT06189079	Bone Metastases		18 Years -	Istituto Ortopedico Rizzoli

Spots Global Cancer Trial Database for arterial embolization