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Intravenous pembrolizumab alone,D8 of 21-day cycle.

Intravenous pembrolizumab preceded by an infusion of bevacizumab (Day 1 of 21-day cycle).

pembrolizumab

* Bevacizumab in Concentrate for Solution
* Bevacizumab in Concentrate for Solution

bevacizumab

Boon Cher Goh

This is a single center, randomized, phase Ib/II open-label study of pembrolizumab (pembro or MK-3475) with or without bevacizumab in patients with recurrent non-curable or metastatic nasopharyngeal carcinoma (NPC).

The study will consist of 2 treatment arms. In Treatment Arm A, patients will be treated with intravenous pembrolizumab alone, 21-day cycle. For Treatment Arm B, patients will receive intravenous pembrolizumab preceded by an infusion of bevacizumab (Day 1 of 21-day cycle). Each treatment cycle is 3 weeks. Up to 48 patients will be enrolled in this study in 2 stages. The first stage will consist of 30 patients and the remaining 18 patients will be added if interim data looks promising.

Eligible patients will be randomized 1:1 into either Treatment Arm A or Arm B. Treatment will continue until tumor progression, intolerance to treatment, or up to 2 years (32 doses of pembrolizumab/bevacizumab). For patients who have progressed on pembrolizumab alone, cross over to Arm B is allowed, with repeat biopsy of the lesions before and 1 week after starting bevacizumab. Patients who discontinue from the trial will not be replaced.

The study will collect serial samples of tumor tissue and blood to determine the PD biomarkers of immune activation, in the tumor and systemically, following treatment. This is expected to provide preliminary evidence for immune stimulation using both pembrolizumab and bevacizumab in NPC. The tumor biopsies will also present an opportunity to determine the molecular details of tissue and tumor response to anti-angiogenic therapy.

Eligible patients will be randomized 1:1 into either Treatment Arm A or Arm B. Treatment will continue until tumor progression, intolerance to treatment, or up to 2 years (32 doses of pembrolizumab/bevacizumab). For patients who have progressed on pembrolizumab alone, cross over to Arm B is allowed, with repeat biopsy of the lesions before and 1 week after starting bevacizumab. Patients who discontinue from the trial will not be replaced.

Bevacizumab and Pembrolizumab Combination in EBER-ISH Positive NPC

Phase Ib/II Open-label Study Evaluating the Combination of Bevacizumab Priming With Pembrolizumab in EBER-ISH Positive Nasopharyngeal Carcinoma (NPC)

Comparison of the two treatment arms will be evaluated using the Fisher's exact test. The treatment effect will be quantified via the relative risk estimate and its associated 95% confidence interval (CI).

This will be summarized using the Kaplan-Meier survival estimate for each group. As an exploratory analysis, the log-rank test will be used for comparing differences in PFS, with its effect quantified based on hazard ratio and its 95% CI.

This is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging assessment or death due to any cause, whichever occurs earlier.

Merck Sharp & Dohme LLC

National University Hospital, Singapore

Neoplasm Metastasis

In this group, the patients will receive multiple high-activity natural killer (HANK) immunotherapies. The check indexes are CT scan and blood tests (including tumor markers, lymphocyte subsets and circulating tumor cell).

In this group, the patients will receive no special treatment and as a control group. The check indexes are CT scan and blood tests (including tumor markers, lymphocyte subsets and circulating tumor cell).

Each treatment: 8\~10 billion cells in all, transfuion in 3 times, i.v.

High-activity natural killer

The aim of this study is the safety and efficacy of high-activity natural killer immunotherapy to small metastases of nasopharyngeal cancer.

By enrolling patients with small metastases of nasopharyngeal cancer adapted to enrolled criteria, this study will document for the first time the safety and the short and long term efficacy of high-activity natural killer cells.

The safety will be evaluated by statistics of adverse reactions. The efficacy will be evaluated according to local relief degree, progress free survival (PFS) and overall survival (OS).

High-activity Natural Killer Immunotherapy for Small Metastases of Nasopharyngeal Cancer

It will be evaluated by the Response Evaluation Criteria in Solid Tumors（RECIST）

Shenzhen Hank Bioengineering Institute

Fuda Cancer Hospital, Guangzhou

Patients who had complete response or partial response after at least 3 cycles (no more than 6 cycles) of chemotherapy combined with immunotherapy receive local radiotherapy 21 days. For those non-CR oligo-metastatic disease or symptomatic lesion, SBRT or conventional RT delivered. Maintenance therapy of immunotherapy for 2 years.

Radiotherapy

Li Ma, MD

Runye Wu, PhD

Incidences of de novo metastatic nasopharyngeal carcinoma range from 6% to 8% at the time of presentation. For the initial diagnosis of metastatic NPC, PD-1 plus chemotherapy yields a satisfactory outcome with1year PFS of 40%. Previous study demonstrated the benefit of adding radiotherapy to chemotherapy in metastatic NPC, however there is no evidence whether radiotherapy can further improve PFS based on chemotherapy plus PD-1 . The purpose of this study is to evaluate the safety and effectiveness of first-line immunochemotherapy combined with radiotherapy for initial diagnosed metastatic NPC.

Combining RT With Immunotherapy and Chemotherapy in Metastatic Nasopharyngeal Carcinoma

A Phase II Study: Safety and Efficacy of Combining Radiation Therapy With Immunotherapy and Chemotherapy in de Novo Metastatic Nasopharyngeal Carcinoma

Incidence of treatment-emergent adverse events would be assessed based on the common toxicity criteria for adverse events version 5.0 (CTCAE v5.0)

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Head of Radiation Oncology

Lutetium Lu 177 dotatate

Treatment with 177Lu-DOTATATE consist of a cumulative dose of 23.68 - 29.6 GBq (640 - 800 mCi) 177Lu-DOTA0-Tyr3-Octreotate; Four administrations of 5.92 - 7.4 GBq (160 - 200 mCi) 177Lu-DOTA0-Tyr3-Octreotate; Concomitant amino acids will be given with each administration for kidney protection; 177Lu-DOTA0-Tyr3-Octreotate will be administered at 8±1-week intervals, which can be extended up to 16 weeks to accommodate resolving acute toxicity.

Treatment will consist of a cumulative dose of 23.68 - 29.6 GBq (640 - 800 mCi) 177Lu-DOTA0 -Tyr3-Octreotate; Four administrations of 5.92 - 7.4 GBq (160 - 200 mCi) 177Lu-DOTA0-Tyr3-Octreotate; Concomitant amino acids will be given with each administration for kidney protection; 177Lu-DOTA0-Tyr3-Octreotate will be administered at 8±1-week intervals, which can be extended up to 16 weeks to accommodate resolving acute toxicity.

77 Lu-DOTA0-Tyr3-Octreotate

Daniel Tan, BSc, MBBS, PhD

Wen-Long Nei

Wen-Long Nei, MBBS, FRCR

Kelvin Loke, MBBS, MRCP(UK), FAMS

This study is the first phase II study of 177Lu-DOTA0-Tyr3-Octreotate in metastatic NPC. Patients whom have failed 2 or more lines of therapy or exhausted standard therapy and are avid on 68Ga-DOTATATE imaging will be eligible to receive up to 4 cycles of 177Lu-DOTA0-Tyr3-Octreotate. The primary outcome will be progression free survival at 6 months.

This would be an open label, single arm, single centre, phase II study designed to evaluate the efficacy of 177Lu-DOTA0-Tyr3-Octreotate in Metastatic NPC.

Patients will first need to go for a 68Ga-DOTATATE scan to determine if they are suitable for 177Lu-DOTA0-Tyr3-Octreotate therapy. A'Hern single stage phase II design (A'Hern, 2001) will be used for conducting the trial. The null hypothesis that the true PFS rate at 6 months is 10% will be tested against the alternate hypothesis of 25%. A total number of 25 patients will be recruited. If there are 5 or more patients who are alive and progression free among these 25 patients at 6 months, we reject the null hypothesis and claim that the treatment is promising.

The design controls the type I error rate at 9.8% and yields a power of 78.6% when the true PFS rate at 6 months is 25%. The first 5 patients will receive 180mCi of 177Lu-DOTA0-Tyr3-Octreotate for the first cycle followed by 200mCi for the remaining 3 cycles if there are no \> Grade 2 toxicities after the first cycle. If there are \>G2 toxicities, the remaining cycles will proceed at 180mCi. A safety review will be done after the first 5 patients. If there are no significant toxicities, the remaining patients will receive 200mCi for 4 cycles. If there are significant toxicities in patients receiving 200mCi for the 2nd to 4th cycle, the remaining patients will receive 180mCi for 4 cycles. If there are significant toxicities in patients receiving 180mCi for the 2nd to 4th cycle, the remaining patients will receive 160mCi for 4 cycles. Dosimetry scans will be done after each cycle of 177Lu-DOTA0-Tyr3-Octreotate at 1h and 96h. Safety and tolerability of 177LuDOTA0-Tyr3-Octreotate will be assessed for the duration of study treatment.

FDG PET/CT scan and 68Ga-DOTATATE scan will be performed at baseline and after cycle 1 (week 4) and cycle 4 (week 28). CT scans will be done at week 12, 24, then 3-monthly starting from week 40. 177Lu-DOTA0-Tyr3-Octreotate treatment will be continued until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, dose adjustment is permitted. A treatment cycle is eight weeks (56 days) and will be repeated without therapy interruption for 4 cycles unless there is dose limiting toxicities.

Phase II 177Lu-DOTATATE Study in Metastatic NPC With a Safety Run-in

A Biomarker Enrichment, Phase II Study of 177Lu-DOTATATE in Metastatic Nasopharyngeal Cancer With a Safety Run-in

PFS is defined as the time from the date of initiating study treatment to the date of documented disease progression as determined by RECIST Criteria, Version 1.1 or death from any cause.

Point estimates for median PFS and PFS rate at 6 month, with corresponding 95% Confidence Intervals (CIs), will be estimated using the Kaplan-Meier method.

ORR is defined as the percentage of patients who had a partial response or complete response according to RECIST 1.1.

The ORR and 95% CI will be calculated.

TTP is defined as the time (number of days) from start of study treatment to objective tumour progression.

OS is defined as the time from the date of start of study treatment to the date of death due to any cause or the date of last contact (censored observation) at the date of data cut-off.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Bevacizumab and Pembrolizumab Combination in EBER-ISH Positive NPC	NCT03813394	Locally Recurre... Metastatic Naso...	pembrolizumab bevacizumab	21 Years - 99 Years	National University Hospital, Singapore
High-activity Natural Killer Immunotherapy for Small Metastases of Nasopharyngeal Cancer	NCT03007836	Metastatic Naso...	High-activity n...	30 Years - 60 Years	Fuda Cancer Hospital, Guangzhou
Combining RT With Immunotherapy and Chemotherapy in Metastatic Nasopharyngeal Carcinoma	NCT05385926	Metastatic Naso...	Radiotherapy	18 Years - 75 Years	Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Combining RT With Immunotherapy and Chemotherapy in Metastatic Nasopharyngeal Carcinoma	NCT05385926	Metastatic Naso...	Radiotherapy	18 Years - 75 Years	Cancer Institute and Hospital, Chinese Academy of Medical Sciences
High-activity Natural Killer Immunotherapy for Small Metastases of Nasopharyngeal Cancer	NCT03007836	Metastatic Naso...	High-activity n...	30 Years - 60 Years	Fuda Cancer Hospital, Guangzhou
Phase II 177Lu-DOTATATE Study in Metastatic NPC With a Safety Run-in	NCT05198479	Metastatic Naso...	77 Lu-DOTA0-Tyr...	21 Years - 75 Years	National Cancer Centre, Singapore

Spots Global Cancer Trial Database for metastatic nasopharyngeal cancer