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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 32
- 试验地点
- 2
- 主要终点
- Proportion of participants with an overall response
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject Inclusion Criteria
- •Be willing and able to provide written informed consent for the trial.
- •Be >= 18 years of age on day of signing informed consent.
- •Have a histologically proven well-differentiated neuroendocrine tumor (WHO grade 1, grade 2, or morphologically and/or clinically well-differentiated grade 3) of any primary site, including unknown primary site.
- •a. For group 1, only well-differentiated grade 2 or 3 tumors with Ki-67 index > 10% that demonstrate somatostatin receptor expression on DOTA or In-111 Octreoscans will be allowed.
- •Radiographic, biochemical, or clinical evidence of tumor progression over a period of up to 12 months in at least one site.
- •Group 1: At least one symptomatic and/or progressive somatostatin receptor positive (SSTR+) lesion over a period of up to 12 months, or have at least one measurable lesion based on RECIST v. 1.
- •Groups 2-3: At least one symptomatic and/or progressive liver lesion over a period of up to 12 months, or have at least two measurable lesions in the liver or at least one measurable lesion in the liver and another measurable lesion elsewhere, based on RECIST v. 1.
- •Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
- •Have a life expectancy of greater than 3 months.
- •Demonstrate adequate organ function.
- •Absolute neutrophil count (ANC) >=1,500 /microliters (mcL).
- •Platelet count >75,000/mcL.
- •Hemoglobin > 9 g/dL (For group 1 only. There is no hemoglobin cut-off level for groups 2-3).
- •Serum creatinine OR Measured or calculated a creatinine clearance (GFR can also be used in place of creatinine or CrCl) <=1.5 X upper limit of normal (ULN) OR >=60 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
- •Serum total bilirubin <= 1.5 X ULN OR Direct bilirubin <= ULN for subjects with total bilirubin levels > 1.5 ULN.
- •AST (SGOT) and ALT (SGPT) <= 5 X ULN.
- •Albumin >= 2.5 mg/dL.
- •International Normalized Ratio (INR) or Prothrombin Time (PT) <=1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thrombin time (PTT) is within therapeutic range of intended use of anticoagulants.
- •Female subject of childbearing potential should have a negative urine or serum pregnancy within 30 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
- •Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
排除标准
- •Has had prior thermal ablation, embolotherapy, radioembolization, or external beam radiation within 30 days of initiation of study therapy.
- •Has had prior peptide receptor radionuclide therapy (group 1 only).
- •Has had biliary tract intervention that resulted in compromise to the Ampulla of Vater or a biliary-enteric anastomosis (groups 2-3 only).
- •Has greater than 75% liver parenchyma replacement by tumor (determined by radiologist investigator).
- •Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- •Has a known history of active Tuberculosis (TB) (Bacillus Tuberculosis).
- •Hypersensitivity to pembrolizumab or any of its excipients.
- •Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., <=Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., <=Grade 1 or at baseline) from adverse events due to a previously administered agent.
- •Note: Subjects with <= Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- •Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •Concurrent somatostatin analog therapy is allowed.
- •Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
- •Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- •Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease.
- •Has an active infection requiring systemic therapy.
- •Has liver fibrosis either determined by imaging or laboratory testing (i.e. total serum bilirubin > 1.5 times ULN, Aspartate Aminotransferase (AST) and alanine aminotransferase (ALT) > 5 times ULN, INR >1.5 times ULN, albumin <2.0mg/dl).
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
- •Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- •Has known active untreated Hepatitis B.
- •Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
研究组 & 干预措施
Group I [pembrolizumab, 177Lu DOTATATE]
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.
干预措施: Pembrolizumab (Biological)
Group I [pembrolizumab, 177Lu DOTATATE]
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.
干预措施: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate (Biological)
Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED)
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.
干预措施: Yttrium-90 Microsphere Radioembolization (Device)
Group II [pembrolizumab, TAE] (CLOSED)
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.
干预措施: Arterial Embolization (Procedure)
Group II [pembrolizumab, TAE] (CLOSED)
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.
干预措施: Pembrolizumab (Biological)
Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED)
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.
干预措施: Pembrolizumab (Biological)
结局指标
主要结局
Proportion of participants with an overall response
时间窗: At 12 weeks
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.
Number of treatment-related adverse events (Group 1)
时间窗: Up to 30 days after the end of treatment
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.
Proportion of Participants With an Overall Response
时间窗: Up to 25 months
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 proportion of participants with a response and 90% confidence interval of overall response rate will be obtained for each of the three groups separately.
Number of Participants With Treatment-related Adverse Events by Maximum Grade (Group 1)
时间窗: Up to 30 days after the end of treatment, approximately 26 months
Adverse events occurring from the start of the treatment regimen until 30 days after the end of treatment will be summarized by number of participants reporting under maximum toxicity grade for participants enrolled in Group 1. All treatment-related adverse events will be graded using NCI CTCAE v5.0.
次要结局
- Immune-related progression free survival (irPFS)(Up to 3 years)
- Duration of response (DOR)(Up to 3 years)
- Number of treatment-related adverse events (Groups 2 & 3)(Up to 30 days after the end of treatment)
- Median Progression free survival (PFS)(Up to 3 years)
- Median Duration of Response (DOR)(Up to 3 years)
- Number of Participants With Treatment-related Adverse Events by Maximum Grade (Groups 2 & 3)(Up to 30 days after the end of treatment, approximately 26 months)
- Median Progression Free Survival (PFS)(Up to 3 years)
- Immune-related Progression Free Survival (irPFS)(Up to 3 years)
研究者
Nicholas Fidelman, MD
Assistant Professor of Clinical Radiology
University of California, San Francisco