Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 38 of 50 for:    DOTA- | Neuroendocrine Tumors

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03457948
Recruitment Status : Recruiting
First Posted : March 8, 2018
Last Update Posted : September 26, 2019
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
BTG International Inc.
Information provided by (Responsible Party):
Nicholas Fidelman, MD, University of California, San Francisco

Brief Summary:
This pilot phase II trial studies how well pembrolizumab in combination with liver-directed therapy or Peptide Receptor Radionuclide Therapy (PRRT) works in treating patients with well-differentiated metastatic neuroendocrine tumors and symptomatic and/or progressive tumors that have spread to the liver. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Liver-directed therapies such as, transarterial embolization (TAE), yttrium-90 microsphere radioembolization (RE), and cryoablation may help to shrink tumors that are not being directly targeted. Somatostatin receptor positive (SSTR+) well- diferentiated neuroendocrine tumors (WD-NETs) may benefit from treatment with peptide receptor radionuclide therapy (PRRT) using 177Lu DOTATATE. Giving pembrolizumab in combination with liver-directed therapy or PRRT may work better in treating patients with well-differentiated metastatic neuroendocrine tumors and symptomatic and/or progressive tumors that have spread to the liver.

Condition or disease Intervention/treatment Phase
Metastatic Malignant Neoplasm in the Liver Neuroendocrine Neoplasm Procedure: Arterial Embolization Procedure: Cryoablation Biological: Pembrolizumab Biological: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate Device: Yttrium-90 Microsphere Radioembolization Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. 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 [World Heath Organization (WHO) grade 1 or 2] neuroendocrine tumors (NET) (WD-NETs).

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab in combination with liver-directed therapies in this patient population.

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

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

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

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

OUTLINE: Patients are assigned to 1 of 4 groups.

GROUP I: 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

GROUP II: 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 transarterial embolization (TAE) over 2-3 hours, 3-7 days following the first dose of pembrolizumab.

GROUP III: 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 radioembolization (RE) 3-15 days following the first dose of pembrolizumab.

GROUP IV: Patients receive pembrolizumab as in Group I. Patients with up to 6 liver lesions, largest being no larger than 4 cm who have < 25% liver parenchyma replacement by tumors, undergo CT-guided cryoablation over 2-3 hours, 3-7 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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : May 18, 2018
Estimated Primary Completion Date : November 30, 2020
Estimated Study Completion Date : May 31, 2030

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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 may have any number of liver and/or extrahepatic lesions with liver parenchyma replacement by tumor < 75%
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Biological: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate
Given IV
Other Names:
  • Lutathera
  • 177Lu-DOTATATE

Experimental: Group II [pembrolizumab, 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 Arterial Embolization (TAE) over 2-3 hours, 3-7 days following the first dose of pembrolizumab.
Procedure: Arterial Embolization
Undergo TAE
Other Names:
  • TAE
  • Transarterial Embolization

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Experimental: Group III [pembrolizumab, yttrium-90 microsphere 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 Radio Embolization (RE) 3-15 days following the first dose of pembrolizumab.
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Device: Yttrium-90 Microsphere Radioembolization
Undergo yttrium-90 microsphere RE
Other Names:
  • Yttrium Y 90 Microsphere Therapy
  • Yttrium-90 Radioembolization
  • Yttrium-90 Microsphere RE

Experimental: Group IV [pembrolizumab, CT-guided cryoablation]
Patients receive pembrolizumab as in Group I. Patients with up to 6 liver lesions, largest being no larger than 4 cm who have < 25% liver parenchyma replacement by tumors, undergo CT-guided cryoablation over 2-3 hours, 3-7 days following the first dose of pembrolizumab.
Procedure: Cryoablation
Undergo CT-guided cryoablation
Other Names:
  • cryosurgery
  • cryosurgical ablation

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. 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 RECIST 1.1 for patients with metastatic WD-NET [ Time Frame: At 12 weeks ]
    The point estimate and 95% confidence interval of overall response rate will be obtained for each of the three liver-directed therapy groups (cryoablation, transarterial embolization(TAE) , radioembolization (RE)) separately. The point estimate and 90% confidence interval of overall response rate will be obtained for each of the three liver-directed therapy groups separately. Assuming the abscopal overall response rate (RECIST v. 1.1) is 25% for each patient group, with 8 patients in each group, there is 80% of power to detect partial response rate significantly different from 1% at alpha of 0.1 by a directional binomial test.

  2. Best observed overall response rate (ORR) to pembrolizumab plus PRRT according to RECIST 1.1 for patients with metastatic grade 3 WD-NET [ Time Frame: At 12 weeks ]
    The point estimate and 90% confidence interval of overall response rate will be obtained for each of the four groups separately. Assuming the overall response rate (RECIST v. 1.1) is 25% for the PRRT group, with 8 patients in the group, there is 80% of power to detect partial response rate significantly different from 1% at alpha of 0.1 by a directional binomial test.


Secondary Outcome Measures :
  1. Duration of response (DOR) evaluated according to RECIST 1.1 [ Time Frame: From the date of first response (CR or PR) until the date of disease progression or death, assessed up to 3 years ]
    Kaplan-Meier method will be used to summarize DOR. Median DOR and its 95% confidence interval will be obtained for each of the three liver-directed therapies and PRRT groups separately.

  2. Incidence of adverse events evaluated according to National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) v 5.0 [ Time Frame: 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. Safety and tolerability will be assessed by clinical review of all relevant parameters including adverse experiences (AEs), laboratory tests, and vital signs. The toxicity grade for laboratory data will be calculated using CTCAE v5.0 and the lab data will be summarized according to the subject's baseline grade and maximum grade for each cycle of therapy. All treatment related adverse events will be graded using NCI CTCAE v5.0. Adverse events assessed as related to study drug and serious adverse events will be summarized similarly. Adverse events leading to treatment discontinuation will also be summarized. Safety analysis will include a tabulation of all toxicities by grade. The frequency of toxicities will be tabulated separately for each cohort. Count of AE will be provided.

  3. Progression free survival (PFS) evaluated according to RECIST v1.1 [ Time Frame: From first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first, assessed up to 3 years ]
    Kaplan-Meier method will be used to summarize progression free survival; median PFS will be estimated with 95% confidence interval for each of the three liver-directed therapies and PRRT groups separately.

  4. Immune-related progression free survival (irPFS) evaluated according to immune-related(ir) response criteria (RC) [ Time Frame: From first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first, assessed up to 3 years ]
    Kaplan-Meier method will be used to summarize immune-related progression free survival; median irPFS will be estimated with 95% confidence interval for each of the three liver-directed therapies and PRRT groups separately.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Subject Inclusion Criteria

  1. Be willing and able to provide written informed consent for the trial.
  2. Be >= 18 years of age on day of signing informed consent.
  3. 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 3 tumors that demonstrate somatostatin receptor expression on Ga-68 DOTA or In-111 Octreoscans will be allowed.

  4. Radiographic, biochemical, or clinical evidence of tumor progression over a period of up to 12 months in at least one site.

    1. 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. 1.1.
    2. Groups 2-4: 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. 1.1.
  5. Patients must agree to have a biopsy of metastatic tissue at baseline and on treatment, and there must be a lesion that can be biopsied with acceptable clinical risk (as judged by the investigator).

    1. Patients with unsuccessful baseline biopsies may undergo an additional biopsy attempt (at the same or a different site, determined by the investigator).
    2. For patients with an intact primary and no metastatic site that can be safely biopsied, biopsy of the primary is acceptable, but must be approved by the principal investigator.
  6. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  7. Have a life expectancy of greater than 3 months.
  8. Demonstrate adequate organ function.

    1. Absolute neutrophil count (ANC) ≥1,500 /microliters (mcL).
    2. Platelet count >75,000/mcL.
    3. Hemoglobin > 9g/dLb (For group 1 only. There is no hemoglobin cut-off level for groups 2-4).
    4. 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.
    5. Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN.
    6. AST (SGOT) and ALT (SGPT) ≤ 5 X ULN.
    7. Albumin >2.5 mg/dL.
    8. 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.
  9. 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.
  10. 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.
  11. 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.

Subject Exclusion Criteria

  1. Has had prior thermal ablation, embolotherapy, radioembolization, or external beam radiation within 30 days of initiation of study therapy.
  2. Has had prior peptide receptor radionuclide therapy (group 1 only).
  3. Has had biliary tract intervention that resulted in compromise to the Ampulla of Vater or a biliary-enteric anastomosis (groups 2-4 only).
  4. Has greater than 75% liver parenchyma replacement by tumor (determined by radiologist investigator).
  5. 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.
  6. 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.
  7. Has a known history of active Tuberculosis (TB) (Bacillus Tuberculosis).
  8. Hypersensitivity to pembrolizumab or any of its excipients.
  9. 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.
  10. 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.

    1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    2. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
    3. Concurrent somatostatin analog therapy is allowed (for control of hormone excess) provided patient has been on stable dose for at least two months and tumor progression has been documented.
  11. 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.
  12. 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.
  13. 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.
  14. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  15. Has an active infection requiring systemic therapy.
  16. 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).
  17. 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.
  18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  19. 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.
  20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  22. Has known active untreated Hepatitis B.
  23. Has received a live vaccine within 30 days of planned start of study therapy. a. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and are not allowed

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03457948


Contacts
Layout table for location contacts
Contact: Nicholas Fidelman, MD 877-827-3222 cancertrials@ucsf.edu
Contact: Andy Chon andrew.chon@ucsf.edu

Locations
Layout table for location information
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94115
Contact: Nicholas Fidelman, MD    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Nicholas Fidelman         
Sponsors and Collaborators
Nicholas Fidelman, MD
Merck Sharp & Dohme Corp.
BTG International Inc.
Investigators
Layout table for investigator information
Principal Investigator: Nicholas Fidelman, MD University of California, San Francisco

Layout table for additonal information
Responsible Party: Nicholas Fidelman, MD, Assistant Professor of Clinical Radiology, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03457948     History of Changes
Other Study ID Numbers: 17705
NCI-2018-00227 ( Registry Identifier: NCI Clinical Trial Reporting Program )
First Posted: March 8, 2018    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Neuroendocrine Tumors
Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents