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Trial record 99 of 2730 for:    Neoplasms | Neuroendocrine Tumors

Pembrolizumab and Liver-Directed Therapy in Well-Differentiated Neuroendocrine Tumors With Liver Metastases

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ClinicalTrials.gov Identifier: NCT03457948
Recruitment Status : Recruiting
First Posted : March 8, 2018
Last Update Posted : May 13, 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 and liver-directed therapy works in treating patients with well-differentiated 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 radiofrequency ablation, transarterial embolization, yttrium-90 microsphere radioembolization, and cryoablation may help to shrink tumors that are not being directly targeted. Giving pembrolizumab and liver-directed therapy may work better in treating patients with well-differentiated 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 Procedure: Radiofrequency Ablation 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 (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. Patients with up to 6 liver lesions, largest being no larger than 4 cm who have < 25% liver parenchyma replacement by tumors, undergo computed tomography (CT)-guided radiofrequency ablation (RFA) over 2-3 hours, 3-7 days following the first dose of pembrolizumab.

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.


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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 for Patients With Well-Differentiated Neuroendocrine Tumors and Symptomatic and/or Progressive Liver 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, CT-guided RFA]
Patients receive pembrolizumab 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. 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 Radiofrequency Ablation (RFA) over 2-3 hours, 3-7 days following the first dose of pembrolizumab.
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Procedure: Radiofrequency Ablation
Undergo CT-guided RFA
Other Name: Radiofrequency Interstitial Ablation

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) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: At 27 weeks ]
    The point estimate and 95% confidence interval of overall response rate will be obtained for each of the three liver-directed therapy groups (radiofrequency ablation, transarterial embolization, radioembolization) separately. The point estimate and 90% confidence interval of overall response rate will be obtained for each of the four liver-directed therapy groups separately. Assuming the abscopal overall response rate (RECIST version [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.


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 therapy groups separately.

  2. Incidence of adverse events evaluated according to National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) v 4.0 [ 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 v4.0 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 v4.0. 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 therapy 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 therapy groups separately.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Be willing and able to provide written informed consent for the trial
  • Have a histologically proven well-differentiated neuroendocrine tumor
  • Radiographic, biochemical, or clinical evidence of tumor progression over a period of up to 12 months in at least one site
  • At least one symptomatic and/or progressive liver lesion over a period of up to 12 months
  • Have at least one measurable lesions in the liver or at least one measurable lesion in the liver and another measurable lesion elsewhere, based on RECIST version (v.) 1.1
  • 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)

    • Patients with unsuccessful baseline biopsies may undergo an additional biopsy attempt (at the same or a different site, determined by the investigator)
    • 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
  • 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
  • Absolute neutrophil count (ANC) >= 1,500 /microliter (mcL)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance [glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl)] >= 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
  • Aspartate aminotransferase (AST) [serum glutamic oxaloacetic transaminase (SGOT)] and alanine aminotransferase (ALT) [serum glutamic pyruvic transaminase (SGPT)] =< 5 x ULN
  • Albumin >= 2.5 mg/dL, should be performed within 10 days of treatment initiation
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin 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

Exclusion Criteria:

  • Has had prior thermal ablation, embolotherapy, radioembolization, or external beam radiation within 30 days of initiation of study therapy.
  • Has had biliary tract intervention that resulted in compromise to the Ampulla of Vater or a biliary-enteric anastomosis.
  • 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 (for control of hormone excess) provided patient has been on stable dose for at least two months and tumor progression has been documented
  • 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 that required steroids or current pneumonitis
  • 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, AST and ALT > 5 times ULN, INR > 1.5 times ULN, albumin < 2.0 mg/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-Programmed Cell Death Protein 1 (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 within 30 days of planned start of study therapy

    • Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) 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
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Contact: Nicholas Fidelman, MD 877-827-3222 cancertrials@ucsf.edu
Contact: Andy Chon andrew.chon@ucsf.edu

Locations
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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
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Principal Investigator: Nicholas Fidelman, MD University of California, San Francisco

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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: CTRP (Clinical Trial Reporting Program) )
17705 ( Other Identifier: University of California, San Francisco )
First Posted: March 8, 2018    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Neoplasms
Neuroendocrine Tumors
Neoplasms, Second Primary
Liver Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents