Clinical Trials /

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

NCT03457948

Description:

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.

Related Conditions:
  • Neuroendocrine Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in With Liver-Directed or Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors With Metastases
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 17705
  • SECONDARY ID: NCI-2018-00227
  • NCT ID: NCT03457948

Conditions

  • Metastatic Malignant Neoplasm in the Liver
  • Neuroendocrine Neoplasm

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Group I [pembrolizumab, 177Lu DOTATATE]
Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-OctreotateLutathera, 177Lu-DOTATATEGroup I [pembrolizumab, 177Lu DOTATATE]

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Group I [pembrolizumab, 177Lu DOTATATE]ExperimentalPatients 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%
  • Pembrolizumab
  • Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate
Group II [pembrolizumab, TAE]ExperimentalPatients 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.
  • Pembrolizumab
Group III [pembrolizumab, yttrium-90 microsphere RE]ExperimentalPatients 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.
  • Pembrolizumab
Group IV [pembrolizumab, CT-guided cryoablation]ExperimentalPatients 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.
  • Pembrolizumab

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nicholas Fidelman, MD

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