Allogeneic NK Cell (“SMT-NK”) in Combination With Pembrolizumab in Advanced Biliary Tract Cancer

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Brief Title

Allogeneic NK Cell ("SMT-NK") in Combination With Pembrolizumab in Advanced Biliary Tract Cancer

Official Title

Phase 1/2a Clinical Trial for the Evaluation of Safety and Efficacy of Allogeneic NK Cell ("SMT-NK") in Combination With Pembrolizumab for Patients With Gemcitabine-refractory Biliary Tract Cancer

Brief Summary

      The term of biliary tract cancer (BTC) or cholangiocarcinoma refers to all tumors that arise
      from the biliary tract or the biliary drainage system, including the gallbladder. According
      to the data from National Cancer Information Center in 2016, annual incidence of the cancer
      in Korea is 6,685 (13.1 per 100,000 population) which corresponds to about 2.9% of all
      cancers.

      BTC is one of the most prognostic cancer with less than 30% of 5-year survival rate and the
      case with long-term survival can be possibly done with early detection of the cancer.
      However, most of BTC is found in advanced stages due to the difficulty of early detection,
      resulting in that the 5-year survival rate of the advanced BTC becomes less than 3%. More
      than 50% of the patients depends on Gemcitabine based chemotherapy but response rate of the
      chemotherapy remains around 30%. Thus, improving the survival rate with the standard
      chemotherapy is very limited and furthermore selection of second-line therapy is not easy.
      For this reason, development of an alternative therapeutic agent is urgently required.

      NK (natural killer) cells are important cytotoxic innate immune cells that are involved in
      the elimination of cancer cells. Two main NK cell subsets have been defined on the basis of
      CD56 and CD16 expression: CD56^brightCD16- NK subset produces abundant cytokines including
      interferon-γ (IFN-γ) and tumor necrosis factor-α, whereas CD56^dimCD16+ NK subpopulation has
      high cytolytic activity and releases the granules containing perforin and granzymes.

      Various clinical studies have been conducted to treat cancers using NK cells worldwide
      including Korea and therapeutic clinical results are shown for various cancers. The clinical
      application of NK cells is carried out by culturing and activating the NK cells isolated from
      blood of either patient (autologous) or blood donor (allogeneic). Recently, NK cell therapy
      for cholangiocarcinoma has been successfully done (NCT03358849) with allogeneic NK cell,
      showing safety and potential efficacy.

      Like T cells, a recent study with digestive cancer has shown that NK cells also express PD-1,
      especially with more number of PD-1 in cancer patients than in healthy individuals,
      suggesting that blocking PD-1 can be used as a potential strategy to increase the anticancer
      activity of NK cells. Therefore, combined therapy with the immune-check point such as
      pembrolizumab can be useful in elevating the anticancer activity of NK cells.
    


Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Phase 1 - Dose Limiting Toxicity of the dose of 'SMT-NK' Inj. in combination with Pembrolizumab.

Secondary Outcome

 Phase 2a - Time to Progression

Condition

Biliary Tract Cancer

Intervention

'SMT-NK' Inj (allogeneic Natural Killer cell)

Study Arms / Comparison Groups

 Experimental: single arm
Description:  Biological: 'SMT-NK' Inj. (allogeneic Natural Killer cell) weekly administration for 2 weeks. After that, 1 week is a withdrawal period. (Phase 1: up to *cycle 3, Phase 2a: up to cycle 9)
Drug: Pembrolizumab administration of Pembrolizumab 200mg/m2 at first week during cycle.
Cycle: 1 cycle is 3 weeks in total.'SMT-NK' Inj is administered at first and second week, and Pembrolizumab is administered at first week. The third week is a withdrawal period.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

40

Start Date

December 3, 2019

Completion Date

June 2, 2021

Primary Completion Date

February 2, 2021

Eligibility Criteria

        [Inclusion Criteria]

        Patients who received a histopathological or cytologic diagnosis of nonresectable, advanced
        biliary tract carcinoma (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder
        cancer) and patients with refractory disease after chemotherapy and/or patients who have
        difficulty with chemotherapy due to side effects of chemotherapy.

          1. A person who receives an explanation from the trial manager about the purpose,
             contents, and characteristics of the Investigational products for the clinical trial
             and is signed by the person, guardian or legal representative in the written informed
             consent.

          2. Be ≥19 years of age on day of signing informed consent.

          3. Histopathological or cytologic diagnosis of advanced adenocarcinoma of the biliary
             tract.

          4. Have a performance status of ≤2 on the ECOG Performance Scale.

          5. Patients who survival period is expected to be at least 3 months.

          6. Patients who meet the following conditions:

               -  ANC(Absolute Neutrophil Count) ≥ 1,500/μL

               -  Hemoglobin≥ 10 g/dL

               -  Platelet> 100,000/μL

               -  Serum BUN & Creatinine ≤ 1.5 x upper limit of normal (ULN)

               -  AST & ALT ≤ 2.5 x upper limit of normal (ULN)

               -  Bilirubin ≤ 3mg/L

          7. Patients who agreed to the allogeneic natural killer cells therapy separated from the
             family of the patient or healthy donor's blood.

          8. Patients have a negative serum or urine pregnancy test (HCG, human chorionic
             gonadotropin) within 72 hours prior to receiving the first dose of study medication
             and agreed to use 2 methods of contraception. The period of contraception is up to 6
             months after the last administration of Pembrolizumab.

          9. Patients who meet one or more of the following conditions.

               -  Patients have at least 1% Combined Positive Score (*CPS) PD-L1 expression
                  detected on the tumor, as determined by **immunohistochemistry performed by a
                  central laboratory.

                  *CPS = (number of PD-L1 positive tumor cells, lymphocytes, macrophage)/ (total
                  number of viable tumor cells) X 100

                  **immunohistochemistry: IHC 22C3 pharmDx test

               -  Patients who have a positive *MSI-H or **dMMR test.

                    -  MSI-high positive tumors analyzed by PCR.

                    -  dMMR positive tumors analyzed by immunohistochemical staining .

                         -  *MSI-H was measured by PCR, and positive finding when two or more
                            unstable markers were detected in PCR for 5 microsatellite markers.

                         -  **dMMR is analyzed by immunohistochemical staining and positive when
                            the discovery of one or more genes in MLH1, MSH2, MSH6 and PMS2
                            staining is lost.

        [Exclusion Criteria]

          1. Patients who have previous history of Immune deficiency or autoimmune disease that can
             be aggravated by immunotherapy(for example: Rheumatoid arthritis, systemic lupus
             erythematosus, vasculitis, multiple sclerosis, Crohn's disease, ulcerative colitis,
             adolescent-developed insulin-dependent diabetes mellitus).

          2. Diagnosis of immunodeficiency or is receiving systemic steroid therapy.

          3. Have with pneumonia, colitis, hepatitis, nephritis, endocrine disorders(for example:
             Pituitary gland, thyroid dysfunction, Type 1 diabetes, etc.) associated with
             immunodeficiency.

          4. Other malignant tumors within 5 years before the study enrollment.

          5. Previous history of anti-angiogenic agent treatment before the study enrollment.

          6. Received chemotherapy not less than 4 weeks old before the first administration of
             investigational products.

          7. Apparent myocardial infarction or uncontrolled arterial hypertension.

          8. Serious allergic history.

          9. Serious mental illness.

         10. Female who are pregnant, breastfeeding or intending to become pregnant during the
             study period.

         11. A person who participated in another clinical trial within 4 weeks prior to the start
             of the study(based on the date of signing the informed consent.).

         12. Previously administrated Pembrolizumab and other anti-PD-1/PD-L1 agent.

         13. Previously administrated natural killer cell.

         14. Patients who did not resolve the adverse event of the drug administered 4 weeks prior
             to enrollment.

         15. Previous history of active central nervous system (CNS) metastasis and/or
             carcinomatous meningitis.

         16. Previous history of non-infectious pneumonia.

         17. Previous history of Has an active infection requiring systemic therapy.

         18. Previous historyof Human Immunodeficiency Virus (HIV).

         19. Previous history of active Hepatitis B (e.g., HBsAg reactive), Hepatitis C, Active
             tuberculosis.

         20. Have received a live vaccine within 4 weeks before the first administration of
             investigational products.

         21. Hypersensitivity to Pembrolizumab additive.
      

Gender

All

Ages

19 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Seung Woo Park, MD. PhD, 82-70-4048-0932, [email protected]

Location Countries

Korea, Republic of

Location Countries

Korea, Republic of

Administrative Informations


NCT ID

NCT03937895

Organization ID

SNK-SIT-02


Responsible Party

Sponsor

Study Sponsor

SMT bio Co., Ltd.


Study Sponsor

Seung Woo Park, MD. PhD, Principal Investigator, Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital


Verification Date

May 2019