Study of Pembrolizumab and Olaparib in Bile Duct Cancer

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Brief Title

Study of Pembrolizumab and Olaparib in Bile Duct Cancer

Official Title

A Phase II, Single-arm Study of Combination Pembrolizumab and Olaparib in the Treatment of Patients With Advanced Cholangiocarcinoma

Brief Summary

      The investigators propose an open label, one-arm study to assess the safety and efficacy of
      olaparib and pembrolizumab in patients with cholangiocarcinoma who have progressed on or
      cannot tolerate gemcitabine-based therapy.
    

Detailed Description

      The primary objective of the study is to assess the ORR of patients with advanced
      cholangiocarcinoma receiving a combination of pembrolizumab and olaparib. It is hypothesized
      that the addition of olaparib will improve the response rate of second line systemic therapy
      from 17.5% to 35% in patients with advanced cholangiocarcinoma.

      The study is designed to enroll 33 subjects (for 85% power) with advanced stage
      cholangiocarcinoma to test the hypothesis that the combination of olaparib and pembrolizumab
      will increase the ORR in comparison with the ORR from second line systemic chemotherapy
      (historical control) in this patient population. As the primary study endpoint, which is also
      being used to determine the sample size of the study, the investigators propose that the
      combination of olaparib and pembrolizumab will increase the ORR to 35% from 17.5% (achieved
      with systemic cytotoxic chemotherapy including mFOLFOX-historical control). To allow a 10%
      patient drop off rate, the investigators expect to enroll a total of 36 subjects into this
      study. In addition, as secondary study endpoints the investigators expect to see an increase
      in the PFS and OS of patients receiving combination therapy compared to cytotoxic
      chemotherapy.

      In this study, the investigators propose the collection of three biopsies-one at baseline
      prior to the start of treatment, one at the beginning of week 4, three weeks after the
      administration of combination olaparib and pembrolizumab, and one at the time of cancer
      progression-for the elucidation of exploratory study endpoints. Patients will have a CT or
      MRI scan at the beginning of treatment and then every 6 weeks thereafter for the first six
      months of study treatment administration, then every 9 weeks for up to 12 months after the
      start of treatment, followed by every 12 weeks up to 24 months on study. All patients will
      continue to receive olaparib and pembrolizumab combination treatment as tolerated unless
      unacceptable toxicities or cancer progression occur, at which time therapy will cease. In the
      absence of any problems, the planned study duration is 20-36 months.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

efficacy in terms of response rate

Secondary Outcome

 efficacy in terms of duration of response

Condition

Cholangiocarcinoma

Intervention

Pembrolizumab

Study Arms / Comparison Groups

 Experimental
Description:  Pembrolizumab Q3W, IV infusion (day 1 of each 3 week cycle)
Olaparib bid, Oral tablet continuously

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

Drug

Estimated Enrollment

29

Start Date

April 1, 2020

Completion Date

December 1, 2022

Primary Completion Date

December 1, 2021

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent/assent for the trial.

          2. Be ≥ 18 years of age on day of signing informed consent.

          3. Patients must have received 1 line of prior systemic therapy for metastatic or
             resectable disease (i.e. patients may have received adjuvant gemcitabine and then
             later platin-based therapy for recurrent metastatic disease)

          4. Histological confirmation of cholangiocarcinoma manifesting as either intrahepatic,
             extrahepatic or gallbladder cancer. Patients with ampullary cancer are excluded.

          5. Have measurable disease based on RECIST 1.1.

          6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a
             tumor lesion. Newly obtained is defined as a specimen obtained up to 6 weeks (42 days)
             prior to initiation of treatment on Day 1. Subjects for whom newly obtained samples
             cannot be provided (e.g. inaccessible or subject safety concern) may submit an
             archived specimen only upon agreement from the sponsor-investigator. Subjects from
             whom a biopsy is not medically possible or safe may be enrolled on the study upon
             agreement from the principal investigator.

          7. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          8. Demonstrate adequate organ function as defined in Table 1. All screening labs will be
             performed within 28 days of registration.

             Table 1: Adequate Organ Function Laboratory Values System Laboratory Value
             Hematological Absolute neutrophil count (ANC) ≥ 1,500 /μL Platelets ≥ 100,000 / μL
             Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7
             days of assessment) Renal Serum creatinine OR Measured or calculateda creatinine
             clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5 X upper limit of
             normal (ULN) OR

             ≥ 50 mL/min for subject with creatinine levels > 1.5 x institutional ULN Hepatic Serum
             total bilirubin ≤ 2.0 X ULN AST (SGOT) and ALT (SGPT) ≤ 3.0 X ULN OR

             ≤ 5 X ULN for subjects with liver metastases Albumin > 2.5 mg/dL Coagulation
             International Normalized Ratio (INR) or Prothrombin Time (PT)

             Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants

             ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is
             within therapeutic range of intended use of anticoagulants aCreatinine clearance
             should be calculated per institutional standard.

          9. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours 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 (Reference
             Section in Appendix 3). 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.

        Exclusion Criteria:

          1. A history of anaphylaxis to olaparib

          2. 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.

          3. A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test
             within 72 hours prior to 1st dose of treatment (see Appendix 3). If the urine test is
             positive or cannot be confirmed as negative, a serum pregnancy test will be required.

          4. Has a known history of active TB (Bacillus Tuberculosis).

          5. Has known hypersensitivity to pembrolizumab or any of its excipients.

          6. 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.

          7. 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.

          8. 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.

          9. 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.

         10. 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.

         11. Has known history of, or any evidence of active, non-infectious pneumonitis.

         12. Has an active infection requiring systemic therapy.

         13. 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 site investigator.

         14. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         15. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment.

         16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         17. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.

         18. Has known active Hepatitis B without HBV treatment (HBV infection with ongoing HBV
             treatment is allowed); chronic Hepatitis C infection is allowed. Any patient receiving
             treatment for HCV should wait at least 14 days after completion of HCV treatment
             before beginning study treatment. No patient should receive HCV treatment while
             receiving study treatment. Note: no testing for Hepatitis B and Hepatitis C is
             required unless mandated by local health authority.

         19. Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04306367

Organization ID

STUDY00000908


Responsible Party

Sponsor

Study Sponsor

Georgetown University


Study Sponsor

, , 


Verification Date

February 2020