Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: Evaluating Combination Immunotherapy for Advanced Cholangiocarcinoma With Pembrolizumab and PEG-Intron

Summary: This is an open-label, single-arm, multicenter Phase II safety and efficacy study of combination therapy with pembrolizumab and PEG-Intron (Peginterferon alpha-2b) in patients with advanced cholangiocarcinoma who have progressed on or cannot tolerate frontline chemotherapy. PEG-Intron will be administered to patients as a 3ug/kg (subject to possible dose modification) subcutaneous injection weekly, while pembrolizumab will be administered as a 200mg IV infusion once every three weeks, starting on week 4 (at the same time as the 4th dose of PEG-Intron). This trial design provides an initial window (3 weeks) to evaluate the effect of PEG-Intron alone on tumor microenvironment in comparison to that of prior therapy: a biopsy prior to treatment will be collected, followed by a, repeat tumor biopsies collected while the patients receive PEG-Intron. Tumor tissue will be collected and analyzed as described in the next paragraph.

Detailed description: If survival is to be further improved in patients with cholangiocarcinoma, new approaches are urgently needed to prevent tumor recurrence after surgical resection of cholangiocarcinomas. Pembrolizumab is a monoclonal antibody that binds to the programmed death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including a strong anti-tumor immune response. Prognostic impact of tumor-infiltrating immune cells on biliary tract cancer was studied in a retrospective study of 375 patients with cholangiocarcinoma. High levels of tumor infiltrating lymphocytes in cholangiocarcinoma were associated with good clinical outcome. Therapies that target the PD-1 receptor have shown yet unmatched rates of lasting clinical responses in patients with a number of cancer types. The response rate of pembrolizumab in patients with advanced cholangiocarcinoma was 17% in a phase I study. Interferon alpha 2b has been shown to increase tumor immune infiltrates. The investigators propose to combine Sylatron with pembrolizumab to improve the response rate of pembrolizumab. It is hypothesized that Sylatron will improve the response rate of pembrolizumab from 17% to 35% by increasing the immune cell infiltrate into the tumor.

Eligibility: Inclusion Criteria:
  1. Be willing and able to provide written informed consent/assent for the trial.
  2. Be at least 18 years of age on day of signing informed consent.
  3. Have measurable disease based on RECIST 1.1.
  4. 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.
  5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  6. Demonstrate adequate organ function, all screening labs should be performed within 10 days of treatment initiation.
  7. 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.
  8. 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.
  9. 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 peginterferon alfa-2b or interferon alfa-2b
  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. 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.
  4. Has a known history of active Bacillus Tuberculosis (TB)
  5. 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. Hepatic decompensation (Child-Pugh score >6 [class B and C])
  14. 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.
  15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  16. 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.
  17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (HCV) (e.g., HCV RNA [qualitative] is detected).
  20. 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.
  21. Has history of bipolar disorder or major depression.
  22. Has history of not tolerating interferon treatment.
  23. Has known serious neuropsychiatric condition.

Relevance to patient case: not relevant