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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02982720
Recruitment Status : Terminated (Manufacturer discontinued Sylatron)
First Posted : December 5, 2016
Results First Posted : June 5, 2019
Last Update Posted : February 16, 2022
Sponsor:
Collaborators:
Merck Sharp & Dohme LLC
Roswell Park Cancer Institute
The Cleveland Clinic
Georgetown University
Hoosier Cancer Research Network
Information provided by (Responsible Party):
Aiwu Ruth He, MD, Hoosier Cancer Research Network

Brief Summary:
This is an open-label, single-arm, multicenter Phase II safety and efficacy study of combination therapy with pembrolizumab and Sylatron (Peginterferon alpha-2b) in patients with advanced cholangiocarcinoma who have progressed on or cannot tolerate frontline chemotherapy.

Condition or disease Intervention/treatment Phase
Advanced Cholangiocarcinoma Drug: Pembrolizumab Drug: Sylatron Phase 2

Detailed Description:

Pembrolizumab and Sylatron Administration:

Pembrolizumab has been evaluated at 2 mg/kg every 3 weeks (Q3W), 10 mg/kg Q3W, or 10 mg/kg Q2W in multiple previous studies for different types of cancer, the response rate at higher dose level seems not improved compared to that of lower dose level. With concerns of increased toxicities from the combination pembrolizumab and sylatron therapy, the pembrolizumab dose is selected to be 200mg administered every three weeks. The approved dose of sylatron for melanoma is induction treatment at 6 μg/kg/week for 8 doses followed by 5 year of maintenance treatment at 3 μg/kg/week for up to 5 years. The approved dose of sylatron for chronic hepatitis C infection in combination with ribavirin is 1.5μg/kg weekly for 24 to 48 weeks.

Each cycle = 21 days or 3 weeks. Based on the approved dosage of sylatron, we decided to treat patients at 200mcg weekly up to 12 weeks (3 weeks as single agent, and 9 weeks in combination of pembrolizumab). Sylatron will start Cycle 1 Day 1 and continue on a weekly basis. We have prepared to reduce the dose of sylatron to 120mcg weekly, or 60mcg weekly if patients experience unacceptable toxicities at the higher dose level of sylatron.

Pembrolizumab will be administered intravenously as a 30 minute infusion at a dose of 200 mg every 3 weeks starting Week 4. Pembrolizumab will start Cycle 2 Day 1 and continue every 3 weeks. All trial treatments will be administered on an outpatient basis.

Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).

With concerns about toxicity while using long-term sylatron, if no additional benefit is seen beyond 12 weeks of treatment on top of that expected from pembrolizumab alone, patients will discontinue sylatron treatment after they have received 12 weeks of this therapy (3 weeks as single agent and 9 weeks in combination with pembrolizumab). Pembrolizumab should be continued in the absence of unacceptable toxicity (based on CTCAE v4) until disease progression-based on RECIST 1.1. In patients who had responded to the combination therapy, when patient shows disease progression while on single agent pembrolizumab treatment, Sylatron may be resumed at the discretion of the site investigator after discussion with the sponsor-investigator.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: Open-Label
Primary Purpose: Treatment
Official Title: A Phase II Multi-center Study Evaluating Combination Immunotherapy for Advanced Cholangiocarcinoma With Pembrolizumab and Sylatron (Peginterferon Alfa-2b) HCRN:GI16-263
Actual Study Start Date : July 5, 2017
Actual Primary Completion Date : February 9, 2018
Actual Study Completion Date : February 9, 2018


Arm Intervention/treatment
Experimental: Pembrolizumab and Sylatron
Pembrolizumab will be administered intravenously at a dose of 200 mg every 3 weeks starting week 4. Sylatron will be administered at a dose of 200mcg subcutaneously weekly starting at week 1.
Drug: Pembrolizumab
Pembrolizumab will be administered intravenously.
Other Name: MK-3475

Drug: Sylatron
Sylatron will be administered subcutaneously.
Other Name: Peginterferon alfa-2b




Primary Outcome Measures :
  1. Asses Objective Response Rate (ORR) of All Patients Receiving Pembrolizumab and Sylatron Combination Therapy [ Time Frame: 12 months ]
    Defined as the proportion of subjects who achieve the best response (CR and PR) determined by RECIST1.1


Secondary Outcome Measures :
  1. Assess Progression Free Survival (PFS) of Patients Receiving Pembrolizumab and Sylatron [ Time Frame: 36 months ]
    Defined as time from start of the treatment till the patient's disease progression or death from any cause (those for whom event of progression or death not observed will be censored).

  2. Asses Overall Survival (OS) of Patients Receiving Pembrolizumab and Sylatron [ Time Frame: 36 months ]
    Defined as time from start of the treatment till the patient's death from any cause (patient who are still alive at the end of the study will be censored).

  3. Assess Objective Response Rate (ORR) [ Time Frame: 36 months ]
    the sum of complete response (CR) + confirmed partial response (PR) and will be determined as per irRC.

  4. Assess Adverse Events, Serious Adverse Events and Serious Adverse Events Leading to Discontinuation of the Treatment (Death) of Combined Pembrolizumab and Sylatron Therapy. [ Time Frame: 36 months ]
    the combination of Sylatron and pembrolizumab as assessed by CTCAE v4



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

  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. 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 gemcitabine/cisplatin for recurrent metastatic disease)
  4. Histological confirmation of cholangiocarcinoma.
  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.
  7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  8. Demonstrate adequate organ function:

    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 calculated creatinine clearance ≤ 1.5 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels
    • (GFR can also be used in place of creatinine or CrCl) > 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) ≤ 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
    • 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
  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 adequate 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.

Exclusion Criteria:

The subject must be excluded from participating in the trial if the subject:

  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. 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 known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  18. Has known active Hepatitis B without HBV treatment (HBV infection with ongoing HBV treatment is allowed); has persistent chronic Hepatitis C infection (successfully treated HCV infection is allowed).
  19. 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.
  20. Has history of bipolar disorder or major depression.
  21. Has history of not tolerating interferon treatment.
  22. Has known serious neuropsychiatric condition.

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): NCT02982720


Locations
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United States, District of Columbia
Georgetown Lombardi Comprehensive Cancer Center
Washington, District of Columbia, United States, 20007
Sponsors and Collaborators
Aiwu Ruth He, MD
Merck Sharp & Dohme LLC
Roswell Park Cancer Institute
The Cleveland Clinic
Georgetown University
Hoosier Cancer Research Network
Investigators
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Study Chair: Aiwu R. He, MD PhD Lombardi Comprehensive Cancer Center Georgetown University
  Study Documents (Full-Text)

Documents provided by Aiwu Ruth He, MD, Hoosier Cancer Research Network:
Additional Information:
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Responsible Party: Aiwu Ruth He, MD, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT02982720    
Other Study ID Numbers: GI16-263
First Posted: December 5, 2016    Key Record Dates
Results First Posted: June 5, 2019
Last Update Posted: February 16, 2022
Last Verified: February 2022
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: No
Keywords provided by Aiwu Ruth He, MD, Hoosier Cancer Research Network:
cholangiocarcinoma
Pembrolizumab
MK-3475
Sylatron
peginterferon alfa-2b
Additional relevant MeSH terms:
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Cholangiocarcinoma
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Peginterferon alfa-2b
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents