Clinical Trials /

Pembrolizumab and Pelareorep in Treating Patients With Advanced Pancreatic Cancer

NCT03723915

Description:

This phase II trial studies the side effects and how well pembrolizumab in combination with pelareorep work in treating patients with pancreatic cancer that has spread to other parts of the body. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. A virus, called reovirus (pelareorep), which has been changed in a certain way, may be able to kill tumor cells without damaging normal cells. Giving pembrolizumab in combination with pelareorep may work better in treating patients with advanced pancreatic cancer.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Pelareorep in Treating Patients With Advanced Pancreatic Cancer
  • Official Title: A Phase 2 Study of Pembrolizumab in Combination With Pelareorep in Patients With Advanced Pancreatic Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: NU 18I01
  • SECONDARY ID: NCI-2018-02319
  • SECONDARY ID: STU00207577
  • SECONDARY ID: NU 18I01
  • SECONDARY ID: P30CA060553
  • NCT ID: NCT03723915

Conditions

  • Pancreatic Adenocarcinoma
  • Stage III Pancreatic Cancer AJCC v8
  • Stage IV Pancreatic Cancer AJCC v8

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, wild-type reovirus)
Wild-type ReovirusReolysinTreatment (pembrolizumab, wild-type reovirus)

Purpose

This phase II trial studies the side effects and how well pembrolizumab in combination with pelareorep work in treating patients with pancreatic cancer that has spread to other parts of the body. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. A virus, called reovirus (pelareorep), which has been changed in a certain way, may be able to kill tumor cells without damaging normal cells. Giving pembrolizumab in combination with pelareorep may work better in treating patients with advanced pancreatic cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the overall response rate (ORR) by Response Evaluation Criteria in Solid
      Tumors (RECIST) version (v) 1.1 criteria of pembrolizumab in combination with Reovirus
      Serotype 3 ? Dearing Strain (pelareorep).

      SECONDARY OBJECTIVES:

      I. To determine progression free survival by RECIST v 1.1 criteria, as well as 1- year,
      2-year and median overall survival with pembrolizumab in combination with pelareorep.

      II. To determine safety and tolerability of pembrolizumab and pelareorep when administered in
      combination as determined by National Cancer Institute (NCI) Common Terminology Criteria for
      Adverse Events (CTCAE) v 4.03.

      III. To determine the effects (immune response) of pembrolizumab and pelareorep when
      administered in combination as determined by analysis of pre-and post-treatment biopsies and
      blood-based immune markers.

      EXPLORATORY OBJECTIVES:

      I. To measure the overall response rate (ORR) by using Immune-Modified Response Evaluation
      Criteria in Solid Tumors (iRECIST) criteria, for the combination of pembrolizumab and
      pelareorep.

      II. To determine progression free survival by iRECIST criteria as well as 1-year, 2-year and
      median overall survival with pembrolizumab in combination with pelareorep.

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
      every 21 days for up to 32 courses in the absence of disease progression, unacceptable
      toxicity, development of an inter-current illness that prevents further administration of
      treatment, patient decides to withdraw, patients not experiencing clinical benefit in the
      judgment of the Investigator, or the treating investigator determines that the patient should
      be taken off treatment for any reason. Patients also receive Pelareorep IV over 60 minutes on
      days 1, 2, 3, and 8 in course 1 and on days 1 and 8 of subsequent courses. Courses repeat
      every 21 days for up to 24 months in the absence of disease progression, unacceptable
      toxicity, development of an inter-current illness that prevents further administration of
      treatment, patient decides to withdraw, patients not experiencing clinical benefit in the
      judgment of the Investigator, or the treating investigator determines that the patient should
      be taken off treatment for any reason. Patients who stop study therapy with stable disease
      (SD) or better may be eligible for up to 1 year of additional Pelareorep and pembrolizumab
      therapy if they progress after stopping study treatment.

      After completion of study treatment, patients are followed up every 3 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, wild-type reovirus)ExperimentalSee Detailed Description
  • Pembrolizumab
  • Wild-type Reovirus

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed advanced (unresectable or metastatic)
             pancreatic adenocarcinoma, documented objective radiographic progression and have
             failed or not tolerated first-line therapy.

               -  Note: First-line therapy denotes systemic chemotherapy for advanced pancreatic
                  adenocarcinoma. Only one line of therapy is permitted in this setting. Intolerant
                  to first line therapy are patients that have developed >= grade 3 adverse events
                  related to first line therapy and treating physician deems continuing of systemic
                  chemotherapy would be detrimental to patient.

          -  Patients must have confirmation of an existing formalin-fixed paraffin-embedded (FPPE)
             tumor sample from archival tissue or from a fresh biopsy of a primary or metastatic
             lesion at baseline, either as a block or unstained slides for performance of
             correlative studies.

               -  Note: Patients must undergo a fresh biopsy if archival tissue is not available.

          -  Patients must have measurable disease as defined by RECIST v 1.1.

          -  Any major surgery (except biopsies) must have occurred at least 28 days prior to first
             day of study treatment.

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance score =<
             1.

          -  Patients must have a life expectancy of >= 6 months.

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL (with or without growth factor use).

          -  Platelets >= 100,000 / mcL.

          -  Hemoglobin >= 9 g/dL, OR >= 5.6 mmol/L with (if clinically indicated)/without
             transfusion or erythropoietin [EPO] dependency).

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN), OR measured or calculated
             creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
             levels > 1.5 x institutional ULN.

               -  (Note: creatinine clearance should be calculated per institutional standard.)

          -  Serum total bilirubin =< 1.5 x ULN, OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 x ULN.

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             ULN, OR =< 5 x ULN for subjects with liver metastases.

          -  Albumin >= 2.5 mg/dL.

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
             subject is receiving anticoagulant therapy. For patients on anticoagulant therapy,
             PT/INR must be within therapeutic range.

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
             anticoagulant therapy. For patients on anticoagulant therapy, PT/INR must be within
             therapeutic range

          -  Thyroid-stimulating hormone (TSH), thyroxine (T4) and corticotropin (ACTH) within
             normal range (prior to registration).

          -  Proteinuria within institutional normal or =< grade 1 OR urinary protein < 1 g/24
             hours (hr) (prior to registration).

          -  Female subject of childbearing potential must have a negative urine or serum pregnancy
             within 7 days of registration. It is to be repeated on day 1 of study treatment,
             before infusion, if it is done greater than 3 days of day 1. If the urine test is
             positive or cannot be confirmed as negative, a serum pregnancy test is required.
             Female subjects of childbearing potential must be willing to use an adequate method of
             contraception (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. Should a female patient become pregnant or
             suspect she is pregnant while participating in this study, she should inform her
             treating physician immediately.

               -  Note: A female of childbearing potential (FOCBP) is any woman (regardless of
                  sexual orientation, having undergone a tubal ligation, or remaining celibate by
                  choice) who meets the following criteria:

                    -  Has not undergone a hysterectomy or bilateral oophorectomy

                    -  Has had menses at any time in the preceding 12 consecutive months (and
                       therefore has not been naturally postmenopausal for > 12 months).

          -  Male subjects of childbearing potential must agree to use an adequate method of
             contraception or be surgically sterile or abstain from heterosexual activity, starting
             with the first dose of study therapy through 120 days after the last dose of study
             therapy.

          -  Patients must have signed an informed consent indicating that the patient is aware of
             the neoplastic nature of their disease and have been informed of the procedures of the
             protocol, the experimental nature of the therapy, alternatives, potential benefits,
             side effects, risks, and discomforts.

          -  Patients must be willing and able to comply with scheduled visits, the treatment plan,
             and laboratory tests.

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks prior first day of
             study drug or those who have not recovered from adverse events due to agents
             administered more than 4 weeks from cycle 1 day 1 are not eligible.

          -  Patients who have 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 study treatment are excluded.

               -  Note: If patient is on high dose of steroid therapy, it needs to be brought down
                  to < 10 mg prednisone or equivalent for at least 7 days prior to day 1 of study
                  treatment.

          -  Patients receiving any other investigational agents for at least 4 weeks before the
             first dose of study treatment are not eligible.

          -  Patients with a known history of active TB (Bacillus tuberculosis) are excluded.

          -  Patients with a hypersensitivity to pembrolizumab or any of its excipients are
             excluded.

          -  Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 28 days
             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.

          -  Patients who have had prior chemotherapy, targeted small molecule therapy, or
             radiation therapy within 28 days prior to study day 1 or who has not recovered (i.e.,
             NCI CTCAE version 4.03 grade =< 1 or at baseline) from adverse events due to a
             previously administered agent are not eligible.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

               -  Exceptions to this criteria are:

                    -  Subjects with =< grade 2 neuropathy or alopecia are an exception to this
                       criterion and may qualify for the study.

          -  Patients receiving palliative radiation are eligible for this study. Palliative
             radiation is allowed during treatment as well. Patients with a known additional
             malignancy that is progressing or requires active treatment within the past 5 years
             are excluded. 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.

          -  Patients with a known active central nervous system (CNS) metastases and/or
             carcinomatous meningitis are excluded.

               -  Note: 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.

          -  Patients with an 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) are excluded.

               -  Note: 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.

          -  Patients with a history of (non-infectious) pneumonitis that required steroids or
             current pneumonitis are excluded.

          -  Patients with an active infection requiring systemic therapy are excluded.

          -  Patients with 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 are excluded.

          -  Patients with a known psychiatric or substance abuse disorders that would interfere
             with cooperation with the requirements of the trial are excluded.

          -  Patients who are 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 are
             excluded.

          -  Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2
             agent are excluded.

          -  Patients with a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
             antibodies) are excluded.

          -  Patients with a known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]
             reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA]
             [qualitative] is detected) are excluded.

          -  Patients who have received a live vaccine within 30 days of planned start of study
             therapy are excluded.

               -  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.

          -  Patients with clinically significant cardiac disease (New York Heart Association,
             class III or IV including pre-existing arrhythmia, uncontrolled angina pectoris, and
             myocardial infarction 1 year prior to registration, or grade 2 or higher compromised
             left ventricular ejection fraction are excluded.

          -  Patients who have dementia or altered mental status that would prohibit informed
             consent are excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:ORR will be estimated using a two stage method.

Secondary Outcome Measures

Measure:Progression free survival (PFS) by RECIST v 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier curves will be used.
Measure:1-year survival by RECIST v 1.1
Time Frame:At 1 year
Safety Issue:
Description:Kaplan-Meier curves will be used.
Measure:2-year survival by RECIST v 1.1
Time Frame:At 2 years
Safety Issue:
Description:Kaplan-Meier curves will be used.
Measure:Median overall survival (OS) by RECIST v 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier curves will be used.
Measure:Incidence of adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:
Measure:Immune response determined by analysis of pre-and post- treatment biopsies and blood-based immune markers
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed for change using paired statistical methods such as paired t-tests or signed rank tests.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

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