Pembrolizumab and Pelareorep in Treating Patients With Advanced Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Phase 2 Study of Pembrolizumab in Combination With Pelareorep in Patients With Advanced Pancreatic Adenocarcinoma

Conditions
-----------------
Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8

Intervention / Treatment
-----------------
* Biological: Pembrolizumab
* Biological: Wild-type Reovirus


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pembrolizumab, wild-type reovirus)<br>See Detailed Description | Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Biological: Wild-type Reovirus<br>* Given pelareorep IV<br>* Other names: Reolysin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 | To determine the overall response rate (ORR) by RECIST v 1.1 criteria for the combination of pembrolizumab with pelareorep. ORR is defined as the number of patients who have a complete or partial response to therapy (CR or PR). The Simon 2 stage design for this study requires 2 or more PR or CR in Stage 1 to continue accrual for Stage 2. Per RECIST v. 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Patients who have taken one dose of either study drug, and completed the first on study scan (last week of Cycle 3) are evaluable. If a patient drops out of the study before the first scan, due to clinical progression, they are evaluable and will not be replaced. | Last week of Cycle 3 (1 Cycle = 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (mPFS) by RECIST v 1.1 | Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (including baseline if that is the smallest). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions is also considered progression. Kaplan-Meier curves will be used. | Up to 2 years | 
| Overall Survival at One Year (12 Months) | Measured from time of treatment initiation until death for any reason. Kaplan-Meier curves will be used. | At 1 year | 
| Overall Survival (OS) at Two Years (24 Months) | Measured from time of treatment initiation until death for any reason. Kaplan-Meier curves will be used. | At 2 years | 
| Median Overall Survival (OS) | Measured from time of treatment initiation until death from any cause. Kaplan-Meier curves will be used. | Up to 2 years | 
| Number of Patients With Adverse Events at Grade 3 Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 | Adverse events graded 3 using CTCAE 4.03 where: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death. | Up to 30 days after last dose | 
| Immune Response Determined by Analysis of pre-and Post- Treatment Biopsies and Blood-based Immune Markers | Will be assessed for change using paired statistical methods such as paired t-tests or signed rank tests. | Up to 2 years |