A Study of Regorafenib in Advanced Pancreatic Cancer Patients

Study Overview
=================
Brief Summary
-----------------
This study tests regorafenib as a single agent in the treatment of metastatic pancreatic cancer patients who have progressed after prior chemotherapy with gemcitabine. The prognosis for these patients is particularly grim, no other standard treatment options exist, and novel approaches are desperately needed.

Detailed Description
-----------------
This is a single arm, single stage Phase II study designed to evaluate progression free survival (PFS) in patients with metastatic pancreatic cancer who have failed at least one prior line of therapy and treatment with gemcitabine. This study is open at the Levine Cancer Institute (LCI). A total of 32 patients will be enrolled over a two years. Following informed consent and eligibility check, all patients will start oral regorafenib therapy (120 mg daily for 3 weeks on / 1 week off; 28 day cycle) with a built-in dose escalation to 160mg after the first cycle as tolerated, and will continue therapy until progression or patient withdrawal. Patients will undergo radiological staging after the first two cycles of regorafenib therapy. Patients with progressive disease will be removed from the study. Patients who have at least stable disease will continue regorafenib therapy, at the Investigator's discretion, and will be radiologically restaged bimonthly.

Official Title
-----------------
A Pilot Study Testing Single-Agent Regorafenib in Advanced Previously-Treated Adenocarcinoma of the Pancreas

Conditions
-----------------
Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: regorafenib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adenocarcinoma of the exocrine pancreas with metastatic disease. The site of the primary tumor confirmed to have been within the pancreas. Progression on at least one prior line of chemotherapy for locally-advanced or metastatic pancreatic cancer. Progression while on treatment with a gemcitabine regimen for advanced pancreatic cancer, or within 12 months of treatment with gemcitabine as part of adjuvant therapy. Measurable disease on axial imaging. Age greater than or equal to 18 years. Life expectancy of at least 8 weeks. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2. Enrollment of patients with PS = 2 will be capped at 7 patients. Subjects must be able to understand and be willing to sign the written informed consent form. Acute toxic effects except alopecia of any prior treatment must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade 1 or less. Adequate bone marrow, renal, and liver function. Warfarin or heparin will be allowed provided that there is no prior evidence of underlying coagulation abnormality. Women of childbearing potential must have a negative pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test. Patients (men and women) of childbearing potential must agree to use adequate contraception Patient must be able to swallow and retain oral medication. Exclusion Criteria: Previous assignment to treatment during this study. Uncontrolled hypertension. Active clinically significant cardiac disease. Cerebrovascular arterial event within 6 months. Evidence or history of bleeding diathesis or coagulopathy. Any bleeding event greater than or equal to NCI CTCAE Grade 3 within 4 weeks. New venous thrombotic or embolic events, such as deep vein thrombosis or pulmonary embolism within 3 months. Previously untreated or concurrent cancer that is distinct in primary site or histology except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor. Patients surviving a cancer that was curatively treated and without evidence of disease for more than 3 years are allowed. Patients with pheochromocytoma. Known history of HIV infection or current chronic or active hepatitis B or C, requiring antiviral medication. Ongoing infection greater than or equal to Grade 2 NCI-CTCAE v4.0. Symptomatic metastatic brain or meningeal tumors. Presence of a non-healing wound, non-healing ulcer, or bone fracture. Renal failure requiring dialysis. Dehydration Grade greater than or equal to 1 NCI-CTCAE v4.0. Patients with seizure disorder requiring medication. Persistent proteinuria greater than or equal to Grade 3 NCI-CTCAE v4.0. Symptomatic interstitial lung disease. Pleural effusion or ascites that cause respiratory compromise. History of organ allograft except corneal transplant. Known or suspected allergy or hypersensitivity to the study drugs. Any severe, uncontrolled malabsorption condition. Women who are pregnant or breast-feeding. Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study. Concurrent anti-cancer therapy other than study treatment (regorafenib). Prior use of regorafenib. Concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, or within 4 weeks. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days. Prior radiation therapy or hepatic arterial therapy is permitted if more than 4 weeks have passed since completion and measurable disease outside of the treated area is present, or if progression since treatment has occurred. Use of St. John's Wort.

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: Single Arm<br>Oral Regorafenib | Drug: regorafenib<br>* Single agent drug therapy with regorafenib<br>* Other names: Stivarga;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Progression Free and Surviving at 16 Weeks as a Percent of All Enrolled Subjects | 16-week progression free survival was determined for each subject as a binary variable indicating whether or not the subject is alive and progression free at 16 weeks after treatment start, with progression defined radiographically using RECIST v1.1 or clinically based upon investigator assessment. | 16 weeks after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | PFS is defined as duration of time from enrollment to the study to time of progression or death. Disease progression (PD) can be objectively determined as per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors, where PD is defined as a 20% increase in the sum of the longest diseased of target lesions, or a measurable increase in non-target lesion, or the appearance of new lesions) or progression can be subjective as determined by the investigator. Evidence for subjective progressions must be documented in medical records. For surviving subjects who do not have documented PD, PFS will be censored at last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented PD, PFS will be censored at last radiologic assessment prior to commencement of subsequent therapy. Subjects who experience a PFS event following an interval equal to two or more scheduled CT assessments will be censored at date of last assessment prior to first missed assessment. | From date of treatment start to date of progression or death, or censored as described above; assessed for approximately 3 years. | 
| Overall Survival | Overall survival is defined as the duration from enrollment date to the date of death from any cause. Subjects who are alive or lost to follow-up at the time of the analysis will be censored at the last known date they were alive. | From date of treatment start to date of death, or censored as described above; assessed for approximately 3 years. | 
| Overall Response | Overall response will be determined as the best treatment response for each patient as a binary variable indicating whether or not the patient achieved a Complete Response (CR) or Partial Response (PR) as determined by RECIST v1.1 criteria. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1):Complete Response (CR) is the disappearance of all lesions (target and non target); Partial Response (PR) is at least 30% decrease in the sum of the diameters of target lesions from baseline and no new lesions or unequivocal progression in non target lesions from baseline; Stable Disease (SD) is neither sufficient shrinkage in target lesions to qualify for PR (less than 30% decrease) nor sufficient increase in target lesions (versus smallest sum of diameters) to qualify for PD (less than 20% increase), with no new lesions or unequivocal progression in non target lesions from baseline. For the purposes of response determination, confirmatory scan for CR and PR is not required. | From enrollment to best response while on regorafenib; Subjects remained on treatment until disease progression or death or discontinuation from study or at least 28 days after last dose (subjects were on treatment for an average of 6 weeks) | 
| Disease Control | Disease control will be determined for each patient as a binary variable indicating whether or not the patient achieved a best overall best response of CR, PR, or stable disease as determined by RECIST v1.1 criteria. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v 1.1): Complete Response (CR) is the disappearance of all lesions (target and non target); Partial Response (PR) is at least 30% decrease in the sum of the diameters of target lesions from baseline and no new lesions or unequivocal progression in non target lesions from baseline; Stable Disease (SD) is neither sufficient shrinkage in target lesions to qualify for PR (less than 30% decrease) nor sufficient increase in target lesions (versus smallest sum of diameters) to qualify for PD (less than 20% increase), with no new lesions or unequivocal progression in non target lesions from baseline. | From enrollment to best response while on regorafenib; Subjects remained on treatment until disease progression or death or discontinuation from study or at least 28 days after last dose (subjects were on treatment for an average of 6 weeks) |