Efficacy of Ginseng for Patients on Regorafenib

A Randomized Phase II Trial to Evaluate the Efficacy of Supportive Therapy With Ginseng for Patients on Treatment With Regorafenib

This is a randomized, multi-center phase II study of ginseng in colorectal cancer patients treated with regorafenib to determine if ginseng will reduce fatigue in this patient population and improve adherence to regorafenib. Ninety (90) subjects will be enrolled and randomized using a 2:1 allocation, with 60 subjects enrolled in the regorafenib + ginseng group and 30 enrolled in the regorafenib + no ginseng group.

OUTLINE: This is a multi-center study.

INVESTIGATIONAL TREATMENT:

Regorafenib will be administered 160 mg orally once daily for the first 21 days of each 28-day cycle. Subjects that randomize to receive ginseng will take 1,000 mg orally twice daily every day for 4 weeks (2 cycles). Subjects that randomize to NOT receive ginseng will not be given ginseng. Subjects will be instructed to take regorafenib with a low-fat meal.

Subjects will undergo fatigue assessments, using the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) instrument and Patient-Reported Outcomes Measurement Information System (PROMIS). Subjects will have a pill count cycle 2 day 1 (C2D1) and at the end of treatment visit. Subjects will have the re-staging scan (CT of chest/abdomen/pelvis) at the end of Cycle 2/ week 8 (±5).

Adequate bone marrow, liver and renal function assessed by the following laboratory values obtained within 7 days prior to registration for protocol therapy:

Hematopoietic:

• Absolute neutrophil count (ANC) count > 1,500/mm^3
• Hemoglobin (Hgb) > 9g/dL
• Platelet count > 100,000/mm^3

Renal:

• Serum creatinine ≤ 1.5 × the upper limit of normal (ULN)

Hepatic:

• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).
• Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x ULN (≤ 5 × ULN for subjects with liver involvement of their cancer)
• Alkaline phosphatase (ALP) limit ≤ 2.5 × ULN (≤ 5 × ULN for subjects with liver involvement of their cancer)

Coagulation:

• International normalized ratio (INR)/Partial thromboplastin time (PTT) ≤ 1.5 × ULN. NOTE: Subjects who are prophylactically treated with an agent such as warfarin or heparin will be allowed to participate if no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable, based on a measurement that is pre-dose as defined by the local standard of care. Warfarin does should not exceed 1 mg.

Inclusion Criteria:

• Subjects must be able to understand and be willing to sign the written informed consent and Health Insurance Portability and Accountability Act of 1996 (HIPAA) authorization for release of personal health information. A signed informed consent form (ICF) must be appropriately obtained prior to the conduct of any trial-specific procedure. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• Life expectancy of at least 12 weeks (3 months) as determined by the treating physician.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 28 days prior to registration.
• Histological or pathologically confirmed stage IV adenocarcinoma of the colon.
• Women of childbearing potential must have a negative serum 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.
• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 2 months after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the treating physician or a designated associate. NOTE: Examples of adequate contraception may include but are not limited to a combination of any two of the following: use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); barrier methods of contraception (condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/ film/cream/vaginal suppository); total abstinence; male/female sterilization
• All subjects must have radiographically assessable disease per RECIST v1.1 obtained by imaging within 28 days prior to registration.
• Must be able to swallow and retain oral medication.
• Subject must be deemed a suitable candidate for regorafenib as per their treating physician.

Exclusion Criteria:

• Subject should not be receiving any agent for fatigue including steroids, megace or opioids. NOTE: Subjects who have a contrast-induced allergy are allowed to receive steroids for their scans.
• Radiotherapy within 2 weeks prior to study registration. Subjects must have recovered from all therapy-related toxicities.
• Prior treatment with regorafenib.
• Previous assignment to treatment during this study. Subjects permanently withdrawn from study participation will not be allowed to re-enter study.
• Congestive heart failure > New York Heart Association (NYHA) class 2: unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), myocardial infarction less than 6 months before study registration; cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted); uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
• Evidence or history of bleeding diathesis or coagulopathy.
• Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to study registration.
• Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months of study registration.
• Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 3 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (Non-invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].
• Subjects with pheochromocytoma.
• Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy.
• Ongoing infection > Grade 2 NCI-CTCAE v4.0.
• Metastatic brain or meningeal tumors (symptomatic or asymptomatic).
• Major surgical procedure or significant traumatic injury, as defined by the site investigator, within 28 days before study registration.
• Renal failure requiring hemo- or peritoneal dialysis
• Dehydration Grade > 2 NCI CTCAE v4 within 7 days prior to registration.
• Subjects with seizure disorder currently requiring medication.
• Persistent proteinuria ≥ Grade 3 NCI CTCAE v4.0 as defined as > 3.5 g/24 hours, measured by urine protein: creatinine ratio on a random urine sample.
• Interstitial lung disease with ongoing signs and symptoms at the time of study registration.
• Pleural effusion or ascites that causes respiratory compromise (≥ NCI CTCAE version 4.0 Grade 2 dyspnea).
• History of organ allograft (including corneal transplant).
• Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial.
• Any malabsorption condition which, in the opinion of the treating physician, will affect the absorption of any of the agents used in this study.
• Women who are pregnant or breast-feeding.
• Any condition, which, in the site investigator's opinion, makes the subject unsuitable for trial participation.
• Substance abuse, medical, psychological, or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
• Treatment with any investigational agent within 28 days prior to registration.