A Multicenter, Non-Randomized, Phase II Study of Regorafenib for Advanced Urothelial Cancer Following Prior Chemotherapy
A Multicenter, Non-Randomized, Phase II Study of Regorafenib for Advanced Urothelial Cancer Following Prior Chemotherapy
This study will test how well Regorafenib controls disease progression in urothelial cancer (cancer occurring in the urinary bladder, ureters, or renal pelvis) following previous therapy with chemotherapy.
Advanced urothelial carcinoma (UC) has a poor long-term prognosis. The disease has not seen improved outcomes despite research efforts in over two decades. Novel therapeutic options are needed. Regorafenib is a novel oral multikinase inhibitor but is more potent than a similar multikinase inhibitor drug that treats advanced renal cell carcinoma and hepatocellular carcinoma. Regorafenib has been shown to have a broader capacity to inhibit blood supply to tumor sources.
This trial evaluates a proof-of-concept using Regorafenib in patients with metastatic progressive urothelial carcinoma following chemotherapy but still have a high level of activity performance in their daily living. The initial dose of Regorafenib will be 120 mg daily and then be escalated to 160 mg daily before gradually tapering.
Inclusion Criteria:
Patients must have pathologically or cytologically proven transitional cell carcinoma of the urothelium.
Progressive disease after 1-3 prior chemotherapy regimens (perioperative chemotherapy within 12 months will be considered one regimen).
Prior regimen must be within 6 months of registration
Measurable disease by RECIST 1.1
Eastern Cooperative Oncology Group (ECOG) Performance status 0-1
Patients with metastatic (lymph node or distant metastasis, i.e. N+ or M1) or locally advanced unresectable (T4b) transitional cell carcinoma.
Age ≥19 years
Life expectancy of at least 12 weeks (3 months)
Subjects must be able to understand and be willing to sign the written informed consent form.
Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements:
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. The definition of adequate contraception will be based on the judgment of the investigator.
Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form until at least 3 months after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate.
Subject must be able to swallow and retain oral medication.
Exclusion Criteria:
Component of small-cell cancer or sarcomatoid cancer
Prior therapy with any systemic therapy (chemotherapy or biologic therapy) within twenty-eight days prior to study entry
Patients must have recovered from toxicities from prior systemic anticancer treatment or local therapies.
Patients who have undergone major surgery <4 weeks or minor surgery <2 weeks prior to registration. Wounds must be completely healed prior to study entry and patients recovered from all toxicities from surgery. Placement of a vascular access device is not considered major or minor surgery in this regard.
Prior radiation therapy is allowed as long as the irradiated area was not the sole source of measurable disease and radiotherapy was completed with recovery from toxicity, at least three weeks prior to enrollment. If the irradiated area is the only site of disease, there must be evidence of progressive disease.
Uncontrolled central nervous system (CNS) metastases (previously treated with radiation and off steroids is acceptable).
Patient with active or uncontrolled infection.
Recent or active bleeding diathesis or arterial vascular event within 4 weeks.
Pregnant or nursing (Fertile patients must use effective contraception during and for up to 3 months after completion of study treatment.)
Patients may not be receiving any other investigational agents.
Previous assignment to treatment during this study. Subjects permanently withdrawn from study participation will not be allowed to re-enter study.
Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure >90 mm Hg on repeated measurement) despite optimal medical management.
Active or clinically significant cardiac disease including:
Evidence or history of bleeding diathesis or coagulopathy.
Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of study medication.
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 start of study treatment within 6 months of informed consent.
Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from breast cancer except cervical cancer in-situ, treated localized basal cell carcinoma, Gleason score 6 prostate cancer or superficial bladder tumor. Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before randomization are allowed. All cancer treatments for another malignancy must be completed at least 3 years prior to study entry (i.e., signature date of the informed consent form).
Patients 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.
Symptomatic metastatic brain or meningeal tumors.
Presence of a non-healing wound, non-healing ulcer, or bone fracture.
Renal failure requiring hemo-or peritoneal dialysis.
Dehydration Grade >1 NCI-CTCAE v4.0.
Patients with seizure disorder requiring medication.
Persistent proteinuria greater than or equal to Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).
Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
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.
Women who are pregnant or breast-feeding.
Any condition which, in the 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.