A Pilot Study of Sorafenib Examining Biomarkers in Refractory or Relapsed T-cell Lymphoma Patients
Trial Purpose and Description
· To study the biological effects of sorafenib 400mg BID on the mitogen-activated protein kinase (MAPK) pathway, specifically the inhibition of ERK phosphorylation, and to correlate with clinical activity in patients with T-cell lymphoma.
- To observe the clinical activity of sorafenib 400mg BID by determining response rate, and progression free survival in patients with T-cell lymphoma. Duration of response and duration of stable disease will also be measured.
- To determine the tolerability of sorafenib in patients with T-cell lymphoma.
- To observe the effects of sorafenib on T-cell subsets (CD4/CD8 ratio, and Tregs), and the effects of sorafenib on the monocytoid population.
- To observe the effects of sorafenib on the serum cytokine profile.
- To observe the effects of sorafenib on the T-cell receptor pathway, i.e. Lck, ZAP-70, and Syk.
To observe changes in lymph node or skin morphology including tumor cell infiltrate, vasculature, and the tumor microenvironment in patients treated with sorafenib by performing serial biopsies of lymph nodes or skin.
- 18 Years and older
- Histologically confirmed T-cell lymphoma including PTCL, AITL, CTCL, ALCL (Alk+, and Alk-), and other transformed T-cell lymphomas.
- Relapsed or refractory to at least one standard chemotherapy regimen. Patients with prior autologous stem cell transplant will be eligible to participate.
- Patients must have discontinued any prior treatment for at least two weeks prior to receiving the first dose of the study drug, sorafenib.
- All prior toxicities from prior treatment must have resolved to grade 1 or less
- Age > 18 years old
- Measureable disease, as defined by the Cheson criteria
- ECOG Performance Status of 0 or 1
- Life expectancy > 12 weeks
- Adequate bone marrow,
liver and renal function as
assessed by the following:
- Hemoglobin > 8.5 g/dl
- Absolute neutrophil count (ANC) > 1000/mm3
- Platelet count >75,000/mm3
- Total bilirubin <1.5 times ULN
- ALT and AST <2.5 times the ULN ( < 5 x ULN for patients with liver involvement)
- Creatinine < 2 times ULN
- INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.
- Patients with hemoglobin < 8.5g/dL, or ANC 500-1000/mm3, or platelets 50,000-75,000/mm3 (Grade 3), whose cytopenias are due to bone marrow involvement by T-cell lymphoma will also be eligible (see Section 6: DOSING DELAYS/DOSE MODIFICATIONS).
- Women of childbearing potential must have a negative serum pregnancy test performed within seven days prior to the start of treatment
- Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib.
- Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
- Prior treatment with sorafenib, or other agents with similar activity, i.e. bevacizumab, imatinib, sunitinib.
- Prior treatment with allogeneic stem cell transplant.
- Patients taking any systemic steroids greater than prednisone 10mg daily or its equivalent.
- Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
- Known CNS metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.
- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
- Known human immunodeficiency virus (HIV) infection.
- Active clinically serious infection > CTCAE Grade 2.
- Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
- Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug.
- Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug.
- Serious non-healing wound, ulcer, or bone fracture.
- Evidence or history of bleeding diathesis or coagulopathy
- Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
- Use of St. John’s Wort or rifampin (rifampicin).
Known or suspected allergy to sorafenib
- Yale Cancer Center
- October 2009
- Last Updated:
- Study HIC#:
Clinicaltrials.gov ID: Yale5062786