Phase I Trial of Carfilzomib (PR-171) in Combination With Vorinostat (SAHA) in Patients With Relapsed/Refractory B-Cell Lymphomas
Vorinostat, a class I/II pan-histone deacetylase inhibitor (HDACI), was the first approved
agent og this class on the basis of activity in refractory cutaneous T-cell Lymphoma. Lethal
mechanisms include anti-apoptotic protein down-regulation, up-regulation of proapoptotic
proteins, induction of ROS, death receptor up-regulation, and disruption of chaperone
function and DNA-repair proteins.
Carfilzomib, is a irreversible proteasome inhibitor of the epoxyketone class that exhibits a
high level of selectivity for the proteosome. This agent induced a dose- and time-dependent
inhibition of proliferation, ultimately leading to apoptosis.
Study Drug Administration:
If you are found to be eligible to take part in this study:
- Vorinostat PO twice daily on Days 1, 2, 3, 8, 9, 10, 15, 16 and 17.
- Daily Carfilzomib 30 minutes infusion on Days 1, 2, 8, 9, 15, 16.
- Administer first daily dose of vorinostat prior to carfilzomib on Days 1, 2, 8, 9, 15,
- Cycle repeated every 28 days, up to 13 cycles.
Carfilzomib will be given at 20mg/m2 for days 1 and 2 of cycle 1 only, then escalated to the
higher dose indicated in the schema on day 8 of cycle 1 and thereafter. Carfilzomib
treatment is to be done early in the morning and have a minimum of a 6 hour observation
period after the infusion. For patients with good tolerability to carfilzomib during the
first cycle, an observation period of 2 hours is recommended. A minimum of 16 hours should
separate doses of carfilzomib, so that the day 1 dose may be given in the afternoon and the
day 2 dose in morning during cycle 2 and subsequent cycles for patients who tolerate the
If two out of 6 patients do not tolerate the initial dose of 20 mg/m2 carfilzomib on days 1
& 2 followed by 27 mg/m2 carfilzomib for subsequent doses and 200 mg/day bid vorinostat, the
next patient should be dose reduced to 20 mg/m2 carfilzomib and 100 mg/day bid vorinostat.
- Baseline within 4 weeks of Cycle 1 Day 1.
- CT or physical exam.
- Bone marrow if needed to follow disease status.
- PET recommended but not required. To document complete response (CR), a PET is
- Optional research tumor biopsy.
- Peripheral blood obtained for PD prior to initiation of treatment and at 48 hours +/- 6
hours after receiving first dose of Carfilzomib , and at Off Study.
- End of Treatment Restaging will take place 6-8 weeks after completion of treatment and
will include an assessment by the physician, labs, and a tumor response evaluation.
- After completion of Restaging exams, Follow up exams will take place every 6 months for
2 years and then annually until disease progression or initiation of another treatment.
- An Off Study visit will take place at the time of disease progression or initiation of
another treatment, which will include assessment by the physician,a tumor response
evaluation, labs, and a final PD sample, by the patient's consent.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants who experience Adverse Events as a Measure of Safety and Tolerability
Determine the recommended phase II doses for the combination of carfilzomib and vorinostat in patients with relapsed or refractory B cell lymphoma.
From date of study entry until the 30 days after the last dose of study treatment.
Jonathan Friedberg, M.D.
University of Rochester
United States: Food and Drug Administration
|Virginia Commonwealth University Massey Cancer Center||Richmond, Virginia 23298-0037|
|University of Rochester||Rochester, New York 14642|