Phase I Trial of Carfilzomib (PR-171) in Combination With Vorinostat (SAHA) in Patients With Relapsed/Refractory B-Cell Lymphomas
18 Years
N/A
Both
Lymphoma
Trial Information
Phase I Trial of Carfilzomib (PR-171) in Combination With Vorinostat (SAHA) in Patients With Relapsed/Refractory B-Cell Lymphomas
Study Drugs:
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,
16
- 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
drug well.
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.
Study Visits:
- 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
REQUIRED.
- 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.
Inclusion Criteria:
- Histologically confirmed B-cell lymphomas, excluding CLL (Chronic Lymphocytic
Leukemia), that is recurrent or refractory after at least one prior therapy and for
which no other potentially curative therapy is available.
- Age ≥ 18 years
- ECOG Performance Status (PS) ≤ 2
- Laboratory parameters
- if SLL, lymphocyte count < 5,000/µL
- Absolute neutrophil count ≥ 1000/µL
- Platelets ≥ 75,000/µL
- Creatinine ≤ 1.5x upper limit of normal or calculated creatinine clearance >
40mL/min
- AST, ALT ≤ 2.5 x upper limit of normal (ULN)
- Bilirubin ≤ 2.0 mg/mL
- Serum potassium ≥ 3.5 mEq/L and serum magnesium ≥ 1.7 mEq/dL (electrolytes may
be corrected with supplementation).
- PT < 1.5 x ULN and PTT < 1.2 x ULN (unless receiving therapeutic
anticoagulation).
- Patient is, in investigator's opinion, willing and able to comply with the protocol
requirements and offers written informed consent.
- Female subject is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control ( i.e., oral injectable hormonal methods;
barrier methods such as intra-uterine device, diaphragm with spermicide, condom with
spermicide, or abstinence)for the duration of the study.
- Male subject agrees to use an acceptable method for contraception for the duration of
study.
Exclusion Criteria:
- History of brain metastasis including leptomeningeal metastasis.
- Chemotherapy of radiotherapy within 3 weeks prior to entering the study.
- Prior histone deacetylase inhibitor as cancer treatment.
- Concurrent treatment with other investigational agents or cancer treatment.
- Unable to take oral medications.
- Active ischemic heart disease or congestive heart failure. If there is suspicion of
cardiac disease, left ventricular ejection fraction (LVEF) must be ≥ 45%, otherwise
study to evaluate EF is not required.
- Persistent blood pressure (BP) of ≥ 160/95 (three separate readings on different
days).
- History of allergic reactions attributed to compounds of similar chemical or
biological composition to carfilzomib and vorinostat.
- Known clinical significant infection including infection with human immunodeficiency
virus (HIV), or active hepatitis B or C, requiring treatment.
- Serious medical or psychiatric illness likely to interfere with patient
participation.
- Pregnant or nursing. Confirmation that a woman is not pregnant must be established by
a negative serum pregnancy test result obtained at screening.
- Pregnancy testing is not required for post-menopausal or surgically sterilized women.
- No prior allogeneic stem cell transplant.
- Patients scheduled for any type of stem cell transplant within 4 weeks of treatment.
- Patients who have valproic acid for epilepsy can enroll, provided that they stopped
drug at least 30 days prior to enrollment and they will be on a stable, effective
dose of an alternative anti-seizure medication.
Type of Study:
Interventional
Study Design:
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Number of Participants who experience Adverse Events as a Measure of Safety and Tolerability
Outcome Description:
Determine the recommended phase II doses for the combination of carfilzomib and vorinostat in patients with relapsed or refractory B cell lymphoma.
Outcome Time Frame:
From date of study entry until the 30 days after the last dose of study treatment.
Safety Issue:
No
Principal Investigator
Jonathan Friedberg, M.D.
Investigator Role:
Principal Investigator
Investigator Affiliation:
University of Rochester
Authority:
United States: Food and Drug Administration
Study ID:
32833
NCT ID:
NCT01276717
Start Date:
January 2011
Completion Date:
May 2014
Related Keywords:
- Lymphoma
- Lymphoma
Name | Location |
|---|---|
| Virginia Commonwealth University Massey Cancer Center | Richmond, Virginia 23298-0037 |
| University of Rochester | Rochester, New York 14642 |
