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Phase I Trial of Carfilzomib (PR-171) in Combination With Vorinostat (SAHA) in Patients With Relapsed/Refractory B-Cell Lymphomas

Phase 1
18 Years
Open (Enrolling)

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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,

- 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

- 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 >

- 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

- 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

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

- 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

- 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:


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:


Principal Investigator

Jonathan Friedberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Rochester


United States: Food and Drug Administration

Study ID:




Start Date:

January 2011

Completion Date:

May 2014

Related Keywords:

  • Lymphoma
  • Lymphoma



Virginia Commonwealth University Massey Cancer CenterRichmond, Virginia  23298-0037
University of RochesterRochester, New York  14642