Clinical trial NCT01276717: Study of Carfilzomib and Vorinostat for Relapsed or Refractory Lymphoma
Official title: Phase I Trial of Carfilzomib (PR-171) in Combination With Vorinostat (SAHA) in Patients With Relapsed/Refractory B-Cell Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma
Lead sponsor: University of Rochester
Sponsor class: OTHER
Collaborators: name: Massey Cancer Center
First posted: 2011-01-13
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This will be a phase I study of carfilzomib in combination with vorinostat in patients with relapsed/refractory B-cell lymphomas. Combination therapy with proteosome inhibitor PR-171 and HDAC inhibitors is highly synergistic in primary DLBCL cells, and both classes of drugs can also synergize powerfully to induce cell death in bortezomib-resistant cells. The purpose of this study is to see if vorinostat can combine with carfilzomib and to safely find the recommended phase II dose.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants who experience Adverse Events as a Measure of Safety and Tolerability
timeFrame: From date of study entry until the 30 days after the last dose of study treatment.
Secondary outcomes:
measure: Number of Participants who Respond to Treatment
timeFrame: From the date of completion of first cycle of treatment until the date of best response to treatment, as determined by restaging scans
Other outcomes:
Locations:
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Richmond
country: United States
facility: Virginia Commonwealth University Massey Cancer Center
state: Virginia
Study officials:
affiliation: University of Rochester
name: Jonathan Friedberg, M.D.
role: PRINCIPAL_INVESTIGATOR
References: