Study of Carfilzomib and Vorinostat for Relapsed or Refractory Lymphoma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Massey Cancer Center
Information provided by (Responsible Party):
University of Rochester
ClinicalTrials.gov Identifier:
NCT01276717
First received: November 10, 2010
Last updated: November 7, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Lymphoma
Drug: Drug: Carfilzomib
Drug: Vorinostat
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Carfilzomib (PR-171) in Combination With Vorinostat (SAHA) in Patients With Relapsed/Refractory B-Cell Lymphomas

Resource links provided by NLM:


Further study details as provided by University of Rochester:

Primary Outcome Measures:
  • Number of Participants who experience Adverse Events as a Measure of Safety and Tolerability [ Time Frame: From date of study entry until the 30 days after the last dose of study treatment. ] [ Designated as safety issue: No ]
    Determine the recommended phase II doses for the combination of carfilzomib and vorinostat in patients with relapsed or refractory B cell lymphoma.


Secondary Outcome Measures:
  • Number of Participants who Respond to Treatment [ Time Frame: From the date of completion of first cycle of treatment until the date of best response to treatment, as determined by restaging scans ] [ Designated as safety issue: No ]
    Determine response rate to combination of carfilzomib and vorinostat.


Estimated Enrollment: 24
Study Start Date: January 2011
Estimated Study Completion Date: July 2014
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vorinostat + Carfilzomib Drug: Drug: Carfilzomib
Carfilzomib 30 minutes infusion daily for days 1, 2, 8, 9, 15, 16, Every 28 days. A maximum of 13 cycles will be administered.
Other Name: PR-171
Drug: Vorinostat
Vorinostat by mouth twice daily on days 1, 2, 3, 8, 9, 10, 15, 16 and 17. Maximum 13 cycles.
Other Name: Zolinza®

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01276717

Locations
United States, New York
University of Rochester
Rochester, New York, United States, 14642
United States, Virginia
Virginia Commonwealth University Massey Cancer Center
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
University of Rochester
Massey Cancer Center
Investigators
Principal Investigator: Jonathan Friedberg, M.D. University of Rochester
  More Information

No publications provided

Responsible Party: University of Rochester
ClinicalTrials.gov Identifier: NCT01276717     History of Changes
Other Study ID Numbers: 32833
Study First Received: November 10, 2010
Last Updated: November 7, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Vorinostat
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 28, 2014