Dose-Escalation Trial of Carfilzomib With and Without Romidepsin in Cutaneous T-Cell Lymphoma

This study is currently recruiting participants.
Verified February 2014 by Northwestern University
Sponsor:
Collaborator:
Onyx Pharmaceuticals
Information provided by (Responsible Party):
Timothy Kuzel, Northwestern University
ClinicalTrials.gov Identifier:
NCT01738594
First received: November 21, 2012
Last updated: February 10, 2014
Last verified: February 2014
  Purpose

This randomized phase I trial studies the side effects and the best dose of carfilzomib when given together with or without romidepsin in treating patients with stage IA-IVB cutaneous T-cell lymphoma. Carfilzomib and romidepsin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving carfilzomib alone is more effective than when given together with romidepsin.


Condition Intervention Phase
Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
Recurrent Mycosis Fungoides/Sezary Syndrome
Stage I Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IA Mycosis Fungoides/Sezary Syndrome
Stage IB Mycosis Fungoides/Sezary Syndrome
Stage II Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IIA Mycosis Fungoides/Sezary Syndrome
Stage IIB Mycosis Fungoides/Sezary Syndrome
Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IIIA Mycosis Fungoides/Sezary Syndrome
Stage IIIB Mycosis Fungoides/Sezary Syndrome
Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IVA Mycosis Fungoides/Sezary Syndrome
Stage IVB Mycosis Fungoides/Sezary Syndrome
Drug: carfilzomib
Drug: romidepsin
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase I Dose-Escalation Trial of Carfilzomib With and Without Romidepsin in Cutaneous T-Cell Lymphoma

Resource links provided by NLM:


Further study details as provided by Northwestern University:

Primary Outcome Measures:
  • Evaluate toxicity by assessing the adverse events of carfilzomib alone and when taken with romidepsin [ Time Frame: During the first 28 days (1 cycle=28 days) ] [ Designated as safety issue: Yes ]
    To determine the maximum tolerated dose (MTD) by assessing the adverse events of both carfilzomib alone and when taken with romidepsin in evaluating toxicity on days 1 and 15 of each cycle of treatment


Secondary Outcome Measures:
  • Overall response rate (ORR) of the disease when treated with carfilzomib alone and when taken with romidepsin [ Time Frame: Baseline and every 56 days (2 cylces) while on treatment ] [ Designated as safety issue: No ]
    Response will be categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The overall response rate of the study treatment will be evaluated based on skin biopsy, CT scans, and blood tests at the beginning of the study as well as every 56 days (2 cycles).

  • Duration of response of the disease when treated with carfilzomib alone and when taken with romidepsin [ Time Frame: Baseline and every 56 days (2 cylces) until disease progression ] [ Designated as safety issue: No ]
    Duration of response will be defined as the time from the point at which response is achieved until the point of disease progression. The duration of response of the study treatment will be evaluated based on skin biopsy, CT scans, and blood tests at the beginning of the study as well as every 56 days (2 cycles).

  • Time to progression of the disease when treated with carfilzomib alone and when taken with romidepsin [ Time Frame: Baseline and every 56 days (2 cylces) until disease progression or toxicity call for discontinuation of treatment ] [ Designated as safety issue: No ]
    The time to progression will be measured as the time from the first dose of study therapy until the point at which disease is determined to have progressed or patients discontinue therapy for toxicity. To measure time to progression, the study treatment will be evaluated based on skin biopsy, CT scans, and blood tests at the beginning of the study as well as every 56 days (2 cycles).


Other Outcome Measures:
  • Proteasome activity will be measured in peripheral blood and tumor tissue samples to observe proteasome inhibition while on treatment [ Time Frame: Blood is collected before & after carfilzomib dosing during cycle 1 (days 1, 2, & 8) & cycle 2 (day 1) & Tumor tissue samples obtained at baseline, 1-4 hours post-first dose of carfilzomib (cycle 1 day 1) & 1-4 hours post-carfilzomib on cycle 1 day 8 ] [ Designated as safety issue: No ]
    Proteasome inhibition will be measured by evaluating proteasome activity in blood and tumor tissue biopsy specimens while on treatment of carfilzomib alone as well as carfilzomib with romidepsin.


Estimated Enrollment: 48
Study Start Date: January 2013
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (carfilzomib)
Patients receive carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16.
Drug: carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm B (carfilzomib, romidepsin)
Patients receive carfilzomib as in Arm A and romidepsin IV over 4 hours on days 1, 8, and 15.
Drug: carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171
Drug: romidepsin
Given IV
Other Names:
  • FK228
  • FR901228
  • Istodax
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of carfilzomib, both as a single agent as well as in combination with romidepsin, in patients with cutaneous T-cell lymphoma (CTCL).

SECONDARY OBJECTIVES:

I. Overall response rate (ORR). II. Duration of response. III. Time to progression (TTP).

TERTIARY OBJECTIVES:

I. Measure proteasome activity concurrently in peripheral blood mononuclear cells (PBMCs) and tumor tissue biopsy specimens in order to gather pilot data on proteasome inhibition in CTCL patients treated with carfilzomib alone as well as carfilzomib with romidepsin.

OUTLINE: This is a dose-escalation study of carfilzomib. Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive carfilzomib intravenously (IV) over 30 minutes on days 1, 2, 8, 9, 15, and 16.

ARM B: Patients receive carfilzomib as in Arm A and romidepsin IV over 4 hours on days 1, 8, and 15.

In both arms, treatment repeats every 28 days for at least 2-4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 1 year.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histological confirmation of a cutaneous T-cell lymphoma (CTCL) of any histology; confirmation of histological diagnosis must be completed prior to enrollment by the lead site (Northwestern)

    • Patients will be stratified by mycosis fungoides (MF) and Sezary syndrome (SS) (report diagnostic or consistent with MF/SS), stage IA-IVB according to TNM blood (TNMB) classification versus other CTCL histologies
  • Patients must have measurable disease (using modified Severity-Weighted Assessment Tool [mSWAT]) and/or use of indicator lesions must be designated prior to study enrollment (from imaging); measurable disease upon physical exam with a negative scan is acceptable
  • Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Patients must have a life expectancy of >= 3 months
  • Patients with MF/SS must have failed at least 1 prior topical therapy (including steroids, nitrogen mustard, retinoids, phototherapy, photochemotherapy, radiation, and total skin electron beam); there is no upper limit for prior therapies
  • Serum creatinine =< 2.0 mg/dL
  • Total bilirubin =< 2.2 mg/dL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2 x upper limit of normal (ULN)
  • Leukocytes >= 3,000/mm^3
  • Absolute neutrophils >= 1,500/mm^3
  • Platelets >= 100,000/mm^3
  • Patients must have an electrocardiogram (EKG) demonstrating QTc =< 500 ms within 28 days prior to registration
  • Females of child-bearing potential and sexually active males must agree to use effective methods of contraception:

    • Child-bearing potential is defined as any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

      • Has NOT undergone a hysterectomy or bilateral oophorectomy; OR
      • Has NOT been naturally menopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)
    • The effectiveness of hormonal contraceptives may be reduced by romidepsin, thus effective methods should include at least 1 form of barrier contraception
  • Females of child-bearing potential must have a negative pregnancy test within 7 days prior to registration
  • Patients must be disease free of any prior malignancies for >= 3 years

    • The exception to this would be currently treated squamous cell and basal cell carcinoma of the skin, carcinoma in situ of the cervix, breast, or bladder, or surgically removed melanoma in situ of the skin (stage 0) with histologically confirmed free margins of excision
  • Patients must give written informed consent prior to registration on the study

Exclusion Criteria:

  • Patients who have received topical therapy, systemic chemotherapy, or biological therapy within 4 weeks prior to registration are NOT eligible for participation
  • Patients who have undergone major surgery within 21 days prior to registration are NOT eligible for participation
  • Patients who have an acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to registration are NOT eligible for participation
  • Patients in whom IV fluid hydration is contraindicated (e.g. due to pre-existing pulmonary, cardiac, or renal impairment) will NOT be eligible for participation
  • Patients who are pregnant and/or lactating are NOT eligible for participation
  • Patients who have had a prior stem cell transplantation are NOT eligible for participation
  • Patients who have had any of the following cardiac conditions are NOT eligible for participation (unless otherwise noted):

    • Unstable angina or myocardial infarction within 4 months prior to registration
    • New York Heart Association (NYHA) class II or IV heart failure
    • Uncontrolled angina
    • A history of severe coronary artery disease
    • Severe, uncontrolled ventricular arrhythmias
    • Sick sinus syndrome
    • Electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities UNLESS the patient has a pacemaker
  • Patients who exhibit uncontrolled hypertension (>= 140/90 mmHg) or uncontrolled diabetes within 14 days prior to registration are NOT eligible for participation
  • Patients who have experienced significant neuropathy (grades 3-4 or grade 2 with pain) within 14 days prior to registration are NOT eligible for participation
  • Patients who have a known history of allergy to Captisol (a cyclodextrin derivative used to stabilize carfilzomib) are NOT eligible for participation
  • Patients who have a contraindication to any of the required concomitant drugs or supportive treatments (including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment) are NOT eligible for participation
  • Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration are NOT eligible for participation
  • Patients who have any serious condition, laboratory abnormality, or psychiatric illness that would prevent them from singing the informed consent form are NOT eligible for participation
  • Patients who have had prior exposure to romidepsin or any proteasome inhibitor are NOT eligible for participation
  • Patients with a known human immunodeficiency virus (HIV) infection are NOT eligible for participation
  • Patients who test positive for infectious hepatitis types A, B, or C within 14 days of registration are NOT eligible for participation
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01738594

Contacts
Contact: Study Coordinator (312)695-1301 cancertrials@northwestern.edu

Locations
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Timothy M. Kuzel    312-695-4544    t-kuzel@northwestern.edu   
Principal Investigator: Timothy M. Kuzel         
Sponsors and Collaborators
Northwestern University
Onyx Pharmaceuticals
Investigators
Principal Investigator: Timothy Kuzel Northwestern University
  More Information

No publications provided

Responsible Party: Timothy Kuzel, Principal Investigator, Northwestern University
ClinicalTrials.gov Identifier: NCT01738594     History of Changes
Other Study ID Numbers: NU 12H06, STU00071042, NCI-2012-01952
Study First Received: November 21, 2012
Last Updated: February 10, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Mycoses
Mycosis Fungoides
Lymphoma
Lymphoma, Non-Hodgkin
Sezary Syndrome
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Romidepsin
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014