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

Primary Purpose

Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Stage I Cutaneous T-cell Non-Hodgkin Lymphoma

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
carfilzomib
romidepsin
laboratory biomarker analysis
Sponsored by
Northwestern University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Northwestern University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm A (carfilzomib)

Arm B (carfilzomib, romidepsin)

Arm Description

Patients receive carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16.

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

Outcomes

Primary Outcome Measures

Number of Patients With Dose Limiting Toxicities (DLTs)
To determine the maximum tolerated dose (MTD) by assessing the adverse events experienced by patients of both carfilzomib alone and when taken with romidepsin for dose limiting toxicities (DLT) on days 1 and 15 of the first 28 days of treatment. Toxicities will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. DLT is defined as any of the following: Grade ≥ 2 neuropathy with pain Grade ≥ 3 non-hematologic toxicity Grade ≥ 3 nausea, vomiting, or diarrhea not controlled Grade ≥ 4 fatigue persisting for > 7 days Grade 4 neutropenia (ANC < 500/mm3) occurring for >7 days Febrile neutropenia [ANC < 1000/mm3 with fever Grade ≥ 3 thrombocytopenia persisting for > 7 days Grade ≥ 3 thrombocytopenia associated with bleeding Any toxicity requiring a dose reduction within Cycle 1 Inability to receive Cycle 2, Day 1 dose due to drug related toxicity persisting from Cycle 1 or drug-related toxicity newly encountered on Cycle 2, Day 1

Secondary Outcome Measures

Overall Response Rate (ORR) of the Disease When Treated With Carfilzomib Alone and When Taken With Romidepsin
Overall Response Rate (ORR) is defined as number of patients who's best response is complete response or partial response. 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
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 (TTP) of the Disease When Treated With Carfilzomib Alone and When Taken With Romidepsin
The time to progression (TTP) 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).

Full Information

First Posted
November 21, 2012
Last Updated
July 24, 2019
Sponsor
Northwestern University
Collaborators
Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT01738594
Brief Title
Dose-Escalation Trial of Carfilzomib With and Without Romidepsin in Cutaneous T-Cell Lymphoma
Official Title
A Randomized Phase I Dose-Escalation Trial of Carfilzomib With and Without Romidepsin in Cutaneous T-Cell Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Terminated
Why Stopped
Slow accrual
Study Start Date
March 22, 2013 (Actual)
Primary Completion Date
October 11, 2016 (Actual)
Study Completion Date
October 11, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Northwestern University
Collaborators
Amgen

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A (carfilzomib)
Arm Type
Experimental
Arm Description
Patients receive carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16.
Arm Title
Arm B (carfilzomib, romidepsin)
Arm Type
Experimental
Arm Description
Patients receive carfilzomib as in Arm A and romidepsin IV over 4 hours on days 1, 8, and 15.
Intervention Type
Drug
Intervention Name(s)
carfilzomib
Other Intervention Name(s)
Kyprolis, PR-171
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
romidepsin
Other Intervention Name(s)
FK228, FR901228, Istodax
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Number of Patients With Dose Limiting Toxicities (DLTs)
Description
To determine the maximum tolerated dose (MTD) by assessing the adverse events experienced by patients of both carfilzomib alone and when taken with romidepsin for dose limiting toxicities (DLT) on days 1 and 15 of the first 28 days of treatment. Toxicities will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. DLT is defined as any of the following: Grade ≥ 2 neuropathy with pain Grade ≥ 3 non-hematologic toxicity Grade ≥ 3 nausea, vomiting, or diarrhea not controlled Grade ≥ 4 fatigue persisting for > 7 days Grade 4 neutropenia (ANC < 500/mm3) occurring for >7 days Febrile neutropenia [ANC < 1000/mm3 with fever Grade ≥ 3 thrombocytopenia persisting for > 7 days Grade ≥ 3 thrombocytopenia associated with bleeding Any toxicity requiring a dose reduction within Cycle 1 Inability to receive Cycle 2, Day 1 dose due to drug related toxicity persisting from Cycle 1 or drug-related toxicity newly encountered on Cycle 2, Day 1
Time Frame
During the first 28 days (1 cycle=28 days) of treatment.
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR) of the Disease When Treated With Carfilzomib Alone and When Taken With Romidepsin
Description
Overall Response Rate (ORR) is defined as number of patients who's best response is complete response or partial response. 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).
Time Frame
Baseline and every 56 days (2 cycles) while on treatment and up to 4 cycles
Title
Duration of Response of the Disease When Treated With Carfilzomib Alone and When Taken With Romidepsin
Description
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 Frame
Baseline and every 56 days (2 cylces) until disease progression
Title
Time to Progression (TTP) of the Disease When Treated With Carfilzomib Alone and When Taken With Romidepsin
Description
The time to progression (TTP) 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).
Time Frame
Baseline and every 56 days (2 cycles) until disease progression or toxicity call for discontinuation of treatment
Other Pre-specified Outcome Measures:
Title
Proteasome Activity Will be Measured in Peripheral Blood and Tumor Tissue Samples to Observe Proteasome Inhibition While on Treatment
Description
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.
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barbara Pro, MD
Organizational Affiliation
Northwestern University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
32632956
Citation
Valipour A, Jager M, Wu P, Schmitt J, Bunch C, Weberschock T. Interventions for mycosis fungoides. Cochrane Database Syst Rev. 2020 Jul 7;7(7):CD008946. doi: 10.1002/14651858.CD008946.pub3.
Results Reference
derived

Learn more about this trial

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

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