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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Phase I Dose-Escalation Trial of Carfilzomib With and Without Romidepsin in Cutaneous T-Cell Lymphoma

Conditions
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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

Intervention / Treatment
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* Drug: carfilzomib
* Drug: romidepsin
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (carfilzomib)<br>Patients receive carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16. | Drug: carfilzomib<br>* Given IV<br>* Other names: PR-171;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm B (carfilzomib, romidepsin)<br>Patients receive carfilzomib as in Arm A and romidepsin IV over 4 hours on days 1, 8, and 15. | Drug: carfilzomib<br>* Given IV<br>* Other names: PR-171;Drug: romidepsin<br>* Given IV<br>* Other names: Istodax;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | During the first 28 days (1 cycle=28 days) of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline and every 56 days (2 cycles) while on treatment and up to 4 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). | Baseline and every 56 days (2 cylces) until disease progression | 
| 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). | Baseline and every 56 days (2 cycles) until disease progression or toxicity call for discontinuation of treatment |