Romidepsin and Lenalidomide in Treating Patients With Previously Untreated Peripheral T-Cell Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate how safe and effective the combination of the study drugs romidepsin and lenalidomide is for treating patients with peripheral t-cell lymphoma (PTCL) who have not been previously treated for this cancer. Currently, there is no standard treatment for patients with PTCL; the most common treatment used is a combination of drugs called CHOP, but this can be a difficult treatment to tolerate because of side effects, and is not particularly effective for most patients with PTCL. Romidepsin (Istodax®) is a type of drug called an HDAC inhibitor. It interacts with DNA (genetic material in cells) in ways that can stop tumors from growing. It is given as an infusion through the veins. Lenalidomide (Revlimid®) is a type of drug known as an immunomodulatory drug, or IMID for short. This drug affects how tumor cells grow and survive, including affecting blood vessel growth in tumors. It is given as an oral tablet (by mouth).

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the efficacy of the combination of romidepsin plus lenalidomide in patients with previously untreated peripheral T-cell lymphoma (PTCL). SECONDARY OBJECTIVES: I. Evaluate the safety of the combination of romidepsin and lenalidomide. II. Further evaluate efficacy of the combination of romidepsin and lenalidomide. III. Evaluate the delay to cytotoxic chemotherapy. TERTIARY OBJECTIVES: I. Evaluate the use of Northwestern Medicine (NM) positron emission tomography (PET)/computed tomography (CT) vs CT imaging in PTCL. II. Validate a new prognostic model for newly diagnosed PTCL. III. Investigate the tumor immunohistochemical profile to identify potential biomarkers associated with prognosis and treatment response. OUTLINE: Patients receive romidepsin intravenously (IV) over 4 hours on days 1, 8, and 15 and lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 1 year in the absence of disease progression, inter-current illness that prevents further administration of treatment, unacceptable toxicity, patient decides to withdraw from study treatment (or study as a whole), or general or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the treating investigator. After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 3 years.

Official Title
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Phase II Study of Romidepsin Plus Lenalidomide for Patients With Previously Untreated PTCL

Conditions
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Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Hepatosplenic T-cell Lymphoma, Peripheral T-cell Lymphoma, 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: romidepsin
* Drug: lenalidomide
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of PTCL (using the most recent edition of the World Health Organization [WHO] Classification of Tumors of Hematopoietic and Lymphoid Tissues as guidance) including: Anaplastic large cell lymphoma, anaplastic large cell kinase (ALK)-negative Angioimmunoblastic T-cell lymphoma Enteropathy-type T-cell lymphoma Extranodal natural killer (NK)/T-cell lymphoma, nasal type Hepatosplenic gamma-delta T-cell lymphoma Peripheral T-cell lymphoma, unspecified (not otherwise specified [NOS]) Transformed mycosis fungoides Subcutaneous panniculitis-like T-cell lymphoma. NOTE: A copy of the pathology report is sufficient to register the patient to the trial; diagnosis of PTCL should have been based on identification in biopsy specimens of a peripheral T-cell lymphoma disorder characterized by positivity in the malignant cell population of at least 3 of the following T-cell markers: betaF1, cluster of differentiation (CD)2, CD3, CD4, CD5, CD7, CD8, and negativity of at least 2 of the following B-cell markers CD19, CD20, CD79alpha and paired box 5 (Pax-5); further, CD56 should be used for the diagnosis of the nasal type, while CD30, ALK-1 and Pax-5 (that should be negative) are required for the anaplastic type; CD10, chemokine (C-X-C motif) ligand 13 (CXCL13), programmed cell death (PD)-1 and CD21 are warranted for the diagnosis of angioimmunoblastic T-cell lymphoma along with Epstein-Barr virus-encoded small ribonucleic acid (RNA) (EBER) in situ hybridization; determination of mindbomb E3 ubiquitin protein ligase 1(Mib-1)/marker of proliferation Ki-67 (Ki-67) to be performed; finally, additional markers useful within the context of anaplastic large cell lymphoma, extranodal NK/T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma are TIA1 cytotoxic granule-associated RNA binding protein (TIA-1), granzyme B and perforin; it is acknowledged that no marker has absolute lineage specificity, and that immunophenotypic studies should be performed with panels of monoclonal antibodies; final diagnoses containing caveats such as suspicious of or presumably are considered inadequate for a patient to be enrolled in the trial NOTE: Patients with adequate archived (well-preserved, formalin-fixed) biopsy tissue remaining will be required to submit a portion for exploratory studies; this is not optional if tissue is available; however, lack of adequate tissue for exploratory studies will not preclude patients from participating Patients must have bi-dimensionally measurable disease (>= 1 cm) by CT imaging NOTE: Patients with marrow-only disease are eligible; response for these patients will be assessed by repeat bone marrow biopsy Patients must fit into one of the following categories: Age >= 18 years to < 60 years with a cumulative illness rating scale (CIRS) score >= 6 OR deemed ineligible for cytotoxic chemotherapy by the treating investigator >= 60 years Patients must have adequate organ and marrow function (documented within 14 days prior to registration) as outlined below: Absolute neutrophil count (ANC) >= 750/mcl Hemoglobin >= 8 g/dl Platelets >= 50,000/mcl Total bilirubin =< 2 x upper limit normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum pyruvate glutamate transaminase [SPGT]) =< 3 x ULN Creatinine =< 2 x ULN Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 All patients must agree to use effective contraception while on study, and all patients must agree to undergo counseling sessions every 28 days about pregnancy precautions and risks of fetal exposure Females of childbearing potential (FCBP) must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide, during lenalidomide therapy, during dose interruptions, and for at least 28 days following discontinuation of lenalidomide therapy Males receiving lenalidomide must agree to use a latex condom during any sexual contact with FCBPs even if they have undergone a successful vasectomy NOTE: A FCBP is 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 Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) FCBP should be referred to a qualified provider of contraceptive methods, if needed FCPB must have a negative urine or serum pregnancy test within 7 days prior to registration, and be willing to adhere to the scheduled pregnancy testing as required in the Revlimid Risk Evaluation and Mitigation Strategies (REMS®) program NOTE: Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Patients must be free of any prior malignancies for >= 1 year NOTE: 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 All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration Exclusion Criteria: Patients with a diagnosis of any of the following are not eligible: Anaplastic large cell lymphoma, ALK-positive Adult T-cell lymphoma/leukemia (ATLL) Anaplastic large-cell lymphoma, primary cutaneous type Precursor T-lymphoblastic lymphoma/leukemia Mycosis fungoides/Sezary syndrome (except transformed Mycosis fungoides [MF]) NK-cell leukemia T-cell granular lymphocytic leukemia T-cell prolymphocytic leukemia Patients must not have received prior systemic therapy for PTCL (except for corticosteroids for 10 or fewer days at any dose, no washout period required as long as they discontinue prior to starting study therapy); NOTE: topical treatment may have been given for prior existence of cutaneous lymphoma that has since become systemic PTCL; however, these topical therapies should be stopped at time of registration Patients who received chemotherapy (including monoclonal antibodies) or radiotherapy, administered for any condition, within 4 weeks prior to registration are not eligible Patients who received prior exposure to any other histone deacetylase (HDAC) inhibitors or immunomodulatory (IMID) agents for any reason are not eligible Patients receiving ongoing treatment with any other investigational agents are not eligible Patients who have known central nervous system (CNS) involvement of lymphoma are not eligible Patients who have an uncontrolled intercurrent illness including, but not limited to, any of the following are not eligible: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements Patients with a known human immunodeficiency (HIV) infection are not eligible Patients who are pregnant or actively nursing an infant are not eligible Patients with a QT interval > 500 msec (using the Bazett's formula) within 28 days prior to registration are not eligible

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (romidepsin, lenalidomide)<br>Patients receive romidepsin IV over 4 hours on days 1, 8, and 15 and lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. | Drug: romidepsin<br>* Given IV<br>* Other names: Istodax;Drug: lenalidomide<br>* Given PO<br>* Other names: Revlimid;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 |
| --- | --- | --- |
| Objective response rate (ORR), as defined per Cheson criteria | ORR will be assessed by imaging after cycles 3 and 6, and then every 6 months up to 3 years. | Assessed after cycles 3 and 6, then every 6 months up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | The frequency and severity of toxicity events will be evaluated. All adverse events will be summarized as to type, severity, frequency, timing and attribution. | Evaluated once per cycle (1 cycle=28 days) up to 1 year | 
| Progression-free survival (PFS) | PFS will be evaluated at 1 and 3 years after treatment has begun. | Reported at 1 and 3 years after the start of treatment | 
| Overall survival (OS) | OS will be assessed at 1 and 3 years after treatment has begun. | Reported at 1 and 3 years after the start of treatment | 
| Duration of response, defined per Cheson criteria | The duration of overall response is measured from the time measurement criteria are met for Complete Remission or Partial Response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. | Assessed from start of therapy for up to 3 years | 
| Delay to cytotoxic chemotherapy | Time to first cytotoxic chemotherapy is defined as the time (in months) from start of study treatment to time of first dose of anti-neoplastic cytotoxic chemotherapy that is administered to treat lymphoma. | Up to 1 year |