Combination Chemotherapy & Lenalidomide in Newly Diagnosed Stage II-IV Peripheral T-cell Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of lenalidomide when given together with combination chemotherapy and to see how well they work in treating patients with newly diagnosed stage II-IV peripheral T-cell non-Hodgkin's lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may stop the growth of peripheral T-cell non-Hodgkin's lymphoma by blocking the growth of new blood vessels necessary for cancer growth. Giving combination chemotherapy with lenalidomide may be a better treatment for peripheral T-cell non-Hodgkin's lymphoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the safety and efficacy of lenalidomide in combination with standard induction therapy (CHOEP- cyclophosphamide, doxorubicin [doxorubicin hydrochloride], etoposide, vincristine [vincristine sulfate] and prednisone) in patients with newly diagnosed stage II, III and IV peripheral T-cell lymphoma not otherwise specified (NOS), anaplastic large cell lymphoma (anaplastic lymphoma receptor tyrosine kinase [ALK] negative) (ALK positive if International Prognostic Index [IPI] 3, 4, or 5), angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma or hepatosplenic gamma delta T-cell lymphoma. II. To establish the maximum tolerated dose of lenalidomide in combination with CHOEP chemotherapy. (Phase I) III. To assess the efficacy (complete response rate) of this combination. (Phase II) SECONDARY OBJECTIVES: I. To evaluate overall response rate (complete response [CR] + partial response [PR]) of the combination of lenalidomide and CHOEP chemotherapy. II. To evaluate the safety and tolerability of the regimen. III. To assess the 2 year progression free survival (PFS) and overall survival (OS) using this regimen. OUTLINE: This is a phase I, dose-escalation study of lenalidomide, followed by a phase II study. Patients receive cyclophosphamide intravenously (IV), doxorubicin hydrochloride IV and vincristine sulfate IV on day 1, etoposide IV over 30-60 minutes on days 1-3, prednisone orally (PO) on days 1-5, and lenalidomide PO on days 1-10. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients responding after 6 courses of treatment may then undergo an autologous stem cell transplant or receive maintenance lenalidomide at the discretion of the physician or patient choice as follows: TRANSPLANT: Patients undergo autologous stem cell transplant per standard of care. MAINTENANCE LENALIDOMIDE: Patients receive lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year.

Official Title
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A Phase I/II Trial of CHOEP Chemotherapy Plus Lenalidomide as Front Line Therapy for Patients With Stage II, III and IV Peripheral T-Cell Non-Hodgkin's Lymphoma

Conditions
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Anaplastic Large Cell Lymphoma, ALK-Negative, Anaplastic Large Cell Lymphoma, ALK-Positive, Hepatosplenic T-Cell Lymphoma, Peripheral T-Cell Lymphoma, Not Otherwise Specified, Stage II Angioimmunoblastic T-cell Lymphoma, Stage II Enteropathy-Associated T-Cell Lymphoma, Stage III Angioimmunoblastic T-cell Lymphoma, Stage III Enteropathy-Associated T-Cell Lymphoma, Stage IV Angioimmunoblastic T-cell Lymphoma, Stage IV Enteropathy-Associated T-Cell Lymphoma

Intervention / Treatment
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* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Cyclophosphamide
* Drug: Doxorubicin Hydrochloride
* Drug: Etoposide
* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide
* Procedure: Peripheral Blood Stem Cell Transplantation
* Drug: Prednisone
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed new diagnosis of stage II, III and IV peripheral T-cell non-Hodgkin's lymphoma not otherwise specified (NOS), anaplastic large cell lymphoma (ALK negative) (ALK positive if IPI 3, 4, or 5), angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma, hepatosplenic gamma delta T-cell lymphoma Pathology material: hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC) slides or a representative formalin-fixed paraffin-embedded (FFPE) tissue block along with the pathology report from initial diagnosis, should be sent to be reviewed, and the diagnosis confirmed by Mayo Clinic department (retrospective diagnostic review: treatment may commence prior to the Mayo Clinic review) No prior therapy with the exception of prior radiation therapy and/or prednisone alone, at the discretion of the investigator based on current diagnosis and clinical condition; this prednisone treatment will not count toward the 6 cycles of treatment given in the study Expected survival duration of > 3 months Karnofsky performance status > 70 Absolute neutrophil count (ANC) > 1000 cells/mm^3, unless cytopenias due to non-Hodgkin lymphoma (NHL) (i.e., bone marrow involvement or splenomegaly) Platelet count > 100,000/uL or > 75,000/uL if bone marrow (BM) involvement or splenomegaly Total bilirubin =< 1.5 x upper normal limit, or =< 3 x upper normal limit if documented hepatic involvement with lymphoma, or =< 5 x upper normal limit if history of Gilbert's disease Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper normal limit (=< 5 x upper normal limit if documented hepatic involvement with lymphoma) Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) > 45 mL/min (Cockcroft-Gault) Prothrombin time (PT) or international normalized ratio (INR), and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal unless patient is receiving anticoagulants; if patient is on warfarin therapy, levels should be within therapeutic range If currently not on anticoagulation medication, willing and able to take aspirin (81 or 325 mg) daily; if aspirin is contraindicated, the patient may be considered for the study if on therapeutic dose warfarin or low molecular weight heparin; patients unable to take any prophylaxis are not eligible Patients with measurable disease; patients with non-measurable but evaluable disease may be eligible after discussion with the principal investigator (PI); baseline measurements and evaluations must be obtained within 6 weeks of registration to the study; abnormal positron emission tomography (PET)/computed tomography (CT) scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging Patients with measurable disease must have at least one objective measurable disease parameter; a clearly defined, bi-dimensionally measurable defect or mass measuring at least 1.5 cm in diameter on the CT portion of a PET/CT or CT scan or magnetic resonance imaging (MRI) (if appropriate) will constitute measurable disease; proof of lymphoma in the liver is required by a confirmation biopsy; skin lesions can be used as measurable disease provided bi-dimensional measurements are possible All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the REMS program Women must not be pregnant or breast-feeding Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program All females of childbearing potential must have a blood test within 2 weeks prior to registration to rule out pregnancy Pregnancy testing is not required for post-menopausal or surgically sterilized women Male and female patients of reproductive potential must agree follow accepted birth control measures Patient must be able to adhere to the study visit schedule and other protocol requirements Patients must be willing to give written informed consent, and sign an institutionally approved consent form before performance of any study-related procedure not part of normal medical care as noted above; with the exception of 1 cycle of chemotherapy based on current diagnosis and clinical condition, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care No serious disease or condition that, in the opinion of the investigator, would compromise the patient's ability to participate in the study Exclusion Criteria: Pregnant or breast feeding females Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); patients who are seropositive ( i.e. hepatitis B core antibody positive; quantitative deoxyribonucleic acid [DNA] negative) are eligible with appropriate prophylaxis Major surgery within 2 weeks of study drug administration Prior malignancies within the past 3 years with exception of adequately treated basal cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason grade 6 or less with stable prostate-specific antigen (PSA) levels Patients with a diagnosis of other peripheral T-cell lymphoma (PTCL) histologies other than those specified in the inclusion criteria Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, or antiviral drugs Any other clinically significant medical disease or condition laboratory abnormality or psychiatric illness that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent Known hypersensitivity to thalidomide or lenalidomide The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, lenalidomide or similar drugs Ejection fraction of < 45% by either multi gated acquisition scan (MUGA) or echocardiogram (ECHO)

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 (combination chemotherapy, lenalidomide)<br>Patients receive cyclophosphamide IV, doxorubicin hydrochloride IV and vincristine sulfate IV on day 1, etoposide IV over 30-60 minutes on days 1-3, prednisone PO on days 1-5, and lenalidomide PO on days 1-10. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients responding after 6 courses of treatment may then undergo an autologous stem cell transplant or receive maintenance lenalidomide at the discretion of the physician or patient choice as follows: TRANSPLANT: Patients undergo autologous stem cell transplant per standard of care. MAINTENANCE LENALIDOMIDE: Patients receive lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous stem cell transplant<br>* Other names: Autologous Stem Cell Transplantation;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo peripheral blood stem cell transplant<br>* Other names: Peripheral Stem Cell Transplantation;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Lenalidomide and CHOEP | MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I) within the first cycle of study treatment. | 21 days | 
| Number of Participants With Adverse Events Graded According to Common Toxicity Criteria (CTC) (Phase I) | Non-hematologic toxicities will be evaluated via the ordinal CTC standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by dose level and patient will be explored and summarized. | Up to 6 cycles of treatment (approximately 5 months) | 
| Complete Response Rate (Phase II) | A success is defined to be an objective status of CR after completion of 6 cycles of treatment. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. A 95% confidence interval for the true overall CR rate will be calculated according to the method of Duffy and Santner. | Up to the completion of course 6 (18 weeks) | 
| Overall Response Rate | The ORR will be estimated by the total number of patients who achieve a PR or CR at the end of six cycles of treatment divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true ORR will be calculated. | Up to the completion of course 6 (18 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events Graded According to CTC (Phase II) | The toxicity profile will be further assessed based on phase II patients. Overall toxicity incidence of maximum tolerated dose level of the Intent to treat (ITT) group of subjects is summarized. 39 subjects were dosed with 10 mg dose of Lenalidamide as the ITT group. | Up to 1 year | 
| Overall Survival | The distribution of overall survival will be estimated using the method of Kaplan-Meier. | Time from registration to death due to any cause, assessed up to 1 year | 
| Progression-free Survival | The distribution of PFS will be estimated using the method of Kaplan-Meier. The PFS rate at 2 years will be estimated. A 2-year PFS rate of 60% will be considered of interest. | Time from registration to progression or death due to any cause, assessed up to 2 years |