Interleukin-12 and Interleukin-2 in Treating Patients With Mycosis Fungoides

Study Overview
=================
Brief Summary
-----------------
Phase I/II trial to study the effectiveness of combining interleukin-12 with interleukin-2 in treating patients who have mycosis fungoides. Biological therapies, such as interleukin-12 and interleukin-2, use different ways to stimulate the immune system and stop cancer cells from growing. Combining more than one biological therapy may kill more tumor cells

Detailed Description
-----------------
OBJECTIVES: I. Determine the response rate (complete and partial) in patients with mycosis fungoides treated with interleukin-12 (IL-12). II. Determine the frequency of refractory disease in patients treated with this drug. III. Determine the toxic effects of this drug in these patients. IV. Determine the feasibility and dose-limiting toxic effects (DLT) of interleukin-2 (IL-2) when administered with IL-12 in patients who have not shown disease progression after 12 weeks of IL-12 and in those who have shown disease progression after 12 weeks of IL-12. V. Determine the maximum tolerated dose and recommended dose of IL-2 when administered with IL-12 in these patients. VI. Determine immune and cytokine response over time in patients treated with this regimen. VII. Determine the frequency of improved clinical response in patients treated with this regimen. VIII. Determine the biologic correlates of response, including levels of interferon gamma production, natural killer cell activity, infiltration of skin lesions by CD8-positive cells, lymphocyte IL-12 receptor expression, signal transducers and activators of transcription protein levels and IL-12 signal transduction, and induction of apoptosis in tumor cells in the skin of patients treated with this regimen. OUTLINE: This is an open-label, multicenter, dose-escalation study of interleukin-2 (IL-2). Patients receive interleukin-12 (IL-12) subcutaneously (SC) twice weekly for 24 weeks. Disease is assessed at 13 weeks. Patients who do not have progressive disease also receive IL-2 SC 3 consecutive days a week during weeks 13-24. Patients with progressive disease at week 13 receive IL-2 SC at a fixed dose during weeks 13-24. Patients with responding disease after week 24 may continue to receive IL-2 and IL-12 for another 12 weeks. Cohorts of 3-6 patients receive escalating doses of IL-2 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. The recommended dose (RD) is the dose preceding the MTD. Additional patients are treated at the RD. Patients are followed at 6 months. PROJECTED ACCRUAL: A total of 18-46 patients will be accrued for this study within 28 months.

Official Title
-----------------
A Phase II Open-Label Study Of Recombinant Human Interleukin-12 (NSC 672423) In Mycosis Fungoides (MF) Patients With Cross-Over To Phase I Evaluation Of Escalating Doses Of Interleukin-2 (NSC 373364) Administered With Interleukin-12

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

Intervention / Treatment
-----------------
* Biological: aldesleukin
* Biological: recombinant interleukin-12
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed mycosis fungoides Stage Ib-IV At least 5% of total blood mononuclear cells must be CD8-positive lymphocytes No CNS disease Performance status - Karnofsky 70-100% At least 6 months WBC ≥ 3,000/mm^3 but ≤ 40,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10 g/dL (transfusion or epoetin alfa allowed) Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2 times ULN Creatinine ≤ 1.5 times ULN Creatinine clearance ≥ 60 mL/min EKG normal No known cardiac and peripheral vascular disease No cardiac arrhythmias requiring medical treatment Chest x-ray normal No history of or clinically significant autoimmune disease (e.g., rheumatoid arthritis), autoimmune hemolytic anemia, or positive Coombs' test No HTLV-I or HTLV-II-associated disease HIV negative Antinuclear antibody negative Rheumatoid factor negative No serious concurrent infection requiring IV antibiotics No clinically significant gastrointestinal bleeding No uncontrolled peptic ulcer disease No history of inflammatory bowel disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No history of peripheral neuropathy No other major illness that would substantially increase the patient's risk Prior interferon allowed Prior denileukin diftitox allowed No prior interleukin (IL)-2 or IL-12 No prior anti-T-cell monoclonal antibody therapy No other concurrent biologic therapy Prior topical imidazole mustard or carmustine allowed Prior bexarotene allowed Prior oral methotrexate allowed At least 3 weeks since prior topical chemotherapy At least 8 weeks since prior treatment with any single chemotherapeutic agent (12 weeks for multiple chemotherapeutic agents) Treatment must not have included steroids No prior systemic chemotherapy No prior fludarabine, pentostatin, or cladribine No concurrent systemic chemotherapy At least 3 weeks since prior topical or systemic steroids more potent than 1% hydrocortisone No concurrent systemic corticosteroids No concurrent low-potency steroid creams No concurrent radiotherapy Not specified At least 3 weeks since prior psoralen-ultraviolet-light (PUVA) or ultraviolet B (UVB) At least 3 weeks since prior retinoids At least 3 weeks since prior investigational drugs Prior photopheresis allowed No other concurrent investigational therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (aldesleukin, recombinant interleukin-12)<br>Patients receive IL-12 SC twice weekly for 24 weeks. Disease is assessed at 13 weeks. Patients who do not have progressive disease also receive IL-2 SC 3 consecutive days a week during weeks 13-24. Patients with progressive disease at week 13 receive IL-2 SC at a fixed dose during weeks 13-24. Patients with responding disease after week 24 may continue to receive IL-2 and IL-12 for another 12 weeks. Cohorts of 3-6 patients receive escalating doses of IL-2 until the MTD is determined. The MTD is defined as the dose at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. The RD is the dose preceding the MTD. Additional patients are treated at the RD. | Biological: aldesleukin<br>* Given SC<br>* Other names: recombinant interleukin-2;Biological: recombinant interleukin-12<br>* Given SC<br>* Other names: Ro 24-7472;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rate defined as the percentage of patients who achieve complete or partial response (Phase I) |  | Up to week 13 | 
| Refractory disease defined as a patient who initially shows clinical improvement in the early weeks of treatment and then exhibits a response plateau for >= 30 days or exhibits progression of their disease (Phase I) | Logistic regression may be employed to explore the relationships between clinical response or refractory disease and baseline patient features. | Up to week 13 | 
| Improved clinical response defined as a patient who had refractory or persistent disease and who subsequently had a >= 25% clinical improvement for >= 30 days during aldesleukin and recombinant interleukin-12 therapy (Phase II) |  | Up to week 25 | 
| Toxicities graded using National Cancer Institute (NCI) Common Toxicity Criteria Version 2.0 (Phase I) |  | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) is defined as any grade 3 or higher hematologic or non-hematologic toxicity (Phase II) |  | Up to week 25 | 
| Maximum tolerated dose (MTD), defined as the dose level at which at least 2 of 3 patients or at least 2 of 6 patients experience DLT, graded according to the NCI CTC v2.0 (Phase II) |  | Up to week 25 | 
| Recommended dose (RD), defined as the dose level at which 0/6 or 1/6 patients experience DLT and at least 2 patients treated at a higher dose level experience DLT (Phase II) |  | Up to week 25 | 
| Interferon gamma production | Compared between the two groups by two independent samples t-test or nonparametric Mann-Whitney test, as appropriate. | Up to week 25 | 
| Infiltration of skin lesions by CD8+ cells |  | Up to week 25 | 
| Induction of apoptosis in infiltrating tumor cells in the skin |  | Up to week 26 |