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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Terminated

CT.gov ID

NCT00052377

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
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	Biological: aldesleukin Biological: recombinant interleukin-12 Other: laboratory biomarker analysis	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Determine the response rate (complete and partial) in patients with mycosis fungoides treated with interleukin-12 (IL-12).
Determine the frequency of refractory disease in patients treated with this drug.
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.
Determine the maximum tolerated dose and recommended dose of IL-2 when administered with IL-12 in these patients.
Determine immune and cytokine response over time in patients treated with this regimen.
Determine the frequency of improved clinical response in patients treated with this regimen.
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

46 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Study Start Date :

Sep 1, 2002

Actual Primary Completion Date :

Jun 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (aldesleukin, recombinant interleukin-12) 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 Given SC Other Names: IL-2 Proleukin recombinant human interleukin-2 recombinant interleukin-2 Biological: recombinant interleukin-12 Given SC Other Names: cytotoxic lymphocyte maturation factor IL-12 interleukin-12 natural killer cell stimulatory factor Ro 24-7472 Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (aldesleukin, recombinant interleukin-12)

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

Given SC

Other Names:

IL-2

Proleukin

recombinant human interleukin-2

recombinant interleukin-2

Biological: recombinant interleukin-12

Given SC

Other Names:

cytotoxic lymphocyte maturation factor

IL-12

interleukin-12

natural killer cell stimulatory factor

Ro 24-7472

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

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) [Up to week 13]
Logistic regression may be employed to explore the relationships between clinical response or refractory disease and baseline patient features.
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

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 [Up to week 25]
Compared between the two groups by two independent samples t-test or nonparametric Mann-Whitney test, as appropriate.
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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