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Interferons

Interleukin 1 Receptor Antagonist Protein

100 mg of Kineret (anakinra) will be administered sub-subcutaneously once a day for 28 days (1 cycle) with a maximum of 7 cycles (28 weeks of treatment)

100 mg of Kineret (anakinra) will be administered sub-subcutaneously twice a day for 28 days (1 cycle) with a maximum of 7 cycles (28 weeks of treatment)

200 mg of Kineret (anakinra) will be administered sub-subcutaneously twice a day for 28 days (1 cycle) with a maximum of 7 cycles (28 weeks of treatment)

escalating doses of drug will be administered to 3 groups of 4 patients for 7 months

Kineret

Jennifer Gallagher, BSc

Geetha Yogendran, BSc

David Spaner, MD

This is a phase I trial of the IL-1 receptor antagonist anakinra in chronic lymphocytic leukemia patients who are predicted to eventually require first-line therapy based on conventional clinical criteria. Three groups of 4 patients will be injected subcutaneously with either 100 mg daily or 100 mg twice daily or 200 mg twice daily for 7 cycles of 4 weeks each to determine the dose-limiting toxicity of anakinra in this population. Clinical responses will be determined by conventional IWCLL criteria. It is hoped anakinra will prevent disease progression with little toxicity. The study is anticipated to be completed within a year.

To avoid unnecessary toxicity from treatments that do not cure, patients with chronic lymphocytic leukemia (CLL) patients are traditionally observed until they develop symptoms that justify first-line therapy. This period of observation is called "watch and wait". Treatment of symptomatic CLL has improved significantly with new drugs such as ibrutinib that provide disease control previously impossible with standard chemotherapy. Unfortunately, these drugs rarely cure and outcomes are poor once they stop working. There is a need for strategies to prevent disease progression during "watch and wait" in order to extend survival and improve the lives of CLL patients.

It has been found that CLL cells from many patients spontaneously make the cytokine interleukin-1 (IL-1). When IL-1 is blocked by the IL-1 receptor antagonist anakinra, CLL cells release high amounts of type 1 interferon (IFN). Since IFN produced at sufficient levels for appropriate times activates immune responses that may prevent progression of cancer and anakinra has a favorable toxicity profile, the hypothesis of this trial is that anakinra administered in the "watch and wait" period may clear CLL cells before they can cause symptoms.

The hypothesis will be addressed in a phase 1 clinical trial. The primary objective is to determine the dose-limiting toxicity (DLT) of anakinra, which has not been established previously in this patient population. The secondary objectives are to determine the effect on disease burden. Anakinra will be provided by Sobi and clinical trial costs supported by the Sunnybrook hematology site group. The trial will involve 3 cohorts of 4 patients in a standard phase 1 design. Eligible patients will be on "watch and wait" but expected to inevitably require treatment as predicted by unmutated IGHV status, presence of lymphadenopathy or splenomegaly, circulating CLL counts greater than 30x106 cells/ml, or IgG levels less than 8 g/L. Cohorts will be treated with 100 mg subcutaneously (SC BID) daily, the dose approved for rheumatoid arthritis, 100 mg SC BID, or 200 mg BID, to approximate doses for genetic inflammopathies. Anakinra will be given daily for seven 4-week cycles based on experience with other immunomodulatory drugs that suggest an average time to best response is \~7 months. Responses will be determined by conventional criteria based on decreases in circulating CLL cell numbers and radiologic measurements of lymphadenopathy. Anakinra will be considered ineffective if no clinical responses are observed after 7 cycles. Based on Gehan criteria, a new drug must show activity in at least 1/13 patients to justify further testing.

The trial will involve 12 patients in a standard dose escalation design. The first cohort of 4 patients will start at 100 mg SC daily, the dose approved for rheumatoid arthritis. If no dose limiting toxicities are experienced by these patients during the first cycle of treatment, then the next cohort of up to 4 patients will be treated at 100 mg SC twice daily (BID). The third cohort of up to 4 patients will be treated at 200 mg BID SC daily, to approximate doses used to treat inflammopathies such as Cryopyrin-Associated Periodic Syndromes.

Anakinra in Previously Untreated Chronic Lymphocytic Leukemia Patients

A Phase 1 Trial of Anakinra in Previously Untreated Chronic Lymphocytic Leukemia Patients at Risk for Progression

The primary endpoints relate to safety and tolerability of anakinra in this patient, including numbers of patients with treatment-related adverse events (AEs) as assessed by CTCAE v4.0

Efficacy, defined as the proportion of patients with complete response (CR) or proportion of patients with partial response as defined by the NCI-WG guidelines on CLL.

Spots Global Cancer Trial Database for type 1 interferon