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Advocacy >  Idelalisib Approval Background  

Last update: 01/13/2015

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By definition, accelerated approvals are 1) based on surrogate markers in populations with an unmet need, and are 2) conditional and therefore need to be confirmed by additional controlled trials.   Another consideration is that the study drug is thought to work by a unique mechanism of action -- relative to approved drugs for the indications.

Because of the different ruling by regulatory agencies, we are providing background on the accelerated approval of idelalisib (Zydelig) for relapsed and refractory CLL and follicular lymphoma - from FDA source documents. 

Mechanism of Action (from FDA)

Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant B-cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells.

Idelalisib inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.

In the News

Science Daily 2015:
Added benefit of idelalisib is not proven http://bit.ly/1AvcxNq

Snip:  The Federal Joint Committee (G-BA) specified "best supportive care" (BSC) as appropriate comparator therapy for the assessment of idelalisib in patients with refractory follicular lymphoma. BSC means a therapy that provides the patient with the best possible, individually optimized, supportive treatment to alleviate symptoms and improve quality of life.
Background on accelerated approval of idelalisib for CLL From www.accessdata.fda.gov http://1.usa.gov/1suELrA
FDA letter of approval - with conditions:

This NDA provides for the use of Zydelig (idelalisib) for relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies and relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.


Populations ... the all-important context for approval:

14.1 Relapsed Chronic Lymphocytic Leukemia

Zydelig was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to coexisting medical conditions, reduced renal function as measured by creatinine clearance <60 mL/min, or NCI CTCAE Grade ≥3 neutropenia or Grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents.

Subjects were randomized 1:1 to receive 8 doses of rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Zydelig 150 mg taken twice daily until disease progression or unacceptable toxicity.

14.2 Relapsed Follicular B-cell non-Hodgkin Lymphoma

The safety and efficacy of Zydelig in patients with FL was evaluated in a single-arm, multicenter clinical trial which included 72 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments.

The median age was 62 years (range 33 to 84), 54% were male, and 90% were Caucasian. At enrollment, 92% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 4.7 years and the median number of prior treatments was 4 (range 2 to 12). The most common prior combination regimens were R-CHOP (49%), BR (50%), and R-CVP (28%). At baseline, 33% of patients had extranodal involvement and 26% had bone marrow involvement.

Patients received 150 mg of Zydelig orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 7.


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