FDA to Discuss the Efficacy of Tipifarnib in Acute Myeloid Leukemia
May 5, 2005 - 6:52:38 AM

The efficacy rate of Johnson & Johnson's oncologic Zarnestra (tipifarnib) in acute myeloid leukemia is likely to be the focus of discussion in FDA's Oncologic Drugs Advisory Committee's review on May 5.

FDA found a confirmed 11% complete response rate with Zarnestra, while J&J reported a 15% rate of complete responses.

J&J is seeking an indication for Zarnestra for 'treatment of elderly patients with newly diagnosed poor-risk acute myeloid leukemia.'

Zarnestra efficacy was primarily established in the 135-patient Cancer Therapy Evaluation Program-20 (CTEP-20) trial in patients with poor-risk AML. The trial enrolled poor-risk AML patients 65-74 years old with previously diagnosed myelodysplastic syndromes or over 75 years of age.

FDA found an 11% CR rate for the trial based on "the sponsor-appointed independent reviewer's assessment of CR's, i.e., 15 subjects with confirmed complete responses," FDA's briefing document states.

J&J, meanwhile, said it identified 20 subjects (15%) as exhibiting complete responses.

The discrepancy lies in J&J's inclusion of two patients, for whom bone marrow slides were unavailable and three patients without CRs confirmed by repeat bone marrow aspirate.

Of the two patients lacking bone marrow slides, one was a confirmed complete responder and one was unconfirmed, J&J's briefing document states.

J&J maintains that the three patients without bone marrow aspirates had peripheral blood counts that confirmed a complete response.

The only other AML therapy indicated specifically for the elderly population, Wyeth's Mylotarg (gemtuzumab ozogamicin), was associated with a 16% complete remission rate in a Phase II trial.

During ODAC's 2000 review of Mylotarg, committee members considered the response rate marginal. However, the panel recommended accelerated approval due to the oncologic's favorable adverse event profile relative to available AML therapies.

Zarnestra would be indicated for a different population than Mylotarg, which is approved as a second-line therapy for elderly CD33+ AML patients who are not candidates for cytotoxic agents.

J&J finished submission of the oncologic under the agency�s Continuing Marketing Application Pilot I program in December, setting a user fee deadline of June 29.

FDA awarded Zarnestra fast-track status due to the potential for the oncologic to meet an unmet medical need.

Currently available AML treatments are associated with treatment-induced mortality rates of as high as 25% in poor-risk patients, FDA noted.

Zarnestra's adverse event profile may make it more attractive for use in the poor-risk AML population.

In CTEP-20, one patient died of Zarnestra-related adverse events (neutropenia, fungal infection and renal dysfunction).

Grade 3 or 4 treatment-emergent adverse events occurred in 83% of patients, and 61% experienced drug-related events. Serious adverse events appearing in greater than 10% of patients were neutropenic fever (41%), infections (27%), thrombocytopenia (17%), fatigue (13%) and pneumonia (10%).

Another advantage for Zarnestra could be its oral dosing (600 mg twice daily), allowing patients to receive treatment outside of a hospital setting. Mylotarg is administered by infusion.

J&J has initiated enrollment for a Phase III confirmatory study of Zarnestra in AML. The study will compare tipifarnib to best supportive care in newly diagnosed AML patients 70 years and older. The sponsor expects study results by the end of 2006.

Wyeth has yet to complete its confirmatory study for Mylotarg due to patient accrual problems. The company expects to complete patient accrual by 2007 and to submit the study to FDA by 2010, a decade after gemtuzumab�s accelerated approval.

Tipifarnib failed to show efficacy previously in trials in pancreatic and colorectal cancer.

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