Novartis, a Swiss multinational pharmaceutical giant, announced positive results from the global phase III RATIFY (CALGB 10603) clinical trial. In the study, adult patients under 60 years of age with newly-diagnosed FLT3-mutated acute myeloid leukemia (AML) who received the investigational compound PKC412 (midostaurin) plus standard induction and consolidation chemotherapy experienced a 23 per cent improvement in overall survival (OS) (hazard ratio [HR] = 0.77, P = 0.0074) compared to those treated with standard induction and consolidation chemotherapy alone.

The median OS for patients in the PKC412 (midostaurin) treatment group was 74.7 months (95 per cent confidence interval [CI]: 31.7, not attained), versus 25.6 months (95 per cent CI: 18.6, 42.9) for patients in the placebo group.

PKC412 is an investigational, oral, multi-targeted kinase inhibitor in development for the treatment of patients with AML with a FLT3 mutation. PKC412 inhibits multiple kinases, or enzymes, including FLT3, that help regulate many essential cell processes, thereby interrupting cancer cells' ability to grow and multiply.

The trial evaluated the addition of either PKC412 or placebo to daunorubicin/cytarabine in the induction phase, followed by high-dose cytarabine in the consolidation phase; patients who achieved complete remission after consolidation chemotherapy continued treatment with PKC412 or placebo as a single agent for up to one year.

The data, collected and analysed in partnership with the Alliance for Clinical Trials in Oncology, are from the largest clinical trial in FLT3-mutated AML to date, with 3,279 patients screened and 717 study participants from around the world. Results were presented at the 57th American Society of Hematology (ASH) Annual Meeting in Orlando, Florida.

PKC412 is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.

"The overall survival results for midostaurin, plus standard chemotherapy, in treating FLT3-mutated AML is a long-awaited advancement for hematologists and the AML community," said Richard M. Stone, MD, professor of Medicine at the Dana-Farber Cancer Institute and Alliance for Clinical Trials in Oncology study chair for the RATIFY trial.

"FLT3 is a common genetic mutation in AML and is currently associated with poorer prognoses, underscoring the critical need for new treatment options."

The treatment strategy in AML has remained unchanged for more than 25 years. Of the approximately 350,000 people with leukemias worldwide, about 25 per cent have AML. One-third of AML patients also harbor a FLT3 gene mutation, which is associated with worse outcomes and shorter survival than in those without the mutation. PKC412 (midostaurin) is the first drug to illustrate an overall survival benefit targeting FLT3 in AML - a hematological malignancy with no approved targeted treatments.

In addition to meeting the primary endpoint of OS, event free survival (EFS, defined as the earliest death, relapse or no complete response within 60 days of the start of induction therapy) was significantly higher in the PKC412 (midostaurin) treatment group versus the placebo group [HR = 0.79, P = 0.0025 and median of 8.0 months (95 per cent CI: 5.14, 10.6) vs. 3.0 months (95 per cent CI: 1.9, 5.9).

No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events (AEs). A total of 37 deaths were reported, with no difference in treatment-related deaths observed between groups.

"The RATIFY study, in partnership with the Alliance for Clinical Trials in Oncology, reflects our relentless pursuit to develop targeted therapies that can improve and extend people's lives," said Alessandro Riva, MD, global head, Novartis Oncology Development and Medical Affairs.

"Based on the results of this trial, we plan to move forward with global regulatory submissions for PKC412 in the first half of 2016."

In order to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with PKC412, Novartis is collaborating with Invivoscribe Technologies, Inc. who will lead regulatory submissions for a companion diagnostic.

RATIFY (Randomized AML Trial In FLT3 in patients <60 Years old; also known as CALGB 10603) was a phase III, international, randomized, placebo-controlled, double-blind group trial of newly-diagnosed AML patients aged 18 to less than 60 with a FLT3 mutation. The study compared PKC412 (midostaurin) to placebo administered orally with up to two cycles of standard induction (daunorubicin/cytarabine) chemotherapy, and up to four cycles of consolidation (high-dose cytarabine) chemotherapy, followed by PKC412 (midostaurin) or placebo treatment as a single agent for up to one year in patients who continue in complete remission after consolidation chemotherapy. The primary endpoint was OS and the key secondary endpoint was EFS.

The data were collected by the Alliance for Clinical Trials in Oncology (Alliance) on behalf of 13 contributing international cooperative groups. The Alliance was the sponsor of the study in North America and Novartis was the sponsor in Europe and Australia. A total of 225 sites from 17 countries participated in this study, spanning North America, Europe and Australia. A total of 3,279 patients with AML were screened, and 717 patients with an activating FLT3 mutation aged 18 to less than 60 were enrolled.

Patients were stratified according to the following mutation subtypes: tyrosine kinase domain (TKD), internal tandem duplications (ITD) high allelic mutation fraction (>0.7) and ITD low allelic mutation fraction (0.05-0.7). All three subtypes treated with PKC412 (midostaurin) demonstrated improved OS versus placebo. Allogeneic hematopoietic stem cell transplantation (SCT) was allowed. PKC412 (midostaurin) benefited patients regardless of whether they went on to receive a SCT.

AML is an aggressive cancer of the blood and bone marrow. It prevents white blood cells from maturing, causing an accumulation of "blasts" which do not allow room for the normal blood cells. AML is the most common acute leukemia in adults, but also has the lowest survival rate. AML accounts for approximately 25 per cent of all adult leukemias worldwide, with the highest incidence rates occurring in the United States, Europe and Australia.

Mutations in specific genes are found in many cases of AML, and biomarker testing is considered standard of care for newly-diagnosed patients to help determine the best possible treatment option. FLT3 is a receptor tyrosine kinase, a type of cell-surface receptor, which plays a role in the proliferation, or increase, in the number of certain blood cells.