11 December 2019 - - US-based pharmaceutical company Bristol-Myers Squibb Company (NYSE: BMY) has released clinical results from the QUAZAR AML-001 study, evaluating investigational agent CC-486 as maintenance therapy in a broad population of patients with front-line, newly diagnosed acute myeloid leukemia who have achieved remission with intensive induction chemotherapy, the company said.

Data were presented during a late-breaker oral presentation at the 2019 ASH annual meeting in Orlando, Fla.

In the QUAZAR AML-001 study, treatment with CC-486 in the maintenance setting provided patients a statistically significant and clinically meaningful improvement in overall survival and relapse-free survival, as compared to those patients treated with placebo.

Patients in the phase 3, international, randomized, double-blind, placebo-controlled study QUAZAR AML-001 were at least 55 years old, had de novo or secondary AML with intermediate or poor-risk cytogenetics and had achieved their first complete remission or complete remission with incomplete count recovery after intensive induction chemotherapy.

Patients had received intensive induction chemotherapy, with or without consolidation chemotherapy per investigator's choice and were deemed not candidates for hematopoietic stem-cell transplant prior to study entry.

Following intensive induction chemotherapy, 81% of patients had achieved a CR and 19% of patients had achieved a CRi. Eighty percent of patients had received at least one cycle of consolidation therapy prior to enrollment in the study.

Four hundred seventy-two patients were then randomized 1: 1 to receive initially either investigational CC-486 300mg (n=238) or placebo (n=234) once daily for 14 days of each 28-day cycle. Patients remained on treatment until unacceptable toxicity or disease progression.

At a median follow-up of 41.2 months, the primary endpoint of OS was significantly improved for patients receiving CC-486 compared to placebo.

Median OS from time of randomization was 24.7 months in the CC-486 arm compared to 14.8 months for placebo (p=0.0009; HR 0.69 [95% CI: 0.55, 0.86]).

Median RFS, the key secondary endpoint, was 10.2 months for those receiving CC-486 compared to 4.8 months for those receiving placebo (p=0.0001; HR 0.65 [95% CI: 0.52, 0.81]).

Improvements in OS and RFS for those treated with CC-486 compared to placebo were demonstrated, regardless of cytogenetic risk category, prior consolidation or CR/CRi status at enrollment.

Health-related quality of life (HRQoL) was preserved from baseline for patients receiving CC-486 compared to placebo during treatment.

The median duration of treatment was 12 cycles for CC-486 and 6 cycles with placebo.

The most commonly occurring adverse events of all grades with CC-486 and placebo, respectively, were nausea (65% vs. 24%), vomiting (60% vs. 10%) and diarrhea (50% vs. 22%).

The most common grade 3-4 AEs for CC-486 and placebo, respectively, were neutropenia (41% vs. 24%), thrombocytopenia (23% vs. 22%) and anemia (14% vs. 13%). Serious AEs were reported in 34% of CC-486 patients and 25% of placebo patients, and were mainly infections, which occurred in 17% and 8% of CC-486 and placebo patients, respectively.

There were 13% of CC-486 patients and 4% of placebo patients who discontinued treatment due to AEs.

Based on the results of QUAZAR AML-001, Bristol-Myers Squibb is planning regulatory submissions in the first half of 2020.

CC-486 is not approved for any use in any country.

Acute myeloid leukemia is the most common type of acute leukemia. AML starts in the bone marrow but moves quickly into the blood.

Unlike in normal blood cell development, in AML the rapid build up of abnormal white blood cells in the bone marrow may interfere with the production of normal blood cells, resulting in decreased healthy white blood cells, red blood cells and platelets.

AML is a complex, diverse disease associated with multiple genetic mutations and usually gets worse quickly if not treated.

There will be an estimated 21,450 new cases of AML in the United States this year, accounting for 1.2% of all cancer cases, with an estimated 10,920 deaths resulting from the disease. There are an estimated 61,048 people living with AML in the United States.

QUAZAR AML-001 is a phase 3, international, randomized, double-blind, placebo-controlled study of CC-486 as AML maintenance therapy in patients who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy (with or without consolidation).

The primary endpoint of the study was overall survival. Secondary endpoints included relapse-free survival, safety and tolerability, healthcare resource utilisation and patient-reported outcomes per the FACIT-Fatigue Scale and EQ-5D questionnaire.

The study enrolled 472 patients, randomized 1: 1 to receive initially either oral CC-486 300mg or placebo once daily for 14 days of a 28-day cycle plus best supportive care. Patients remained on treatment until unacceptable toxicity or disease progression.

CC-486 is an oral hypomethylating agent that incorporates into DNA and RNA allowing for sustained epigenetic regulation due to prolonged exposure.

The main mechanism of action is thought to be hypomethylation of DNA, as well as direct cytotoxicity to abnormal hematopoietic cells in the bone marrow.

Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation.