Oral Azacitidine Benefits Some Older Adults With AML

In continuation of my update on azacitidine 

For older patients with acute myeloid leukemia (AML) who are in remission after chemotherapy, those receiving maintenance therapy with the oral formulation of azacitidine (CC-486) versus placebo had longer overall and relapse-free survival, according to a study published in the Dec. 24 issue of the New England Journal of Medicine.

Andrew H. Wei, M.B., B.S., Ph.D., from Monash University in Melbourne, Australia, and colleagues conducted a phase 3 randomized trial of CC-486 as maintenance therapy for patients with AML in first remission after intensive chemotherapy. A total of 472 patients aged 55 years and older who were in complete remission and were not candidates for hematopoietic stem cell transplantation were randomly assigned to receive either CC-486 or placebo once daily for 14 days per 28-day cycle (238 and 234 patients, respectively).

The researchers observed significantly longer median overall survival from the time of randomization with CC-486 versus placebo (24.7 versus 14.8 months). The corresponding median relapse-free survival was also significantly longer (10.2 versus 4.8 months). In most subgroups defined according to baseline characteristics, similar benefits of CC-486 were seen with respect to overall and relapse-free survival. During CC-486 treatment, overall health-related quality of life was preserved.

"Despite demonstrable survival advantages with CC-486 maintenance therapy, the risk of eventual relapse and death from AML remains problematic," the authors write. "Whether CC-486 may benefit patients with AML when it is used in other clinical contexts requires further investigation."

The study was funded by Celgene (a wholly owned subsidiary of Bristol Myers Squibb), which manufactures azacitidine.

https://en.wikipedia.org/wiki/Azacitidine

Oral Azacitidine Benefits Some Older Adults With AML 

FDA Approves Onureg (azacitidine tablets) as Continued Treatment for Adults in First Remission with Acute Myeloid Leukemia

Bristol Myers Squibb (NYSE: BMY) announced that the U.S. Food and Drug Administration (FDA) has approved Onureg (azacitidine 300 mg tablets, CC-486) for the continued treatment of adult patients with acute myeloid leukemia (AML) who achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy and who are not able to complete intensive curative therapy.  AML is one of the most common acute leukemias in adults.

The approval is based on results from the pivotal Phase 3 QUAZAR® AML-001 study in which treatment with Onureg resulted in a statistically significant and clinically meaningful improvement in overall survival (OS), the study’s primary endpoint, of nearly 10 months compared to placebo. Median OS from time of randomization was greater than two years (24.7 months; 95% Confidence Interval [CI]: 18.7 to 30.5) among patients who received Onureg compared to 14.8 months (95% CI: 11.7 to 17.6) among patients receiving placebo (Hazard Ratio [HR]: 0.69, 95% CI: 0.55 to 0.86; p=0.0009). Onureg was continued until disease progression or unacceptable toxicity. Onureg has warnings and precautions for risks of substitution with other azacitidine products, myelosuppression, increased early mortality in patients with myelodysplastic syndromes (MDS) and embryo-fetal toxicity. Due to substantial differences in the pharmacokinetic parameters, Onureg should not be substituted for intravenous or subcutaneous azacitidine as it may result in a fatal adverse reaction. New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received Onureg, respectively. Febrile neutropenia occurred in 12% of patients. Complete blood counts should be monitored, dosing should be modified as recommended and standard supportive care should be provided if myelosuppression occurs. Enrollment was discontinued early in the study AZA-MDS-003 due to a higher incidence of early fatal and/or serious adverse reactions in the Onureg arm compared with the placebo arm. Treatment of MDS with Onureg is not recommended outside of controlled trials. Onureg can cause fetal harm when administered to a pregnant woman.

https://en.wikipedia.org/wiki/Azacitidine

FDA Approves Onureg (azacitidine tablets) as Continued Treatment for Adults in First Remission with Acute Myeloid Leukemia

Agios Announces FDA Approval of Tibsovo as Monotherapy for Newly Diagnosed Adult Patients with IDH1 Mutant Acute Myeloid Leukemia (AML) Not Eligible for Intensive Chemotherapy

Agios Pharmaceuticals, Inc., a leader in the field of cellular metabolism to treat cancer and rare genetic diseases,  announced the U.S. Food and Drug Administration (FDA) approved a supplemental New Drug Application (sNDA) to update the U.S. Prescribing Information for Tibsovo, an isocitrate dehydrogenase-1 (IDH1) inhibitor, to include adult patients with newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. The sNDA was granted Priority Review and accepted under the FDA's Real-Time Oncology Review pilot program, which aims to make the review of oncology drugs more efficient by allowing the FDA access to clinical trial data before the information is formally submitted to the agency. Tibsovo received initial FDA approval in July 2018 for adult patients with relapsed or refractory (R/R) AML and an IDH1 mutation1.

“Despite several new AML medicines approved in the last two years, many newly diagnosed patients are still not eligible for existing therapies or combination regimens because of age and other comorbidities,” said Chris Bowden, M.D., chief medical officer at Agios. “With today’s additional Tibsovo approval, we are now able to provide a targeted, oral therapy to patients with an IDH1 mutation who may not have other treatment options. In addition, we are continuing our work to expand the utility of Tibsovo in newly diagnosed AML patients in ongoing Phase 3 trials in combination with both intensive chemotherapy and azacitidine. I would like to thank the patients, nurses, physicians and caregivers who participated in the clinical trial, as well as the tremendous employees at Agios whose focus on patients made this possible.”

AML is a cancer of the blood and bone marrow marked by rapid disease progression and is the most common acute leukemia affecting adults with approximately 20,000 new cases estimated in the U.S. each year2,3. AML patients are typically older or have comorbidities that preclude the use of intensive chemotherapy4. These patients typically have a worse prognosis and poor outcomes5. The majority of patients with AML eventually relapse6. The five-year survival rate is approximately 28%2. For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia7. IDH1 mutations have been associated with negative prognosis in AML.

“The Phase 1 results for Tibsovo demonstrated that this oral, single agent therapy can induce durable responses in newly diagnosed AML patients with an IDH1 mutation,” said Gail J. Roboz, M.D., Professor of Medicine, Director of the Leukemia Program and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center*. “Many patients included in the study had features associated with particularly aggressive and challenging forms of AML, including secondary disease, adverse risk genetics and prior treatment with hypomethylating agents.”

Tibsovo Safety and Efficacy Data

The efficacy of Tibsovo was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly diagnosed AML with an IDH1 mutation who were assigned to receive a 500 mg daily dose. The cohort included patients who were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy (baseline Eastern Cooperative Oncology Group [ECOG] performance status of ≥2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, or creatinine clearance <45 mL/min). Patients had a median age of 77 years (range of 64 to 87) and 68% had AML with myelodysplasia-related changes. The primary endpoint is the combined complete remission (CR) and complete remission with partial hematologic improvement (CRh) rate. CRh is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

In this trial, Tibsovo demonstrated:

• CR+CRh rate of 42.9% (12 of 28 patients) (95% CI: 24.5, 62.8).
• The CR rate was 28.6% (8 of 28 patients) (95% CI 13.2, 48.7) and the CRh rate was 14.3% (4 of 28 patients) (95% CI 4.0, 32.7).
• Median durations of CR and CR+CRh were not estimable, with 5 patients (41.7%) who achieved CR or CRh remaining on Tibsovo treatment (treatment duration range: 20.3 to 40.9 months) as of the data cutoff.
• 58.3% (7 of 12) of patients who achieved CR or CRh were in remission at 1 year after receiving treatment.
• For patients who achieved a CR or CRh, the median time to best response of CR or CRh was 2.8 months (range, 1.9 to 12.9 months).
• Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 7 (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period.
• Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, 6 (54.5%) remained transfusion independent during any 56-day post-baseline period.

The safety profile of single-agent Tibsovo was evaluated in 28 patients with newly diagnosed AML with an IDH1 mutation treated with a dose of 500 mg daily. The median duration of exposure to Tibsovo was 4.3 months (range, 0.3 to 40.9 months). In the clinical trial, 25% (7 of 28) of patients treated with Tibsovo experienced differentiation syndrome, which can be fatal if not treated. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. QTc interval prolongation occurred in patients treated with Tibsovo. The most common adverse reactions (≥20%) of any grade in patients with newly diagnosed AML were diarrhea, fatigue, decreased appetite, edema, nausea, leukocytosis, arthralgia, abdominal pain, dyspnea, myalgia, constipation, differentiation syndrome, dizziness, electrocardiogram QT prolonged, mucositis and vomiting.

About Tibsovo (ivosidenib)

Tibsovo is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

Adult patients with relapsed or refractory AML.

https://www.rxlist.com/tibsovo-drug.htm#indications

https://en.wikipedia.org/wiki/Ivosidenib

Agios Announces FDA Approval of Tibsovo as Monotherapy for Newly Diagnosed Adult Patients with IDH1 Mutant Acute Myeloid Leukemia (AML) Not Eligible for Intensive Chemotherapy

Cyclacel Presents New Phase 2 Data of Sapacitabine for MDS

We know that, Sapacitabine is an oral nucleoside analog prodrug that acts through a dual mechanism. The compound interferes with DNA synthesis by causing single-strand DNA breaks and induces arrest of the cell division cycle at G2 phase. Both sapacitabine and its major metabolite, CNDAC, have demonstrated potent anti-tumor activity in both blood and solid tumors in preclinical studies. In a liver metastatic mouse model, sapacitabine was shown to be superior to gemcitabine (Gemzar; Lilly) or 5-FU, two widely used nucleoside analogs, in delaying the onset and growth of liver metastasis.

Cyclacel has initiated a number of clinical trials to evaluate sapacitabine in both solid and hematological tumors laying the foundation for future Phase 2 studies and combination studies with other anti-cancer agents. Three Phase 1 studies have been completed, which evaluated safety and pharmacokinetics of a variety of dosing schedules in approximately 120 patients with solid tumors. Sapacitabine is currently being evaluated in two Phase 2 trials in patients with advanced cutaneous T-cell lymphoma (CTCL) and in elderly patients with acute myeloid leukemias (AML).

Now Cyclacel Pharmaceuticals, Inc. announced new data from an ongoing, multicenter, Phase 2 randomized trial of oral sapacitabine capsules in older patients with myelodysplastic syndromes (MDS) after treatment failure of front-line hypomethylating agents, such as azacitidine or decitabine.