Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Savona, Michael R.; Kolibaba, Kathryn S.; Conkling, Paul; Kingsley, Edwin C.; Becerra, Carlos; Morris, John C.; Rifkin, Robert M.; Laille, Eric; Kellerman, A. J.; Ukrainskyj, Stacey M.; Dong, Qian; Skikne, Barry S.

doi:10.1002/ajh.25216

Cited by 54 publications

(47 citation statements)

References 36 publications

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“…New HMAs are being tested in MDS and AML, including guadecitabine (SGI‐110), a HMA resistant to the action of cytidine deaminase , resulting in extended exposure (Adès et al , ; Garcia‐Manero et al , ; Sébert et al , ), an oral formulation of azacitidine (CC‐486) (Savona et al , ) and an oral formulation of decitabine (E 7727) but their place (are they more effective than azacitidine and decitabine, or are they just more convenient, as oral forms ?) remains to be determined.…”

Section: How We Treat Higher Risk Mds (Hr‐mds)mentioning

confidence: 99%

How we manage adults with myelodysplastic syndrome

2019

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Summary The prognosis in Myelodysplastic syndromes (MDS), although recently refined by molecular studies, remains largely based on conventional prognostic scores [International Prognostic Scoring System (IPSS), revised IPSS], classifying patients into “lower risk” MDS (LR‐MDS) and “higher risk” MDS (HR‐MDS). In LR‐MDS, treatment mainly aims at improving cytopenias, principally anaemia, while in HR‐MDS it aims at delaying disease progression and prolonging survival. In LR‐MDS without deletion 5q, anaemia is generally treated first by erythropoietic stimulating factors, while second line treatments are currently not approved [lenalidomide, hypomethylating agents (HMA), luspatercept] or rarely indicated (antithymocyte globulin). Lenalidomide has major efficacy in LR‐MDS with deletion 5q. Allogeneic stem cell transplantation (allo‐SCT) is sometimes considered in LR‐MDS, and iron chelation can be considered when multiple red blood cell transfusions are required. Allo‐SCT is the only potentially curative treatment for HR‐MDS; however, it is rarely applicable. It is generally preceded by intensive chemotherapy (IC) or HMA in patients with excess of marrow blasts (especially if >10%). In other patients, HMA can improve survival. The role of new drugs, including venetoclax or, in case of specific mutations, IDH1 or IDH2 inhibitors, is investigated. IC is mainly indicated as a bridge to allo‐SCT, in the absence of unfavourable karyotype.

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Section: How We Treat Higher Risk Mds (Hr‐mds)mentioning

confidence: 99%

How we manage adults with myelodysplastic syndrome

2019

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“…The single 300-mg CC-486 Formulation B tablet was found to be bioequivalent to two 150-mg Formulation A tablets, that have been shown efficacious and generally well-tolerated in clinical trials [14], and the 300-mg CC-486 tablet can be taken with or without food. The single-tablet formulation will be more convenient for patients and will be used for registration purposes to support further development of CC-486 for use in various malignancies.…”

Section: Discussionmentioning

confidence: 94%

“…CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure and thus maximize hypomethylating effects [12,13]. Early clinical studies showed CC-486 to be bioavailable, well-tolerated, and clinically active in patients with MDS, AML, or chronic myelomonocytic leukemia (CMML) [11,12,14]. When administered for 7 days per treatment cycle, global DNA hypomethylation with CC-486 was less extensive than with 7-day administration of SC azacitidine [11], but extended CC-486 dosing schedules-taken for 14 or 21 days per cycle-were associated with sustained hypomethylation through the end of the treatment cycle [12,13].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer

Babiker

Milhem

Aisner

et al. 2020

Cancer Chemother Pharmacol

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Purpose CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure to malignant cells and maximize clinical activity. CC-486 300 mg daily, administered for 14 or 21 days of 28-day treatment cycles, is currently under investigation in two ongoing phase III trials. The 300-mg daily dose in these studies is administered as two 150-mg tablets (Formulation A). Methods We evaluated the bioequivalence of one 300-mg CC-486 tablet (Formulation B) with Formulation A and food effect on Formulation B, in adult patients with cancer in a 2-stage crossover design study. Results The ratios of the geometric means of the maximum azacitidine plasma concentration (C max ) and of the area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC ∞ ) were 101.5% and 105.7%, demonstrating the bioequivalence of Formulations A and B. Formulation B was rapidly absorbed under fasted and fed conditions. The geometric mean of C max was significantly decreased by ~ 21% in the fed state. Median T max was reached at 2 h and 1 h post-dose in fed and fasted states, respectively (P < 0.001). Nevertheless, systemic drug exposure (AUC) in fed and fasted states was within the 80-125% boundaries of bioequivalence and differences in C max and T max are not expected to have a clinical impact. Conclusion The single 300-mg CC-486 tablet was bioequivalent to two 150-mg tablets, which have shown to be efficacious and generally well-tolerated in clinical trials, and can be taken with or without food.

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“…Experience with CC-486 monotherapy as front-line or salvage therapy in AML is limited; in 9 patients with AML treated with extended CC-486 dosing regimens who received a median (range) of 1 (1-9) CC-486 treatments, the overall response (CR/CRi/CRp) rate was 22%. 36 A phase 3 study of CC-486 as maintenance therapy (300 mg daily for 14 days per 28-day cycle) for patients with AML in first CR after intensive chemotherapy (NCT01757535) is expected to be completed in 2019.…”

Section: Cc-486mentioning

confidence: 99%

Response Kinetics and Clinical Benefits of Nonintensive AML Therapies in the Absence of Morphologic Response

Stein

DiNardo

Pollyea

et al. 2020

Clinical Lymphoma Myeloma and Leukemia

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The ultimate goal of treatment for acute myeloid leukemia (AML) is to improve survival, and the best means of doing so is through the induction of morphologic remission, which is historically most reliably achieved with intensive chemotherapy regimens. Older patients with AML are less likely to be candidates for or to benefit from intensive chemotherapy. Patients deemed ineligible for intensive therapy may nevertheless benefit from lower-intensity therapies and from newly available targeted AML treatments. Recently approved lower-intensity treatments for AML include enasidenib, ivosidenib, glasdegib, venetoclax, midostaurin, and gilteritinib, and additional promising agents are in later stages of clinical development. Noncytotoxic agents may result in slower kinetics of therapeutic activity compared to intensive regimens, and although they are generally better tolerated than intensive chemotherapy, bone marrow responses are less frequent and may take longer to achieve. Notably, newer therapies might have been considered ineffective had they been judged solely by 2003 International Working Group response criteria for AML, which were based on experience with intensive regimens in predominantly younger patients. Lower-intensity therapies may require several treatment cycles to induce responses, and failure to achieve rapid morphologic remission may not signal the need for treatment cessation or transition to alternative therapies. Additionally, even in the absence of a conventional complete remission, lower-intensity therapies may provide meaningful clinical benefit, including improved survival and quality of life, by inducing hematologic improvement and transfusion independence. Reviewed here are the mechanisms of activity and response kinetics of lower-intensity AML therapies, as well as the clinical benefits resulting from nontraditional AML responses.

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Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Cited by 54 publications

References 36 publications

How we manage adults with myelodysplastic syndrome

How we manage adults with myelodysplastic syndrome

Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer

Response Kinetics and Clinical Benefits of Nonintensive AML Therapies in the Absence of Morphologic Response

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