Hematologic Malignancies
`
`Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic
`Syndromes and Acute Myeloid Leukemia
`CHRISTOPHER R. COGLE,a BART L. SCOTT,b THOMAS BOYD,c GUILLERMO GARCIA-MANEROd
`aDivision of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA;
`bFred Hutchinson Cancer Research Center, Seattle, Washington, USA; cNorth Star Lodge Cancer Center, Yakima, Washington, USA;
`dDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
`Disclosures of potential conflicts of interest may be found at the end of this article.
`
`Key Words. Leukemia x Myeloid x Acute x Myelodysplastic syndromes x Azacitidine
`
`ABSTRACT
`
`The myelodysplastic syndromes (MDS) comprise a heteroge-
`neous group of clonal myeloid malignancies characterized by
`multilineage cytopenias, recurrent cytogenetic abnormali-
`ties, and risk of progression to acute myeloid leukemia (AML).
`AML, which can occur de novo as well as secondary to MDS, is
`characterized by malignant clones of myeloid lineage in the
`bone marrow and peripheral blood, with dissemination into
`tissues. The cytidine nucleoside analog and epigenetic
`modifier azacitidine is approved in the U.S. for the treatment of
`all French-American-British subtypes of MDS and in many
`countries for the treatment of AML with 20%–30% blasts and
`multilineage dysplasia according to the World Health Organi-
`zation classification. Benefits of azacitidine treatment of
`patients with AML with .30% blasts have also been shown
`in a recent phase III trial. Oral administration of azacitidine may
`
`enhance patient convenience, eliminate injection-site reac-
`tions, allow for alternative dosing and scheduling, and enable
`long-term treatment. Phase I studies with oral azacitidine
`(CC-486) have shown biological activity, clinical responses,
`and tolerability in patients with MDS and AML. Extended
`dosing schedules of oral azacitidine (for 14 or 21 days of
`28-day cycles) are currently under investigation as frontline
`therapy in patients with lower risk MDS, as maintenance
`therapy for patients with AML not eligible for stem cell
`transplant, and as maintenance therapy for patients with
`MDS or AML following stem cell transplant. This review
`presents clinical data supporting the use of injectable
`azacitidine in MDS and AML and examines the rationale for
`and results of the clinical development of oral azacitidine.
`The Oncologist 2015;20:1404–1412
`
`Implications for Practice: Injectable azacitidine can prolong survival, reduce transfusions, and improve quality of life compared
`with conventional care regimens in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
`An oral formulation improves convenience and eliminates injection-site reactions but also enables testing of novel, longer term,
`low-dose schedules that may enhance therapeutic activity of azacitidine by increasing exposure to cycling malignant cells. In early
`phase trials, oral azacitidine (CC-486) in extended dosing regimens was biologically and clinically active in patients with MDS and
`AML. Oral azacitidine is being further evaluated in an ongoing phase III program.
`
`INTRODUCTION
`
`The myelodysplastic syndromes (MDS) are a heterogeneous
`group of clonal myeloid malignancies arising from a stem cell
`source and characterized by multiple genetic abnormalities and
`subclonal architectures [1–4]. There is considerable heteroge-
`neity in genetic mutations among patients with MDS that may
`explain the diversity of clinical presentations that differ in the
`numbers and depths of cytopenias, risks toward progression
`to acute myeloid leukemia (AML), responses to treatment, and
`survival times [5–8]. Gene mutations affecting epigenetic
`chemical modifications, such as mutations in TET2 and DNMT3A,
`are among the most common in MDS [9–11].
`
`MDS is primarily a disease of older adults, and advanced
`age at diagnosis is associated with decreased overall survival
`(OS) [12, 13]. The reported incidence rate of MDS overall is
`5.70 per 100,000 persons in the U.S. [14] and 1.82 per 100,000
`persons in Europe [15]. In patients aged $65 years, the
`incidence rate is higher, at 12.97 per 100,000 persons or higher
`in the U.S. [14] and 5 per 100,000 persons or higher in Europe
`[15]; however, these are likely underestimates of true in-
`cidence. Large numbers of MDS cases go unreported by state
`cancer registries due to difficulties in disease diagnosis, under-
`appreciation of MDS as a malignancy, under-reporting by
`
`Correspondence: Christopher R. Cogle, M.D., University of Florida, Medicine/Hematology and Oncology, 1600 SW Archer Road, Box 100278,
`Gainesville, Florida 32610, USA. Telephone: 352-273-7493; E-Mail: christopher.cogle@medicine.ufl.edu Received April 22, 2015; accepted for
`publication August 21, 2015; published Online First on October 13, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/
`10.1634/theoncologist.2015-0165
`CELGENE 2073
`APOTEX v. CELGENE
`IPR2023-00512
`©AlphaMed Press 2015
`
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`Cogle, Scott, Boyd et al.
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`1405
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`outpatient clinics, changing guidelines for defining MDS,
`and lack of resources [15–18]. When accounting for the
`uncaptured cases, MDS is one of the most common he-
`matologic malignancies.
`The current MDS treatment paradigm is based on prog-
`nostic risk assessment [8, 13, 19, 20]. Patients at lower risk for
`early death or evolution to AML are treated with agents
`to primarily reduce or eliminate blood transfusions and to
`improve quality of life (QOL), whereas patients at higher risk for
`early death or AML progression are generally treated with
`more intensive therapies aiming to induce disease remission
`and lengthen survival [8, 21, 22].
`AML is a multigenetic malignancy characterized by ma-
`lignant clones and subclones of myeloid lineage in the bone
`marrow and peripheral blood, with dissemination into tissues
`[23–25]. It is the most common acute leukemia in adults [23],
`with an estimated incidence rate of 4.06 per 100,000 persons in
`the U.S. [14] and 3.62 per 100,000 persons in Europe [15].
`Similar to MDS, AML incidence increases with advancing age,
`with incidence rates in the U.S. and Europe of 10 per 100,000
`persons or higher for patients aged $65 years [14, 15]. AML
`has a poor prognosis, particularly in older patients and those
`with adverse disease characteristics (e.g., secondary AML,
`complex cytogenetic abnormalities, or FLT3 mutation) [26–30].
`Three-quarters of patients with AML die within 5 years of
`diagnosis, and survival decreases with increasing age [26].
`Disease characteristics and performance status are closely
`considered when evaluating patient eligibility for treatment
`with intensive therapies (e.g., induction followed by consol-
`idation chemotherapy or stem cell transplant [SCT]) versus
`low-intensity options such as injectable azacitidine or de-
`citabine [27–29, 31–33].
`
`AZACITIDINE FOR INJECTION
`Azacitidine is a cytidine nucleoside analog with a substitution
`of the carbon at position 5 with nitrogen that prevents
`methylation by covalently binding DNA methyltransferases
`[32, 34] (Fig. 1). The epigenetic modifier azacitidine is in-
`corporated into DNA and RNA [34, 35]. Antileukemic effects of
`azacitidine are thought to include direct cytotoxicity from
`inhibition of protein synthesis and DNA damage and re-
`expression of aberrantly silenced tumor suppressor genes due
`to DNA hypomethylation [32, 34–37]. Azacitidine is approved
`in the U.S. for the treatment of all French-American-British
`(FAB) subtypes of MDS [32] and is approved in many countries
`(e.g., European Union, Australia, Republic of Korea, Taiwan)
`for patients not eligible for SCT with intermediate-2 (Int-2)
`and high-risk MDS according to the International Prognostic
`Scoring System (IPSS) and patients with AML with 20%–30%
`blasts and multilineage dysplasia according to World Health
`Organization (WHO) classification [38]. Azacitidine is also
`approved by the U.S. Food and Drug Administration for chronic
`myelomonocytic leukemia (CMML) and by the European
`Medicines Agency for “CMML with 10%–29% marrow blasts
`without myeloproliferative disorder.”
`The approved dosing of azacitidine is 75 mg/m2 per day on
`days 1–7 of 28-day cycles [32, 38]. Alternative dosing schedules
`have been explored, including 5-day and 5-2-2-day dosing
`regimens to avoid weekend administration [39–41], but are
`not approved. Although hematologic improvement (HI) with
`
`Figure 1. Structure of azacitidine. Substitution of carbon at
`position 5 with nitrogen prevents DNA methylation [34].
`
`5-day dosing in patients with MDS is compelling, clinicians
`should not extrapolate data for injectable azacitidine based on
`the approved 7-day dosing regimen, especially in patients with
`higher risk MDS. The 5-day and 5-2-2-day alternate regimens
`require more rigorous testing.
`Initial approval was based primarily on results from two
`phase III studies. CALGB-9221 was a phase III multicenter
`randomized controlled trial of subcutaneous (s.c.) azacitidine
`(75 mg/m2 per day on days 1–7 in 28-day cycles; n 5 99) versus
`best supportive care (BSC; n 5 92) in patients with all FAB
`MDS subtypes [42]. In this trial, the overall response rate (ORR)
`with azacitidine was significantly improved versus BSC (60%
`vs. 5%, p , .0001) [42]. Response rates to azacitidine were
`comparable in patients with lower and higher risk MDS [42].
`Myelosuppression was the most common toxicity, and adverse
`events (AEs) were generally transient, resolving before the
`next treatment cycle [42].
`AZA-001 was a phase III multicenter randomized con-
`trolled trial of s.c. azacitidine (75 mg/m2 per day on days 1–7
`in 28-day cycles) versus conventional care regimens (CCR:
`BSC, low-dose cytarabine [LDAC], or intensive chemotherapy
`[IC]) in patients with IPSS-defined higher risk (Int-2 or high-
`risk) MDS (N 5 358) [43]. Azacitidine treatment resulted
`in significantly longer OS (median: 24.5 vs. 15 months;
`p 5 .0001), higher rates of hematologic response (p 5 .0001)
`and HI (p , .0001) assessed by International Working Group
`(IWG) 2000 criteria [21], and longer durations of response
`(median: 13.6 vs. 5.2 months; p 5 .0002) versus CCR [43].
`Azacitidine prolonged OS compared with CCR regardless of
`IPSS cytogenetic risk group [43].
`A multivariate analysis of AZA-001 showed that achieve-
`ment of hematologic response or HI (IWG 2000 criteria [21])
`was associated with improved OS with azacitidine treatment
`[44], and patients who achieved a hematologic response to
`azacitidine had significantly prolonged OS and reduced risk of
`death versus patients who achieved a response to CCR [44]. In
`addition, stable disease or achievement of complete re-
`sponse (CR), marrow CR (mCR), partial response (PR) or HI
`(IWG 2003 [45] and 2006 criteria [22]) with alternative dosing
`schedules of azacitidine has been shown to significantly
`reduce the risk of death versus disease progression (p , .001)
`[39].
`In the AZA-001 study, the median time to first response
`with azacitidine was 2 cycles (range: 1–16), with 91% of
`responding patients achieving first response within 6 cycles
`and all but 1 achieving first response by cycle 12 [46].
`Continued treatment improved response quality in 48% of
`patients [46], with a median of 3 cycles from first to best
`
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`1406
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`Oral Azacitidine (CC-486) for MDS and AML
`
`response. By cycle 12, 92% of responding patients achieved
`their best response. Based on this experience, some cli-
`nicians have advised administering at least six cycles of
`azacitidine [47], and the National Comprehensive Cancer
`Network guidelines for MDS recommend at least four to six
`cycles before assessing for treatment failure [8]. Assess-
`ments for treatment failure include evaluation of peripheral
`blood, bone marrow aspiration or biopsy, cytogenetic testing,
`and genetic studies. If response is achieved, azacitidine is
`typically continued until disease progression, unacceptable
`toxicity, or definitive therapy with SCT. If no response is
`achieved after six cycles of azacitidine, then prognosis is
`generally poor [48, 49]. Small case series have shown that
`decitabine treatment after azacitidine failure yields modest
`responses (ORR: 0%–28%) that are generally short lived [48,
`50–53]; however, this is not currently standard treatment
`practice. The current standard of care for patients with MDS
`who have not responded after at least six cycles of azacitidine
`treatment is to consider clinical trials [48, 49] or proceed
`with SCT [51].
`The most common grade 3/4 AEs with azacitidine treatment
`in patients with MDS in the AZA-001 trial were cytopenias [43],
`and most were transient and resolved during therapy [54].
`The highest rates of AEs reported with azacitidine in AZA-001
`occurred during cycles 1–2, with decreased frequency with
`continued treatment. Median duration of hematologic AEs
`was 14–16 days.
`Azacitidine has also been investigated for the treatment of
`patients with AML. In a subanalysis of AZA-001 of low-blast-
`count AML (20%–30% blasts; n 5 113), the 2-year OS rate for
`patients treated with azacitidine was 50%, and the median OS
`was 24.5 months compared with 16.0 months for patients
`treated with CCR (p 5 .005) and 16.4 months for patients not
`preselected to receive IC (BSC or LDAC; p 5 .004) [31]. Survival
`benefits with azacitidine may not require CR because CR rates
`were similar for azacitidine versus CCR (18% vs. 16%; p 5 .8),
`whereas rates of red blood cell transfusion independence
`(RBC-TI) were significantly higher with azacitidine (41% vs.
`18%; p 5 .04) [31].
`Recently, the global phase III randomized open-label AZA-
`AML-001 study of azacitidine (75 mg/m2 per day on days 1–7 in
`28-day cycles) versus CCR extended these findings in patients
`aged $65 years with newly diagnosed AML with .30% blasts
`(N 5 488) [55]. Azacitidine treatment demonstrated a clinically
`meaningful improvement in median OS of 10.4 months versus
`6.5 months with CCR (p 5 .1009). Azacitidine significantly
`improved 1-year survival: 46.5% versus 34.2% with CCR,
`a 12.3% difference (95% confidence interval: 3.5%–21.0%). In
`patients who did not achieve CR (IWG 2003 criteria [45]),
`median OS was prolonged from 6.9 months with azacitidine
`versus 4.2 months with CCR (p 5 .0170).
`The safety profile of azacitidine for the treatment of AML
`was consistent with previous observations [31, 43, 55]. The
`most common grade 3/4 hematologic AEs were cytopenias,
`which occurred more frequently during earlier treatment
`cycles [31, 55].
`
`RATIONALE FOR ORAL ADMINISTRATION OF AZACITIDINE
`Oral administration of azacitidine avoids injection-site re-
`actions and may enhance patient convenience compared
`
`©AlphaMed Press 2015
`
`with an injectable formulation [56, 57]. It allows for the
`evaluation of alternative doses and schedules,
`including
`extended dosing schedules. Early trials with injectable
`azacitidine showed decreased toxicity and increased efficacy
`at lower doses over several days versus a single higher dose
`[58–61]. In addition, in patients with MDS, continued treat-
`ment with s.c. azacitidine was shown to improve response
`quality [46].
`The benefits of extended azacitidine dosing and long-
`term treatment are likely related to the impact on hypo-
`methylation. Hypomethylating effects are cell cycle dependent
`[62], and serial cycles of DNA replication are needed to in-
`duce hypomethylation [63, 64]. Extensive demethylation
`requires prolonged drug exposure [63]. Due to the short
`plasma half-life of azacitidine [34, 38] and cell cycle-restricted
`DNA incorporation [62], extended dosing schedules enabled
`by oral administration have the potential to enhance clinical
`activity of azacitidine by increasing exposure to cycling ma-
`lignant cells.
`
`CLINICAL INVESTIGATIONS WITH ORAL AZACITIDINE
`(CC-486)
`
`Pilot Study of Oral Azacitidine
`The bioavailability and safety of oral azacitidine was initially
`studied in an open-label, pharmacokinetic (PK), and feasibility
`pilot study of patients with MDS, leukemia, or solid tumors
`[56]. Four patients received 60- or 80-mg single doses of oral
`azacitidine. All four patients had measurable plasma concen-
`trations, allowing for comparison with historical s.c. azacitidine
`PK data. The 80-mg oral azacitidine dose had mean bio-
`availability of 17% of that of s.c. azacitidine [56, 65]. No severe
`drug-related toxicities were observed, and results from this
`pilot study led to the development of a phase I study of oral
`azacitidine.
`
`Dose-Finding Study of Oral Azacitidine
`Because of the demonstrated safety and efficacy of inject-
`able azacitidine in patients with MDS and AML [32, 38], the
`oral azacitidine phase I program initially focused on these
`patient populations. AZA PH US 2007 CL 005 was a phase I
`open-label dose-escalation study that evaluated the safety,
`PK, and pharmacodynamics (PD) of oral azacitidine in
`patients with MDS, CMML, or AML [66]. This trial had two
`parts (Fig. 2) [57, 66]: In part 1, 41 patients (71% MDS, 10%
`CMML, 20% AML) received 7-day dosing of s.c. azacitidine
`for a single 28-day cycle, followed by oral azacitidine for
`7 days of 28-day cycles (cycles 2 and beyond; Table 1). Dur-
`ing cycles 1 and 2, PK (days 1 and 7) and PD (days 1, 3, 8, 15,
`22, and 28) profiles were assessed.
`The maximum tolerated dose (MTD) of oral azacitidine
`was 480 mg once daily (QD) for 7 days [66]. Dose-limiting
`toxicities (DLTs) were reported in 2 of 3 patients treated
`with oral azacitidine 600 mg QD for 7 days (1 grade 3
`diarrhea and 1 grade 4 diarrhea despite medical interven-
`tion) with no other DLTs observed. Gastrointestinal AEs
`were the most common nonhematologic AEs and were
`primarily grade 1/2 and manageable [66] with gastric
`acid-reducing agents, antiemetics, and antidiarrheal
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`Cogle, Scott, Boyd et al.
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`Figure 2. Trial schema for AZA PH US 2007 CL 005, the phase I trial of oral azacitidine (CC-486) in patients with myelodysplastic syndromes,
`acute myeloid leukemia, and chronic myelomonocytic leukemia [67].
`Abbreviations: BID, twice daily; QD, once daily; s.c., subcutaneous.
`
`Table 1. Summary of clinical results from the expanded phase I study of oral azacitidine (CC-486) in patients with MDS and AML [66,
`69, 71]
`
`Variable
`
`Dosing
`
`Patient
`population,
`n (%)
`
`Key safety
`data
`
`Key efficacy
`data
`
`Dose-finding study in MDS,
`CMML, and AML [66]
`Cycle 1: s.c. AZA 75 mg/m2
`QD 3 7 days
`Cycles $2: CC-486 120–600 mg
`QD 3 7 days
`MDS: 29 (71)
`CMML: 4 (10)
`AML: 8 (20)
`
`MTD: 480 mg QD 3 7 days
`DLTs: grade 3 or 4 diarrhea
`Most common grade 3/4 AEs:
`febrile neutropenia (20%),
`diarrhea (12%)
`First-line patients: 73% ORR,
`56% any HI, 33% mCR
`Previously-treated patients:
`35% ORR, 38% any HI, 67% mCR
`
`Extended-dosing in patients
`with lower risk MDS [69]
`CC-486 300 mg QD 3 14 or 21
`days
`
`IPSS low-risk MDS: 15 (28)
`IPSS Int-1 risk MDS: 38 (72)
`RBC-TD: 30 (57)
`Platelet-TD: 4 (8)
`Most common AEs (any grade)
`were gastrointestinal in origin
`Most common grade 3/4 AEs:
`neutropenia (13%)
`8 patients D/C due to AEs
`300 mg QD 3 14 days: 42%
`ORR, 27% any HI, 20% RBC-TI
`sustained 84 days
`300 mg QD 3 21 days: 37%
`ORR, 30% any HI, 33% RBC-TI
`sustained 84 days
`
`CC-486 300 mg QD or 200 mg
`BID 3 14 or 21 days
`
`Subset analysis: 7-day and extended dosing in patients
`with AML [71]
`Cycle 1: s.c. AZA 75 mg/m2
`QD 3 7 days
`Cycles $2: CC-486
`120–600 mg QD 3 7 days
`De novo AML: 13 (57)
`Secondary AML: 10 (43)
`RBC-TD: 14 (61)
`Platelet-TD: 8 (35)
`Most common AEs (any grade) were gastrointestinal in
`origin
`Most common grade 3/4 AEs: febrile neutropenia (35%),
`pneumonia (17%), syncope (17%), nausea (13%)
`6 patients D/C due to AEs
`38% ORR, 13% HI, 25%
`mCR, 13% mPR, 25%
`RBC-TIa
`
`47% ORR, 27% HI, 40% RBC-
`TI, 17% platelet-TI, 33%
`mPRb
`
`aEight evaluable patients for each, except four evaluable patients for RBC-TI.
`bFifteen evaluable patients for ORR and HI, 10 evaluable patients for RBC-TI, 6 evaluable patients for platelet-TI, and 9 evaluable patients for mPR.
`Abbreviations: AE, adverse event; AML, acute myeloid leukemia; AZA, azacitidine; BID, twice daily; CMML, chronic myelomonocytic leukemia; D/C,
`discontinued; DLT, dose-limiting toxicity; HI, hematologic improvement; Int-1, intermediate-1; IPSS, International Prognostic Scoring System; mCR,
`marrow complete response; mPR, marrow partial response; MDS, myelodysplastic syndromes; MTD, maximum tolerated dose; ORR, overall response
`rate; QD, once daily; RBC, red blood cell; s.c., subcutaneous; TD, transfusion dependence; TI, transfusion independence.
`
`medications [67]. The most common ($10%) grade 3/4 AEs
`were febrile neutropenia (20%), diarrhea (12%), and fatigue
`(10%). Notably, 4 of 8 patients with grade 3/4 febrile
`neutropenia had an absolute neutrophil count #500/mL at
`baseline [66]. Grade 3/4 nausea and vomiting were each
`reported in 7% of patients. Three patients discontinued due
`to an AE.The investigators of part 1 of the trial concluded that
`7-day oral azacitidine dosing was clinically active (Tables 1,
`2). Responses in patients treated with oral azacitidine as
`first-line therapy included a 73% ORR, 56% with any HI, and
`33% with mCR. Notably, responses were also achieved in
`previously treated patients: 35% ORR, 38% any HI, and 67%
`mCR [66].
`
`Extended Dosing of Oral Azacitidine in Patients With
`Lower Risk MDS
`Approximately two-thirds of newly diagnosed patients with
`MDS present with lower risk disease (IPSS low or Int-1 risk) [19].
`Lower risk patients are generally viewed as having favorable
`prognoses, with a median OS of 5.7 years for low-risk and 3.5
`years for Int-1 risk disease [19]. However, a subgroup within the
`lower risk MDS population actually has a worse prognosis, with
`shortened survival time and clonal evolution to AML [68].
`Approximately one-third of patients with lower risk MDS were
`shown to have poor prognostic features, with a median OS of
`only 1.2 years [68], the same as that reported for patients with
`Int-2 risk disease [19]. Severe anemia and thrombocytopenia
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`Oral Azacitidine (CC-486) for MDS and AML
`
`Table 2. Hematologic responses in patients with MDS, CMML,
`or AML treated with 1 cycle of s.c. azacitidine followed by oral
`azacitidine (CC-486) in 7-day dosing schedules [66]
`
`Table 3. Hematologic responses in patients with IPSS
`lower-risk MDS treated with oral azacitidine (CC-486) in
`extended dosing regimens [69]
`
`First-line-treated
`patients
`
`Previously
`treated
`patientsa
`
`Total
`
`Response
`
`300 mg QD 3
`14 days
`
`300 mg QD 3
`21 days
`
`Total
`
`EP, n R, n (%)
`
`EP, n R, n (%)
`
`EP, n R, n (%)
`
`Response
`
`Overall
`responseb
`CRc
`Any HI
`HI-E
`HI-P
`HI-N
`mCRd
`TI
`
`RBC
`Platelet
`
`EP, n
`
`R, n (%)
`
`EP, n R, n (%) EP, n R, n (%)
`
`15
`
`15
`9
`4
`6
`7
`6
`3
`3
`0
`
`11 (73)
`
`6 (40)
`5 (56)
`2 (50)
`2 (33)
`2 (29)
`2 (33)
`1 (33)
`1 (33)
`0
`
`17
`
`17
`16
`10
`14
`10
`9
`5
`3
`4
`
`6 (35)
`
`0
`6 (38)
`3 (30)
`5 (36)
`0
`6 (67)
`0
`0
`0
`
`32
`
`32
`25
`14
`20
`17
`15
`8
`6
`4
`
`17 (53)
`
`6 (19)
`11 (44)
`5 (36)
`7 (35)
`2 (12)
`8 (53)e
`1 (13)
`1 (17)
`0
`
`aIncludes erythropoiesis-stimulating agents, chemotherapy,
`hypomethylating agents, and investigational and/or other agents.
`bDoes not include patients with mCR only.
`cPatients achieving CR were not included in other categories.
`dTwo patients with mCR in the first-line group also had HI (HI-P [n 5 1]
`and HI-E and HI-N [n 5 1]) and 1 patient with mCR in the previously
`treated group also had HI (both HI-E and HI-P); these patients were
`included in the mCR and HI categories.
`eIn the 8 patients with mCR, the response began in cycle 1 of s.c. dosing
`(n 5 4) or very early in cycle 2 of CC-486 dosing (n 5 4); therefore, a single
`cycle of azacitidine s.c. likely contributed to the response.
`Abbreviations: AML, acute myeloid leukemia; CMML, chronic
`myelomonocytic leukemia; CR, complete response; E, erythroid; EP,
`evaluable patients; HI, hematologic improvement; mCR, marrow
`complete response; MDS, myelodysplastic syndromes; N, neutrophil; P,
`platelet; R, responders; RBC, red blood cell; s.c., subcutaneous; TI,
`transfusion independence.
`
`are common poor prognostic features in patients with lower
`risk MDS [19, 68].
`Although part 2 of AZA PH US 2007 CL 005 was initially
`designed to investigate extended dosing schedules of oral
`azacitidine (300 mg QD or 200 mg twice daily [BID] for 14 or
`21 days per 28-day cycle) in patients with MDS, CMML,
`or AML (Fig. 2) [57], because of the new prognostic in-
`formation about lower risk MDS, the trial was amended to
`focus on patients with lower risk MDS with poor prognostic
`features (low platelet count and/or low hemoglobin and/or
`RBC transfusion dependence [TD] and/or platelet TD). Part
`2 included 53 patients with IPSS low-risk (28%) or Int-1 risk
`(72%) MDS; most patients were RBC-TD [69] (Table 1).
`Extended dosing with oral azacitidine (300 mg QD for 14 or
`21 days of repeated 28-day cycles) resulted in response (IWG
`2006 criteria [22]) in more than one-third of patients with
`lower risk MDS (Tables 1, 3), and the rate of RBC-TI increased
`from baseline with increasing cycles of treatment. The most
`common nonhematologic AEs were gastrointestinal, and
`there were no unexpected AEs based on the known safety
`profile of injectable azacitidine [32, 38, 69]. Eight patients
`(four in each arm) discontinued due to an AE. The most
`common grade 3/4 AEs ($10%) were neutropenia (8% and
`19%, respectively), pneumonia (15% and 4%), anemia (12%
`
`©AlphaMed Press 2015
`
`26
`
`26
`23
`17
`10
`
`15
`
`15
`
`11 (42)
`
`27
`
`10 (37)
`
`53
`
`21 (40)
`
`7 (27)
`4 (17)
`4 (24)
`3 (30)
`
`27
`25
`15
`6
`
`8 (30)
`6 (24)
`3 (20)
`0
`
`53
`48
`32
`16
`
`15 (28)
`10 (21)
`7 (22)
`3 (19)
`
`8 (54)
`
`15
`
`6 (40)
`
`30
`
`14 (47)
`
`3 (20)
`
`15
`
`5 (33)
`
`30
`
`8 (27)
`
`Overall
`responsea
`Any HI
`HI-E
`HI-P
`HI-N
`RBC-TI
`Sustained
`56 days
`Sustained
`84 days
`aComplete response, partial response, any HI, and TI by International
`Working Group 2006 criteria.
`Abbreviations: E, erythroid; EP, evaluable patients; HI, hematologic
`improvement; IPSS, International Prognostic Scoring System; MDS,
`myelodysplastic syndromes; N, neutrophil; P, platelet; QD, once daily; R,
`responders; RBC, red blood cell; TI, transfusion independence.
`
`and 7%), thrombocytopenia (12% and 4%), diarrhea (8% and
`11%), and febrile neutropenia (4% and 11%) [69].
`
`Preliminary data in patients with MDS, CMML, and
`AML suggest that oral azacitidine in extended dosing
`regimens may be associated with significant DNA
`hypomethylation through cycle end; however, this
`correlation must be confirmed in a larger patient
`population.
`
`Oral Azacitidine in Patients With AML
`IC is not appropriate for all patients with AML, and eligibility is
`influenced by age, performance status, comorbidities, and
`preexisting MDS [27–29, 70]. There is an unmet need for
`effective treatment options for patients who are ineligible or
`unwilling to receive IC [29]. Data from patients with AML in
`parts 1 and 2 of AZA PH US 2007 CL 005 were pooled (n 5 23;
`13 patients with de novo disease and 10 secondary to MDS)
`to assess response (IWG 2003 [45] and 2006 criteria [22]) to
`oral azacitidine [71] (Table 1). At baseline, 52% and 35% of
`patients had intermediate and unfavorable cytogenetics,
`respectively; 61% and 35% of patients were RBC-TD and
`platelet-TD, respectively; and 57% of patients were relapsed
`or refractory to prior treatment [71]. Of 8 patients treated
`with oral azacitidine at 120–600 mg QD for 7 days, 3 achieved
`a response (38%), including 1 with HI, 1 with RBC-TI, 2 with
`mCR, and 1 with marrow PR. Of 15 patients treated with oral
`azacitidine in extended dosing schedules (300 mg QD or 200
`mg BID for 14 or 21 days), 7 achieved a response (47%),
`including 4 with HI, 4 with RBC-TI, 1 with platelet-TI, and 3
`
`TheOncologist®
`
`

`

`Cogle, Scott, Boyd et al.
`
`1409
`
`with marrow PR [71]. No patients with AML achieved CR or
`PR. The most common AEs were gastrointestinal, and 6
`patients discontinued due to an AE.The most common grade
`3/4 AEs (7-day and extended dosing regimens combined,
`$10%) were febrile neutropenia (35%), pneumonia (17%),
`syncope (17%), and nausea (13%) [71].
`
`PK and PD of Oral Azacitidine
`For patients with MDS, CMML, or AML in the AZA PH US 2007
`CL 005 study, the maximum concentration (Cmax) of oral
`azacitidine occurred at 1.0 hour (range: 0.3–3.6 hours) after
`dosing, with a mean half-life of 0.6 hour [66]. In patients with
`lower risk MDS, oral azacitidine 300 mg QD for 14 or 21 days
`had a mean exposure per cycle of 38% and 56%, respectively, of
`that of s.c. azacitidine 75 mg/m2 QD for 7 days (the approved
`dosing regimen) [72]. Exposure generally increased with dose,
`and no drug accumulation was observed following multiple
`administrations.
`In patients evaluated for DNA methylation, 7-day dosing
`with s.c. azacitidine or oral azacitidine resulted in maximal
`decreases in highly methylated DNA loci at day 15 that
`returned to near-baseline levels by cycle end [66, 72].
`Preliminary data in patients with MDS, CMML, and AML
`suggest that oral azacitidine in extended dosing regimens
`may be associated with significant DNA hypomethylation
`through cycle end [72]; however, this correlation must be
`confirmed in a larger patient population. The use of hypo-
`methylation to predict response to hypomethylating agents
`remains controversial [73]. Other potential biomarkers for
`azacitidine response actively being investigated include
`mutations in TET2 and IDH1/2, which are involved in DNA
`methylation [74–76].
`Two phase I studies in patients with MDS, CMML, or AML
`evaluated the PK of immediate-release, enteric-coated, and
`capsule formulations of oral azacitidine and the effect of
`food and gastric pH alterations with concomitant admin-
`istration of proton-pump inhibitors (PPIs) on PK parameters
`(n 5 47) [67]. An immediate-release formulation was
`chosen for upcoming studies because it had the greatest
`mean oral bioavailability relative to s.c. azacitidine. PK
`parameters were similar under fasting and postprandial
`conditions; Cmax was delayed by ∼0.5 hour, and time to
`reach Cmax was significantly delayed from 1.0 hour to 2.0
`hours (p , .05) under postprandial conditions. Coadmin-
`istration of the PPI omeprazole did not significantly affect
`PK parameters [67]. The lack of food effect or need for dose
`adjustments with PPIs allows for convenient administration
`of oral azacitidine.
`
`KEY ONGOING OR PLANNED TRIALS OF ORAL AZACITIDINE
`(CC-486) IN MDS AND AML
`Promising results of the expanded phase I program for oral
`azacitidine in MDS and AML led to the initiation of several
`additional studies, including two ongoing phase III trials.
`
`QUAZAR Lower Risk MDS (AZA-MDS-003) Study
`No currently approved therapies have demonstrated signif-
`icantly prolonged survival in patients with lower risk MDS
`with thrombocytopenia and TD anemia. An alternative-
`dosing study of injectable azacitidine in patients with MDS
`
`(most with lower-risk disease) suggested that prolonged
`exposure to a lower dose of azacitidine may benefit patients
`with multiple cytopenias [40]. The phase III QUAZAR Lower
`Risk MDS (AZA-MDS-003) study (ClinicalTrials.gov identifier
`NCT01566695) has a planned enrollment of 386 patients
`with RBC-TD anemia (average of $2 RBC units per 28 days,
`confirmed for $84 days immediately preceding randomiza-
`tion) and thrombocytopenia (2 platelet counts #75 3 109/L
`$21 days apart) due to IPSS lower risk MDS [77]. This study
`will assess the efficacy of oral azacitidine (300 mg QD for 21
`days of 28-day cycles) plus BSC versus placebo plus BSC in
`these patients. Enrolled patients must have MDS (WHO 2008
`classification; excludes secondary MDS unless patients
`received their last dose of prior antineoplastic therapy $24
`weeks prior to randomization), have Eastern Cooperative
`Oncology Group (ECOG) performance status 0–2, have no prior
`treatment with hypomethylating agents, have no prior
`treatment with lenalidomide within 24 weeks prior to
`randomization, and be SCT ineligible with no prior transplant.
`The primary outcome of interest is RBC-TI, with key secondary
`outcomes of survival, progression to AML, platelet-TI, he-
`matologic response, platelet HI, erythroid HI, safety, health-
`related QOL (HRQOL), and health care resource utilization
`[77].
`
`An alternative-dosing study of injectable azacitidine in
`patients with MDS (most with lower risk disease)
`suggested that prolonged exposure to a lower dose
`of azacitidine may benefit patients with multiple
`cytopenias.
`
`QUAZAR AML Maintenance (CC-486-AML-001) Study
`Most patients with AML currently will relapse following
`achievement of remission with IC, and it has been shown that
`duration of first remission is predictive of response to salvage
`therapies and long-term outcomes [78]. To improve out-
`comes, there is a need to prolong remissions, particularly
`in patients unable or unwilling to receive SCT. The phase
`III