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Journal of Clinical Oncology logoLink to Journal of Clinical Oncology
. 2009 Nov 23;28(2):285–291. doi: 10.1200/JCO.2009.25.0209

Phase I Clinical and Pharmacokinetic Study of Oral Sapacitabine in Patients With Acute Leukemia and Myelodysplastic Syndrome

Hagop Kantarjian 1,, Guillermo Garcia-Manero 1, Susan O'Brien 1, Stefan Faderl 1, Farhad Ravandi 1, Robert Westwood 1, Simon R Green 1, Judy H Chiao 1, Patricia A Boone 1, Jorge Cortes 1, William Plunkett 1
PMCID: PMC3340938  PMID: 19933907

Abstract

Purpose

Sapacitabine is an oral deoxycytidine nucleoside analog with a unique mechanism of action that is different from cytarabine.

Patients and Methods

To define the dose-limiting toxicities (DLT) and maximum-tolerated dose (MTD) of sapacitabine given orally twice daily for 7 days every 3 to 4 weeks, or twice daily for 3 days for 2 weeks (days 1 through 3 and days 8 through 10) every 3 to 4 weeks, in refractory-relapse acute leukemia and myelodysplastic syndrome (MDS). A total of 47 patients were treated in the phase I study that used a classical 3 + 3 design. Sapacitabine was escalated from 75 to 375 mg twice daily for 7 days (n = 35) and from 375 to 475 mg twice daily for 3 days on days 1 through 3 and days 8 through 10.

Results

The DLTs with both schedules were gastrointestinal. The MTDs were 375 mg twice daily for 7 days and 425 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. The recommended phase II single-agent dose schedules were 325 mg twice daily for 7 days and 425 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. Responses were observed in 13 patients (28%); four were complete responses, and nine were marrow complete responses.

Conclusion

Sapacitabine is a new, safely administered, oral deoxycytidine analog that has encouraging activity in leukemia and MDS. Phase II studies are ongoing.

INTRODUCTION

Despite recent progress in acute myeloid leukemia (AML), modern combination-chemotherapy regimens result in complete response (CR) rates of 40% to 70% and long-term event-free survival rates of only 20% to 50%, depending on patient ages, comorbid conditions, and leukemia karyotypes.1,2 Similar results are noted in adult acute lymphocytic leukemia (ALL), for which long-term event-free survival rates are only 30% to 40%.3,4 In myelodysplastic syndrome (MDS), several recent studies with azacitidine, decitabine, and lenalidomide have shown encouraging results.57 However, the median survival remains short, in the range of 2 to 3 years. These findings indicate the need to discover new strategies that might improve the outcomes in leukemia and MDS. Nucleoside analogs represent a major group of antitumor cytotoxic agents. Several agents in this class have shown activity in leukemia and MDS. These include deoxyadenosine analogs, such as fludarabine, deoxycoformycin, chlorodeoxyadenosine, and clofarabine,8,9 or cytosine nucleoside analogs, such as cytarabine,1,2 azacitidine, and decitabine.

2′-C-Cyano-2′-deoxy-β-D-arabino-pentofur anosylcytosine (CNDAC) is a rationally designed analog of deoxycytidine with a unique mechanism of action.10 On phosphorylation to the triphosphate and incorporation into DNA, replication is not inhibited at cytotoxic concentrations, unlike cytarabine, fludarabine, or clofarabine. Rather, after additional polymerization, the strong electrophilic properties of the cyano group cause a rearrangement of the nucleotide to a form that lacks a 3′-hydroxyl moiety.11,12 This results in a single-strand break that is repaired to only a small extent by the transcription-coupled nucleotide excision pathway.13 On a subsequent round of DNA replication, unrepaired single-strand breaks are converted to double-strand breaks, which leads to cell death.14

During the discovery phase, many derivatives of CNDAC were studied. Sapacitabine (previously designated CS-682), an N4-palmitoyl derivative of CNDAC, was chosen for clinical development because of its broad range of antitumor activity in preclinical studies.11 The palmitoyl side chain on CNDAC allows for improved oral absorption of sapacitabine and protects the N4 amino group from deamination, which is a major route of inactivation for this class of molecule.11 After oral administration, sapacitabine is converted to CNDAC by amidases and esterases in the gastrointestinal tract, plasma, and liver, and it becomes bioavailable15,16 at concentrations that reduce clonogenic survival of cells in vitro.13

CNDAC has shown positive preclinical activity in a broad spectrum of human tumor cells, including leukemic cell lines. The phase I studies of single-agent sapacitabine in solid tumors identified myelosuppression as the dose-limiting toxicity (DLT).15,16 This is generally a favorable feature for agents that ultimately demonstrate activity in leukemia at three-fold to 20-fold of the maximum-tolerated doses (MTDs) observed in solid tumors. These findings, together with the oral bioavailability of sapacitabine, led to the interest in developing it for hematologic malignancies.

PATIENTS AND METHODS

Patient Eligibility

Adults with relapsed or refractory acute leukemia, MDS, or untreated disease who were unwilling to proceed with conventional systemic chemotherapy were eligible. Other eligibility criteria included age of 18 years or older; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; adequate hepatic (ie, bilirubin ≤ 1.5 mg/dL; ALT ≤ 2.5 × upper limit of normal [ULN] or ≤ five times ULN if hepatic abnormality related to leukemia) and renal functions (ie, creatinine ≤ 2.0 mg/dL or creatinine clearance > 60 mL/min); no prior chemotherapy, radiation therapy, or investigational anticancer therapy in the previous 2 weeks; absence of CNS involvement by leukemia; and absence of uncontrolled intercurrent illnesses, including infections, cardiac conditions, or other organ dysfunctions. All patients signed an informed consent form according to institutional guidelines and in compliance with the Declaration of Helsinki.

Study Design and Treatment Plan

This study used a classical 3 + 3, phase I design. The starting dosage of sapacitabine was 75 mg orally twice daily (to total 150 mg daily) for 7 consecutive days every 3 to 4 weeks on the basis of safety data from phase I trials in solid tumors. The timing of the subsequent cycles of treatment varied depending on the disease status and toxicities. The dose was escalated to 100, 125, 175, 225, 275, 325, and 375 mg orally twice daily. The dose level of 100 mg was entered with only one patient and was skipped to 125 mg because of the safety data that emerged from a phase I trial in solid tumors. After the DLT and MTD were defined with the twice daily dosage schedule for 7 days, a second dosing schedule of twice daily oral sapacitabine for 3 consecutive days weekly for 2 weeks, every 3 to 4 weeks, was implemented. Dose levels evaluated on this second dosing schedule were 375, 425, and 475 mg twice daily.

DLT and Dose Escalation Rules

A DLT was defined as the occurrence of any clinically significant and drug-related, grades 3 to 4, nonhematologic toxicity despite maximum supportive care, or prolonged pancytopenia in the presence of a hypocellular bone marrow (ie, cellularity 5% or fewer without evidence of leukemia) that lasted longer than 42 days from the start of therapy. Three patients were entered at each dose level. If no DLT was observed, patients were treated at the next-higher dose level. If one DLT was observed, three more patients were treated at that dose level. MTD was defined as the dose that produced grades 3 to 4 toxicity in at least two of six patients treated. The recommended dose for future phase II studies would be the dose level immediately before the MTD. The duration of therapy was indefinite as long as there was benefit to the patient.

Response and Toxicity Criteria and Statistical Methods

Response criteria were standard.17,18 Complete remission (CR) in patients with AML or ALL was defined as normalization of the blood and bone marrow with 5% or fewer blasts in normocellular or hypercellular bone marrow, a granulocyte count of 109/L or greater, and a platelet count of 100 × 109/L or greater. A partial response (PR) was defined as the same as CR but with at least a 50% decrease to 6% to 25% marrow blasts. A CR without platelet count recovery (CRp) was defined as the same as CR but without platelets recovery to 100 × 109/L or greater. A marrow CR (CRi) was defined as the same as CR but without granulocytes recovery to 109/L and/or platelets recovery to 100 × 109/L or greater. Response in MDS was defined according to the modified International Working Group (IWG) criteria.18

Toxicity was graded on a scale of 0 to 5 by using the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) version 3.0.19 The 4-week mortality (from start of sapacitabine) was calculated as a combined measure of the drug efficacy and safety, regardless of a causal relationship to the study drug. Survival and response durations were analyzed by the Kaplan-Meier method.

Clinical Pharmacology

Patients who consented to participate in pharmacokinetic (PK) and pharmacodynamic studies were instructed to fast (ie, no food or drink except water) after midnight before the morning of day 1 of cycle 1. The dose of sapacitabine was administered about 1 hour before breakfast. Peripheral blood samples were taken predose (time 0) and at 1, 2, 4, 6, 8, and 24 hours after the dose of sapacitabine was given. The 24-hour time point for day 1 was obtained in the morning of day 2 before the patient took the second dose of sapacitabine. All blood samples (10 mL) were collected in green stopper vacutainer tubes coated with heparin and containing 400 μmol/L tetrahydrouridine (THU), the latter of which was added to inhibit deamination of CNDAC by cytidine deaminase (CDA). Immediately after collection, the blood samples were chilled in an ice-water bath, and plasma was separated from peripheral-blood mononuclear cells (PBMCs) by centrifugation at 4°C. Plasma samples were stored at −70°C, and cell pellets were processed additionally for pharmacodynamic analysis.

Plasma Pharmacology

Plasmas samples were spiked with radioactive-labeled sapacitabine (carbon-13 nitrogen-15 [13C15N4]) and CNDAC (carbon-13 nitrogen15 [13C15N4]), as the internal standards and levels of sapacitabine and CNDAC were determined by a validated high-performance liquid chromatography and tandem mass spectrometric detection (LC/MS/MS) assay. The lower limits of quantification (LOQs) for sapacitabine and CNDAC were 0.2 ng/mL and 1 ng/mL, respectively. Actual sampling times were used in all PK analyses. The maximum plasma concentration (Cmax) and time to Cmax (Tmax) were taken directly from the data. Because of the lack of a log-linear decay during the 8-hour sampling period, no estimate could be made for the elimination rate constant, λz, and half-life (t1/2). Area under the curve from zero to the final sample with a concentration at LOQ or greater (AUC0-t) was calculated by using the linear trapezoidal method. All PK calculations were done and all individual patient plasma concentration–time graphs were prepared by using SAS for Windows version 9.1.3 (SAS Institute, Cary, NC). Graphs of mean plasma concentration versus time were prepared by using SigmaPlot for Windows version 11.0.

Cellular Pharmacology

Cell pellets collected from blood samples were washed with phosphate-buffered saline (PBS). PBMCs were isolated by Ficoll-Hypaque density-gradient centrifugation, were washed with PBS, and were counted with an electronic particle counter. Approximately 1 to 2 × 107 cells were used to extract nucleotides, and the nucleotides were separated by strong anion-exchange high-performance liquid chromatography and were quantitated by using ultraviolet absorbance with reference to standards.20 The remaining cells, if available, were incubated with 1.0 μCi hydrogen-3–thymidine for 30 minutes to determine DNA synthesis in triplicates of 2 × 106 cells.

RESULTS

Patient Characteristics and Treatment Administration

A total of 47 patients were treated. The characteristics are listed in Table 1. The median age was 65 years (range, 35 to 90 years); 17 patients (36%) were women. Forty-two patients had AML, one had ALL, and four had MDS (Table 1). Seven patients with AML had received no prior chemotherapy. The median number of treatment cycles was three (range, one to 16 cycles). Five patients completed six or more treatment cycles, including one patient who completed 16 cycles.

Table 1.

Baseline Demographic and Clinical Characteristics of the Study Group

Characteristic Patients (N = 47)
No. %
Diagnosis
    AML 42 89
    MDS 4 9
    ALL 1 2
ECOG performance status
    0 9 19
    1 33 70
    2 5 11
Treatment status*
    Frontline 7 17
    Salvage 1 7 17
    Salvage 2 15 36
    Salvage 3 4 9
    Salvage 4 or more 10 23
Age, years
    Median 65
    Range 35-90
Prior intensive chemotherapy* 32 74
Karyotype
    Diploid metaphases 12 26
    Chromosome 5 or 7 abnormalities 14 30
    Non-complex abnormalities (< 3) 7 15
    8± other 5 11
    Complex abnormalities (≥ 3) 5 11
    >Insufficient metaphases 4 9
Hemoglobin, g/dL
    Median 9.6
    Range 7.7-14.3
WBC, ×109/L
    Median 3.0
    Range 0.3-119.5
Platelets, ×109/L
    Median 32
    Range 5-353
Marrow blasts, %
    Median 40
    Range 1-88
Lactic dehydrogenase, U/L
    Median 564
    Range 277-3,134

Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; ALL, acute lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group.

*

Acute leukemia only (n = 43).

DLTs and MTDs

The number of patients treated at each dose level and the observed DLTs are listed in Table 2. Drug-associated gastrointestinal adverse effects were dose limiting at the sapacitabine dose level of 375 mg orally twice daily for 7 days; this level included one drug-related death as a result of neutropenic colitis. The dose schedule of sapacitabine chosen for phase II studies was 325 mg orally twice daily for 7 days; this schedule could be given frequently (eg, every 3 to 4 weeks), in the outpatient setting, with minimal extramedullary (gastrointestinal) or medullary toxicity that may provide better control of the leukemia. After the completion of investigation of the 7-day schedule, patients received sapacitabine at 375, 425, and 475 mg orally twice daily for 3 days, weekly for 2 weeks (days 1 through 3 and days 8 through 10). Again, gastrointestinal toxicity was dose limiting at the sapacitabine dose of 475 mg orally twice daily. Although only one patient experienced the DLT of grade 3 diarrhea at this dose level, a decision was made not to expand this dose level because of significant thrombocytopenia observed in another patient who had a decrease in platelet count from normal to less than 10 × 109/L during the first treatment cycle. The phase II recommended dose with this schedule was 425 mg orally twice daily on days 1 to 3 weekly for 2 weeks.

Table 2.

Dose Escalations and Dose-Limiting Toxicities

Dose level, mg No. of Patients Dose-Limiting Toxicity
Twice daily × 7 days 35
    75 3 None
    100 1 None
    125 3 None
    175 3 None
    225 3 None
    275 6 Diarrhea and neutropenic colitis, grade 3*
    325 9 Diarrhea, grade 3*
    375 7 Abdominal pain and small-bowel obstruction, grade 3*; neutropenic colitis, death*
Twice daily for 3 d/wk × 2 weeks 12
    375 3 0
    425 6 0
    475 3 Diarrhea, grade 3
*

No. of patients = 1.

Recommended phase II dose.

Safety and Tolerability

The most common drug-related adverse events (Table 3) were constitutional (fatigue), gastrointestinal (anorexia, abdominal pain, diarrhea, nausea, and vomiting), and hematologic (neutropenia and thrombocytopenia). Myelosuppression-associated complications in the first course included febrile episodes in 14 patients (30%). These consisted of fever of unknown origin in nine patients (19%) and infections in five patients (11%). Two deaths occurred within 4 weeks of start of therapy. The first death was a 75-year-old man with AML who was treated at the dose level of 375 mg twice daily for 7 days every 21 days. On day 12 of treatment cycle 1, he was admitted to the hospital with abdominal pains and distention, nonbloody diarrhea, and neutropenic fever. No peritoneal signs were present by physical exam. Abdominal CT scan showed no bowel obstruction or free air, but there were slightly prominent loops of small bowel with significant bowel wall thickening. The clinical suspicion was neutropenic colitis. The patient was treated with broad-spectrum antibiotics and bowel rest. Despite aggressive treatment, he developed hypotension, pulmonary insufficiency, and acidosis, and he died on day 22. The death was considered definitely related to the study drug. The second death occurred in a 51-year-old man with refractory AML who died on day 27 with persistent AML, pneumonia, and multiorgan failure.

Table 3.

Patients With Drug-Related Toxicity by Dosing Schedule

Toxicity No. of Patients by Dosage Regimen and Toxicity Grade
Twice Daily × 7 Days (n = 35)
Twice Daily × 3 d/wk × 2 Weeks (n = 12)
Grades 1-2 Grades 3-4 Grades 1-2 Grades 3-4
Hematologic
    Anemia 0 1 1 0
    Leukopenia 1 6 0 7
    Neutropenia 0 5 0 4
    Thrombocytopenia 1 1 1 7
Nonhematologic
    Abdominal pain 4 1 0 0
    Constipation 2 0 0 0
    Diarrhea 9 1 1 1
    Nausea 13 0 6 0
    Neutropenic colitis 0 2* 0 0
    Small bowel obstruction 0 1 0 0
    Stomatitis 2 0 1 0
    Vomiting 5 0 2 0
    Oral mucosal petechiae 0 0 1 0
    Mucosal hemorrhage 0 0 1 0
    Mucosal inflammation 1 0 0 0
    Asthenia 2 0 0 0
    Fatigue 6 0 4 0
    Increase in ALT 1 0 0 0
    Increase in alkaline phosphatase 1 0 0 0
    Anorexia 2 0 1 0
    Decreased in appetite 1 0 0 0
    Dysgeusia 0 0 1 0
    Dyspnea 1 0 0 0
    Hiccups 1 0 0 0
    Alopecia 8 0 1 0
    Petechiae 1 0 1 0
*

One patient died as a result of neutropenic colitis.

PKs

PK data were available from 10 patients who received doses of 125 mg (n = 2), 325 mg (n = 4), 375 mg (n = 1), 425 mg (n = 2), and 475 mg (n = 1) twice daily (Table 4). The median Tmax of plasma sapacitabine for all courses was 120 minutes (range, 60 to 360 minutes), and it was similar for CNDAC (median, 120 minutes; range, 60 to 480 minutes). There was no apparent dose-related change in the individual patient plasma concentrations of sapacitabine or CNDAC on either day 1 or day 8. Similarly, there was no apparent relationship between either Cmax or AUC0-t and dose for either analyte. Although there was an apparent trend toward an increase in Cmax and AUC0-t for sapacitabine, the relationships were not significant.

Table 4.

Summary of Pharmacokinetic Parameters for Sapacitabine and CNDAC

Parameter Dose (mg)
125 325 375 425 475
Sapacitabine*
    Cycle 1, day 1 3.16 35.10 14.90 35.30 2.77
        Cmax, ng/mL 2.00 2.14 15.60
5.79
27.50
        Tmax, minutes 250 135 119 360 240
380 65 120
65
120
        AUC(0-t), min × ng/mL 755.5 16,463 1,671 9,160 536
406.7 181.5 2,629
903
3,529
    Cycle 1, day 8
        Cmax, ng/mL 5.43 8.88
        Tmax, minutes 240 360
        AUC(0-t), min × ng/mL 774.7 3,437
CNDAC*
    Cycle 1, day 1 15.5 19.8 6.76 67.3 11.6
        Cmax, ng/mL 8.23 2.88 34.6
9.98
63.7
        Tmax, minutes 250 135 119 480 240
65 65 120
120
120
        AUC(0-t), min × ng/mL 3,738 3,100 463.4 18,315 1,493
1,998 242.9 5,325
1,647
12,169
    Cycle 1, day 8
        Cmax, ng/mL 4.65 16.9
        Tmax, min 240 120
        AUC(0-t), min × ng/mL 709.1 4,490

NOTE. N = 10 patients.

Abbreviations: CNDAC, 2′-C-Cyano-2′-deoxy-β-d -arabino-pentofuranosylcytosine; Cmax, maximum plasma concentration; Tmax, time to maximum plasma concentration; AUC(0-t), area under the curve from zero to the final sample with a concentration.

*

Each value represents an individual patient.

Adequate leukemia blasts for nucleotide pool analyses throughout the sampling time course were recovered from five patients (125 mg, n = 2; 325 mg, n = 2; 475 mg, n = 1). In no case was the level of CNDAC triphosphate quantifiable, likely because the plasma Cmax concentrations of CNDAC in the range 33 to 250 nmol/L would not generate triphosphate concentrations detectable by ultraviolet absorbance20 There was no consistent inhibition of DNA synthesis in leukemia blasts observed in the ex vivo assays.

Response

Overall, 13 patients (28%) achieved objective responses: four had CR, two had CRp, and seven had CRi. Several patients had extensive prior therapy. The details of the patients are listed in Table 5. Two patients with AML had experienced relapsed leukemia cutis with numerous skin nodules. Both patients achieved a significant reduction in the number of skin nodules, and one patient had complete resolution of all skin nodules. In addition to our observations in patients with objective responses, we observed prolonged stable disease in one patient. This patient had AML in second relapse after standard induction chemotherapy. The baseline bone marrow had 34% blasts with an absolute granulocyte count of 0.25 × 109/L. This patient received a total of 16 cycles of treatment and had a reduction in bone marrow blast to as low as 6% and normalization of granulocyte count greater than 109/L. In addition, 20 patients (43%) had at least 1-log reduction of peripheral blasts (n = 12) and/or at least 50% reduction of marrow blasts (n = 8). Two patients died in the first 4 weeks of therapy. The estimated 4-week mortality for the total study group was only 4%. Survivals of the overall group and of responders are shown in Figure 1.

Table 5.

Characteristics of Responders

Patient Age (years) Diagnosis Salvage Status CG Prior Treatment Response to Prior Treatment CRD1 Last CRD Sapacitabine Twice Daily × 7 or Days 1-3 Each Week × 2 Weeks (mg/m2) Response Type Duration of Response (months) Patient % BM Blasts
PLTs (× 109/L)
% PB
PMN (× 109/L)
Comments
Pretransplantation Post-Transplantation Pretherapy Post-Therapy Pretherapy Post-Therapy Pretherapy Post-Therapy
14 59 MDS→EMD S2 IM HDAC NR 0 4 225 × 7 CR ≥ 3.9 14 1 1 72 82 0 0 2.5 1.1 CR of EMD; off therapy because of concurrent disease
Allo SCT CR
DLI CR
32 66 CMML→AML S3 del 13q* Decitabine CR 1 0 325 × 7 CRp 2.2 32 50 3 38 44 8 0 6.6 1.6
clofarabine (for MDS) NR
41 57 AML S1 Diploid IA PR 0 425 × 3/wk × 2 CR ≥ 1 41 21 3 261 > 100 0 0 2.3 > 1.0 Off for SCT
45 85 AML S5 abn 5/7 DA CR 22 84 475 × 3/wk × 3 CR ≥1 45 40 2 41 120 0 0 0.5 1.5 Off for consolidation therapy
DA CR
FIA CR
FAM CR
12 75 MDS-RAEB S1 Diploid Azacitidine Unknown 225 × 7 BM CR 0.5 12 8 4 31 51 4 0 0.1 0.17
13 79 MDS-CMML S1 Diploid DAC CR 15 225 × 7 CR 3.3 13 17 2 324 372 2 0 0.28 1.3
6 82 AML S2 Complex DAC NR 0 0 125 × 7 CRp 2.1 6 77 2 45 83 66 0 2.4 3.2
GO NR
9 53 MDS→ Diploid IA/tipinarnib CR 3 175 × 7 BM CR 2 9 18 1 20 14 1 0 0.7 0.6
AML S3 CDDO NR
10 56 AML S1 IM IA CR 1 175 × 7 BM CR ≥ 1.9 10 14 2 30 42 8 0 1.2 0.18 Off for cord SCT
15 73 MDS-CMML S1 Other (noncomplex) DAC CR 12 275 × 7 BM CR 2 15 9 5 28 4 0 0 3.3 0.03
17 90 MDS→AML F Other (noncomplex) 275 × 7 BM CR 2.5 17 40 5 27 32 8 0 0.04 0.34
22 69 Treatment related AML F Complex 325 × 7 BM CR 0.5 22 33 2 24 14 5 0 12.2 0.4
23 55 AML/(+EMD) S4 Diploid IA CR 3 325 × 7 BM CR 1.5 23 10 4 151 52 0 0 3.4 1.0 > 50% reduction in EMD
IA CR
Flud/AraC NR

Abbreviations: CG, cytogenetics; CRD1, duration of first complete response; CRDlast, duration of last complete response; BM, bone marrow; PLTs, platelets; PB, peripheral blood; PMN, granulocytes; MDS, myelodysplastic syndrome; EMD, extramedullary disease (leukemic cutis); S2, second salvage; IM, insufficient metaphases; HDAC, high-dose cytarabine; NR, no response; CR, complete response; AlloSCT, allogeneic stem-cell transplantation; DLI, donor lymphocyte infusions; CMML, chronic myelomonocytic leukemia; AML, acute myeloid leukemia; S1, first salvage; IA, idarubacin and cytarabine; CDDO, 2-cyano-3, 12 dioxoolean-1, 9-dien-28-oic acid; PR, partial response; SCT, stem-cell transplantation; DA, daunorubicin and cytarabine; FIA, fludarabine, idarubacin, cytarabine; FAM, fludarabine, cytarabine, mitoxantrone; RAEB, refractory anemia with excess blasts; DAC, decitabine; CRp, complete response without platelet recovery; GO, gemtuzumab ozogamicin; S3, third salvage; F, front-line; S4, fourth salvage; Flud, fludarabine; AraC, cytarabine.

*

del13q represents deletion in the long arm of chromosome 13.

abn 5/7 represents chromosome 5 or 7 abnormalities.

Fig 1.

Fig 1.

Survival overall and in responders.

DISCUSSION

Sapacitabine is an oral prodrug of CNDAC, a rationally designed analog of deoxycytidine. Despite its structure and chemical similarity to cytarabine, it has unique properties in causing single-strand DNA breaks because of the presence of a cyano group within the deoxyribose moiety of the molecule. As myelosuppression was the DLT in solid tumor studies, we evaluated sapacitabine in a phase I study in acute leukemias and MDS. We defined the new extramedullary DLT to be gastrointestinal. Two phase II dose schedules were recommended for future studies: 325 mg orally twice daily for 7 days every 3 to 4 weeks and 425 mg orally twice daily on days 1, 2, 3 weekly for 2 weeks every 3 to 4 weeks. Although the plasma levels of sapacitabine and CNDAC were highly variable and were not dose proportional, it appears that the sapacitabine dose could be titrated to reach MTD by an increment of 100 mg/d in patients with leukemias and MDS. PK data were available for 10 patients entered into five dose levels that ranged between 125 and 475 mg. Given this relatively small cohort and the inherent variability of oral administration, it is not surprising that a significant dose-response relationship was not evident. Additional clinical studies are presently administering sapacitabine in different schedules at doses within this range and will address more appropriately the sapacitabine dose-response relationship.

The drug was well tolerated and showed encouraging antileukemic activity in the setting of poor-prognosis AML and MDS. Among 47 patients, 13 achieved objective responses, and an additional 20 patients had significant reductions of their blasts. Objective responses also were observed in extramedullary disease (ie, leukemic cutis).

The prognosis of patients with AML remains poor. Overall, only 25% to 30% of patients with newly diagnosed disease are cured. The prognosis is significantly worse in elderly patients with AML and in patients who have AML with poor karyotypes, for whom the cure rates are less than 10%. In elderly patients with AML, standard intensive chemotherapy is associated with a high mortality rate (ie, 30% to 50% in the first 6 to 8 weeks).3 Such patients may benefit from novel agents, like sapacitabine, that provide antileukemic efficacy and ease of administration (oral outpatient therapy) without the concurrent high mortality.

Although survival of patients with MDS has improved with the introduction of hypomethylating agents, the prognosis remains poor. The median survival of patients with higher-risk MDS treated with azacitidine is only 20 to 25 months. Once patients with MDS experience failure on therapy with hypomethylating agents, the prognosis is poor; the median survival after failure of hypomethylating-agent therapy is only 4 to 6 months.21 Therefore, effective anti-MDS agents are needed for this orphan indication. Randomized studies of sapacitabine to evaluate different dose schedules are ongoing in elderly patients with newly diagnosed or first-relapsed AML and in patients with MDS who have failed hypomethylating agents.

In conclusion, sapacitabine has demonstrated a reasonable safety profile in this phase I study and has encouraging antileukemic activity. Current studies are evaluating its role as a single agent in elderly patients with AML and in MDS. The development of combinations of sapacitabine with other antileukemic agents is warranted.

Footnotes

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Simon R. Green, Cyclacel Pharmaceuticals (U); Judy H. Chiao, Cyclacel Pharmaceuticals (C) Consultant or Advisory Role: None Stock Ownership: Judy H. Chiao, Cyclacel Pharmaceuticals Honoraria: None Research Funding: Hagop Kantarjian, Cyclacel Pharmaceuticals Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Hagop Kantarjian, Guillermo Garcia-Manero, Susan O'Brien, Judy H. Chiao, Jorge Cortes, William Plunkett

Administrative support: Robert Westwood, Simon R. Green

Provision of study materials or patients: Stefan Faderl, Farhad Ravandi, Judy H. Chiao

Collection and assembly of data: Hagop Kantarjian, Farhad Ravandi, Judy H. Chiao, Patricia A. Boone

Data analysis and interpretation: Hagop Kantarjian, Guillermo Garcia-Manero, Judy H. Chiao, William Plunkett

Manuscript writing: Hagop Kantarjian, Judy H. Chiao, William Plunkett

Final approval of manuscript: Hagop Kantarjian, Guillermo Garcia-Manero, Susan O'Brien, Stefan Faderl, Farhad Ravandi, Robert Westwood, Judy H. Chiao, Jorge Cortes, William Plunkett

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