Eniluracil + 5-fluorouracil + leucovorin (EFL) vs. capecitabine Phase 2 trial for metastatic breast cancer (AHX-03-202) Rivera E1, Chang JC2, Semiglazov V3, Gorbunova V4, Manikhas A5, Krasnozhon D6, Kirby MG7, Spector T7 1Banner MD Anderson Cancer Center. Phoenix, AZ USA; 2The Methodist Hospital Cancer Center. Houston, TX, USA December 4‒8, 2012 3Road Clinical Hospital of the Russian Railways. St. Petersburg, Russia; 4Russian Oncological Research Center n.s. Blokhin RAMS. Moscow, Russia 5City Clinical Oncology Center. St. Petersburg, Russia; 6 Institution Leningrad Regional Oncology Center. Leningrad Region, Russia; 7Adherex Technologies, Inc. Res. Tri. Pk., NC, USA Abstract Objectives Preliminary Interim Results Conclusions
Based on a modified dosing protocol designed to optimize efficacy, an open-label EFL
Efficacy
vs. capecitabine (4:3 randomization) Phase 2 trial for metastatic breast cancer is in
As of Oct. 29, 2012, 122 patients had tumor assessments. Approximately
progress. Eniluracil inactivates dihydropyrimidine dehydrogenase, thereby preventing the formation of α-fluoro-β-alanine, and conferring 100% oral bioavailability and a 5 hr
Table 1. Arm 1 vs. Arm 2
20% of patients were treated as 1st-line for metastatic disease (80% as
half-life on 5-fluorouracil (5-FU). Study drugs are administered orally for 1st- or
Safety, antitumor response rate, disease control rate, duration of response,
2nd-line) and 70% had previous 5-FU treatment(s).
Evaluated CR + PR + SD*
2nd-line treatment for metastatic disease in patients previously treated with an
patients
anthracycline and a taxane. Arm 1: eniluracil (40 mg) taken 11-16 hr before 5-FU
Preliminary tumor response rate was 25%, 26%, and 17% in Arms 1, 2, &
(30 mg/m2); leucovorin (30 mg) taken with 5-FU and the next day. The regimen is
X, respectively. One CR occurred in Arm 1.
administered once/week for 3 weeks/4 weeks. Arm 2: capecitabine (1000 mg/m2)
Study Design
taken bid for 14 days/21 days. Arm 2 patients with disease progression could
Preliminary clinical benefit was 76%, 74%, and 61% in Arms 1, 2, & X,
crossover to take EFL in Arm X. Two sites in the USA and 19 in Russia are enrolling.
* Clinical benefit. CR = Complete Response, PR = Partial Response, SD = Stable Disease
Currently, 115 patients (21% are 1st-line, 70% had previous 5-FU treatment) are
enrolled and 83 have had tumor assessments. EFL was well tolerated with no
Table 2. Arm X: Arm 2 Patients with PD Who Crossed Over to Take EU/5-FU/Lv
unexpected toxicities. As of May 2012, there were 11, 7, & 1 partial responses in
Arm 1: Oral EU/5-FU/Lv vs. Arm 2: Oral Capecitabine (4:3 Randomization)
Arms 1, 2, & X, respectively. The primary endpoint, progression-free survival, will be
Evaluated CR + PR + SD*
Eight of the 9 (89%) crossover patients in Arm X who had rapidly
determined approximately 7.5 months after the trial is enrolled with 140 evaluable
patients failed capecitabine experienced clinical benefit on EU/5-FU/Lv.Three Arm X: Subjects in Arm 2 (capecitabine) who have radiologically documented disease
progression may crossover to receive EU/5-FU/Lv.
of these patients (33%) had PRs and two patients are still being (All Subjects) treated with EU/5-FU/Lv. Background Key Inclusion Criteria (Rapid Capecitabine Failures)#
5-Fluorouracil (5-FU) is rapidly inactivated by dihydropyrimidine dehydrogenase (DPD)
Women needing 1st- or 2nd-line treatment for metastatic breast cancer
and then converted to α-fluoro β-alanine (F-Bal). F-Bal is neurotoxic, may contribute to
* Clinical benefit. # Subjects who progressed (PD) on Arm 2 within 70 days (one scan)
EU/5-FU/Lv could potentially allow patients who rapidly fail capecitabine to
Previous treatment with an anthracycline and a taxane
hand-foot syndrome and may interfere with antitumor activity of 5-FU. Levels of DPD
continue with another oral 5-FU therapy rather than switching to the less
are highly variable causing markedly variable 5-FU pharmacokinetics that significantly
Table 3. Rapid Capecitabine Failures Subsequently Treated in Arm X
well-tolerated intravenous microtubule-interfering agents, ixabepilone
affect 5-FU efficacy and safety. Eniluracil (EU) irreversibly inactivates DPD, thereby
Adjuvant/Neoadjuvant
(Ixempra®) and eribulin mesylate (Halaven®).
eliminating the problems associated with 5-FU variability and the formation of F-Bal.
EU confers linear, consistent pharmacokinetics, 100% oral bioavailability and a 5-hr
Study Drug Administration Treatm ent(s)
A small clinical trial in patients with metastatic breast cancer who
half-life on 5-FU1,2, and markedly reduces the incidence of hand-foot syndrome3. In
(All drugs are self-administered oral tablets)
PFS (Days) failed capecitabine within 70 days (one scan) may be an attractive
the year 2000, oral EU/5-FU failed to achieve non-inferiority in overall survival vs.
Response Response path to rapidly demonstrate the clinical usefulness of EU/5-FU/Lv.
intravenous 5-FU/leucovorin (Lv) for colorectal cancer3. Subsequently, a study in
Arm 1 & Arm X: EU/5-FU/Lv: (28-day cycle):
laboratory animals revealed that the high EU:5-FU ratio in those Phase 3 studies could
Taken weekly for 3 consecutive weeks followed by 7 days off treatment
References
The current study is based on a promising Phase 1 trial with weekly dosed oral EU,
2nd Day: 5-FU (30 mg/m2) and Lv (30 mg) taken 11-16 hr after Eniluracil
5-FU, and Lv that produced durable tumor responses in patients with advanced
1. Spector T, Porter DJT, Nelson DJ, Baccanari DP, Davis ST, Almond MR, et al. 5-Ethynyluracil
colorectal cancer that was refractory to intravenous 5-FU/Lv5. The regimen was
Arm 2: Capecitabine: (21-day cycle)
(776C85), A Modulator Of The Therapeutic Activity Of 5-Fluorouracil. Drugs of The Future.
Capecitabine (1000 mg/m2) twice daily for 14 days followed by 7 days off treatment
Administer a high EU dose to eliminate all DPD, including DPD in nervous tissue to
2. Paff MT, Baccanari DP, Davis ST, Cao S, Tansik RL, Rustum YM, et al. Preclinical development
Assessments
of eniluracil: enhancing the therapeutic index and dosing convenience of 5-fluorouracil. Invest
Allow excess EU to be cleared before dosing with 5-FU
Tumor evaluations by CT or MRI every 6 weeks using RECIST 1.1
3. Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, et al. Randomized, open-
Administer 5-FU when the EU:5-FU ratio is very low to optimize efficacy
Routine safety and hand-foot syndrome assessments every clinic visit
# PFS was calculated starting from the first EU/5-FU/Lv dose (a conservative estimate)
label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous
Administer Lv with 5-FU and 24 hr afterwards to potentiate 5-FU efficacy.
fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal
Statistics
cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26.
The study compares the efficacy and safety of this regimen to capecitabine (Xeloda®),
4. Spector T, Cao, S. A Possible Cause and Remedy for the Clinical Failure of 5-Fluorouracil plus
an oral prodrug of 5-FU, for treatment of metastatic breast cancer. Patients with
The sample size of 140 patients (80 Arm 1, 60 Arm 2), has at least 68% power
Both EU/5-FU/Lv (Arm 1) and capecitabine (Arm 2) were generally well-tolerated and
Eniluracil. Clinical Colorectal Cancer. 2010;9(1):52-4.
disease progression on capecitabine may crossover to take EU/5-FU/Lv. Capecitabine
(1-sided, 5% significance level) to detect a difference of 15% more patients in Arm 1
produced the historically-expected 5-FU side effects. Arm 1 had three drug-related
5. Guo XD, Harold N, Saif MW, Schuler B, Szabo E, Hamilton JM, et al. Pharmacokinetic and
would not be effective in patients who have deficiencies in one or more of the three
(43%) achieving progression-free survival (PFS) than patients in Arm 2 (28%) after 7.5
SAEs. One of these, metrorrhagia, was unexpected and possibly related. To date, no
pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly
enzymes required to convert it to 5-FU, and/or have elevated DPD. EU/5-FU/Lv
months follow-up. The Kaplan-Meier method will be used to estimate PFS at 6 and 7.5
drug-related SAEs have occurred in Arm 2 and Arm X.
schedule. Cancer Chemother Pharmacol. 2003 Jul;52(1):79-85.
circumvents and/or eliminates these problems and the others described above.
EU/5-FU/Lv would also avoid the rare, but severe toxicity caused by DPD deficiency in capecitabine treated patients.
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Eniluracil + 5-fluorouracil + leucovorin (EFL) vs. capecitabine