Phase I/II study of oral fluoropyrimidine S-1 plus oral Leucovorin as first-line treatment for metastatic colorectal cancer

T. Yoshino1, W. Koizumi2, K. Yamaguchi3, Y. Miyata4, T. Kato5, Y. Toh6, A. Sawaki7, I. Hyodo8, T. Nishina9, N. Boku1

1Shizuoka Cancer Center, Shizuoka, JAPAN, 2Kitasato University East Hospital, Kanagawa, JAPAN, 3Saitama Cancer Center, Saitama, JAPAN, 4Saku Central Hospital, Nagano, JAPAN, 5Minoh City Hospital, Osaka, JAPAN, 6National Kyushu Cancer Center, Fukuoka, JAPAN, 7Aichi Cancer Center Hospital, Nagoya, JAPAN, 8University of Tsukuba, Tsukuba, JAPAN, 9NHO Shikoku Cancer Center, Matsuyama, JAPAN.

Background: The results of phase I portion of the treatment with the oral S-1 (a new oral fluoropyrimidine) plus oral leucovorin (LV) in patients (pts) with untreated metastatic colorectal cancer (mCRC) was reported at ESMO 2006. Dose limiting toxicities (DLTs) were grade 3 stomatitis/pharyngitis, nausea, diarrhea, ileus and exanthema. The recommended doses (RDs) for this phase II portion were determined to be S-1 40-60 mg/body and LV 25 mg/body orally given twice daily on days 1 to 14 of a 28-day cycle. The PK profiles of S-1 plus LV were similar to those of S-1 monotherapy and UFT plus LV, respectively. The main purpose of this phase II portion is to evaluate the efficacy and safety of S-1 plus LV at RD level in pts with untreated mCRC.

Methods: Pts were eligible as follows; unresectable mCRC with no prior chemotherapy or receiving adjuvant chemotherapy completed at least 6 months before, histologically proven adenocarcinoma, PS(ECOG) 0-2, age 20 to 75, measurable lesions, adequate organ function and written informed consent. The pts received 40-60 mg/body of S-1 plus 25 mg/body of LV twice daily as RD in this phase II portion. The primary endpoint was the objective response rates (RRs), and secondary endpoints were time to progression (TTP) and toxicities.

Results: Between Sep 2004 and Jun 2006, 56 pts of 65 enrolled pts received the treatment at RD level. The objective RRs were 57% (37 of 65) for all pts and 57% (32 of 56) for pts at RD, extramurally. Disease control rates (DCRs) were 86% (56 of 65) for all pts and 86% (48 of 56) for pts at RD. Median TTP was 6.8 months for pts at RD. The median survival time is under investigation. During the 6 courses from starting the treatment, the most common grade 3/4 toxicities at RD were as follows: neutropenia, 13%; diarrhea, 27%; stomatitis, 20%; and anorexia 21%.

Conclusions: A combination of S-1 plus oral LV is an effective, well tolerated, and convenient regimen in pts with untreated mCRC, without the addition of either oxaliplatin or irinotecan. This trial was supported by Taiho pharmaceutical co., Ltd., Tokyo, Japan.

Updated Abstract

A novel oral fluoropyrimidine derivative consists of 1M tegafur (FT; prodrug of 5-FU), 0.4M of gimeracil (CDHP) and 1M of potassium oxonate (Oxo)

A oral leucovorin (LV) enhances anti-tumor activity of S-1

DPD

CDHPF--AlaNeuro toxicity

Liver and Tumor

Oxo

Tumor

GItract

Bonemarrow

FdUMP

FdUMP

GI toxicity（Diarrhea, Stomatitis）

Myelo toxicity

OPRT

Cardio toxicity

Hand-Foot Syn.

N

O

OF

O

NH

N

O

OF

O

NH

1tegafur

Cat

abo

lism

0.4

An

abo

lism

1CDHP oxo

OHCI

OHN

OHCI

OHN N

O

O

NH

H

N

KO2C N

O

O

NH

H

N

KO2C

FdUMP5-FU

CYP-2A6

5-MeTHF

ThymidineSynthase

Anti-tumorActivity↑

oralleucovorin

Biological action of S-1 and Leucovorin

Background

S-1 monotherapy showed promising activity (response rate (RR) of 37% as 1st line chemotherapy) against previously untreated metastatic colorectal cancer (mCRC) with conventional dosage (40-60 mg/body BID) and schedule (28 days of administration periods followed by 14 days rest)

Better activity against mCRC is expected when leucovorin (LV) is orally administered with S-1

The efficacy and safety of S-1 plus oral LV have not been studied yet in clinical trials

Study Rationale

Level 2 (S-1 28 days administration) is the maximum tolerated dose (MTD) of this combination therapy

Level 0 (S-1 14 days administration) is the recommended dose (RD), in terms of the continuity of planned 2 courses without any cessation or dose reduction

DLTs were diarrhea, stomatitis/pharyngitis, nausea , ileus, and exanthema

S-1 plus oral LV may be promising treatment against untreated mCRC, achieving a high response rate of 66.7 % (95% confidence interval; 38.4~88.2 %)

The PK parameters of S-1/LV, especially 5-FU and 5-MeTHF, were similar to those of S-1 alone and UFT/LV, respectively

Summary of Phase I portion

day1 28

S-1+LV p.o. BID

14 21 35 42

level 0

level 1

level 2

7

2 wks-on and 2wks-off

3 wks-on and 2wks-off

4 wks-on and 2wks-off

RD

MTDday1 28

S-1+LV p.o. BID

14 21 35 42

level 0

level 1

level 2

7

2 wks-on and 2wks-off

3 wks-on and 2wks-off

4 wks-on and 2wks-off

RD

MTD

Administration periods of S-1/LV

Dosage of S-1: 40-60 mg/body BID

Dosage of LV: 25 mg/body BIDadministered orally together with S-1

Summary of Phase I portion 　(continue)

LS mean LS meanCmax (ng/mL) 1688 1505 - 1894 1891 1630 - 2194

AUC0-8 (hr*ng/mL) 9399 8304 - 10641 10882 9273 - 12773Cmax (ng/mL) 258 210 - 318 221 169 - 289

AUC0-8 (hr*ng/mL) 1077 900 - 1289 957 759 - 1206Cmax (ng/mL) 27.0 17.8 - 40.8 57.5 33.7 - 98.3

AUC0-8 (hr*ng/mL) 107.3 75.3 - 152.8 232.8 147.4 - 367.4Cmax (ng/mL) 153 129 - 183 119 95 - 149

AUC0-8 (hr*ng/mL) 686 582 - 808 558 451 - 690Cmax (ng/mL) 334 267 - 419 429 376 - 489

AUC0-8 (hr*ng/mL) 1891 1507 - 2374 2435 2133 - 2780Cmax (ng/mL) 332 273 - 404 405 361 - 454

AUC0-8 (hr*ng/mL) 1473 1176 - 1844 1707 1497 - 1947

LV

5-MeTHF

95% CIPresent S-1/LV study

FT

CDHP

Oxo

5-FU

Drug parameter S-1 alone or UFT/LV study**

95% CI

** The PK parameters were recalculated using those from two previous studies1,2). The values of concentrations at the same sampling time with the present S-1/LV study were used in calculation, and the data from patients with gastrectomy were excluded from this analysis. 1) Hirata K. et al., Clin Cancer Res 5 2000-2005 (1999) 2) Shirao K. et al., J Clin Oncol 22 (17) 3466-3474 (2004)

PK parameter

Objectives

To assess the response rate of S-1/LV at the RD

To evaluate the following at the RD

Primary endpoint

Secondary endpoints

Time to progression (TTP) Time to treatment failure (TTF)

Overall survival (OS)

the safety profile

the efficacy about

Key Eligibility CriteriaHistologically or pathologically confirmed colorectal adenocarcinoma

Advanced, metastatic and unresectable cancer with measurable disease

Age 20 – 75 years

No prior chemotherapy for the metastatic disease. The adjuvant chemotherapy was allowed if chemotherapy had finished more than 180 days before the entry.

Performance Status (ECOG scale) : 0-2

Adequate hematological, renal and liver function 　

Written informed consent

Life expectancy ＞ 90 days

Treatment

S-1+LV p.o. BID

2 wks-on 2wks-off

S-1: 40-60 mg/body BID

Initial dosage

(tegafur equivalent)

< 1.25

1.25 - < 1.5<1.5

40 mg BID

50 mg BID

60 mg BID

Body surface area (m2)

LV: 25 mg/body BID administered orally together with S-1

-

Statistical Analysis

RR of S-1 monotherapy was 16.7% - 39.5%

Defined as minimum activity was 30% and target activity was 50% error was 0.05 and error was 0.2

We estimated 54 patients (pts) of full analysis set were required

Results of phase I/II portion at the

recommended dose

Period From October 2005 to June 2006

Center 12 centers

Patient 56 pts (6 pts – phase I portion)

Response RECIST (extramurally)

Safety NCI CTCAE v3.0

Patients and Assessments

Patients Characteristics n=56 (RD)Characteristics No. % Characteristics No. %

sex Performance Statusmale 30 53.6 0 53 94.6

female 26 46.4 1 3 5.4age primary site

＜65 38 67.9 colon 32 57.1　 ≧65 18 32.1 rectum 24 42.9

stagebody surface area (BSA) (m2) IV 42 75.0 1.25 -＜ 1.50 23 41.1 reccurent 14 25.0 1.50 ≦ 33 58.9 Primary resection

yes 46 82.1Initial dose of S-1 (mg) no 10 17.9

50 23 41.1 Metastatic site60 33 58.9 liver 39 69.6

dosage (mg/m2) lung 26 46.4 ＜ 35.0 18 32.1 lympho node 24 42.9 35.0 - ＜ 37.5 23 41.1 others 10 17.9 37.5 ≦ 15 26.8 Prior adjuvant chemotherapy

yes 10 17.9（range 31.3-39.6 median 36.4）

（range 1.27-1.92 median 1.56）

（range 32-72 median 62）

Treatment Courses

Total courses during the 6 courses from starting the treatment

No. %course

1 56 (100.0)2 52 (92.9)3 49 (87.5)4 46 (82.1)5 41 (73.2)6 31 (55.4)Total 275

level 0 (n=56)

Efficacy

Response Rate

CI: Confidence Interval*: reviewed extramurally

level 0(n=56)

Confirmed response * CR 0PR 32SD 16PD 8Response Rate % 57.1 [95%CI] [43.2-70.3]Disease Control Rate % 85.7 [95%CI] [73.8-93.6]

Relative Dose Intensity (RDI) of S-1

During the 6 courses from starting the treatment

RDI(%) is calculated by actual DI based on planed DI

Level 0 (N=56)N (%)

RDI (%)N 56 Mean(S.D.) 82.1( 14.5) Median 82.0 Range(Min - Max) 47.1 - 104.3

The analysis of RDI (%)

＜ 80% 23 ( 41.1)80% －＜ 90% 13 ( 23.2)90% ≦ 20 ( 35.7)

Time to Progression (TTP)

TTP; 203 days (6.8 Months)[ 95％ CI; 164.0～ 241.0]

0102030405060708090

100

0 3 6 9 12 15 18 21 24

Time (Months)

TTP e

stim

ate

(%)

Time to Treatment Failure (TTF)

TTF; 182 days (6.0 Months)[ 95 ％ CI; 164.0 ～ 237.0]

0102030405060708090

100

0 3 6 9 12 15 18 21 24

Time (Months)

TTF e

stim

ate

(%)

Overall Survival (OS)

MST: not reachedMedian follow-up time : 447 days

0

10

20

30

40

50

60

70

80

90

100

0 100 200 300 400 500 600 700 800 900

Days

esti

mate

d p

robabil

ity （

％）

Common Toxicities

During the 6 courses from starting the treatmentCTCAE v3.0

>G3 %Hematologic hemoglobin 2 3.6 leukopenia 0 0.0 neutropenia 7 12.5 thrombocytopenia 1 1.8Non-hematologic hyperbillirubinemia 0 0.0 diarrhea 15 26.8 stomatitis 11 19.6 nausea 4 7.1 vomiting 1 1.8 abdominal pain 0 0.0 anorexia 12 21.4 fatigue 0 0.0 skin rash 1 1.8 hand-foot syndrome 0 0.0

toxicitylevel 0 (n=56)

Reason for treatment Discontinuation

Progressive disease 48 pts

Rescue surgery due to tumor shrinkage

1 pts

Toxicity 2 pts

Pt’s refusal 1 pts

Total 52 pts

level 0 (RD): Four pts are ongoing

Summary

Major adverse reactions are gastrointestinal toxicities, without Gr4 severe toxicities

There are no treatment-related death and the incidence of treatment discontinuation due to toxicity is only 3.8%

Promising anti-cancer effect of S-1 with oral LV is shown in this study

A combination of S-1 plus oral LV is an effective, well tolerated, and convenient regimen in pts with untreated mCRC

Further investigations of this combination chemotherapy with adding other active agents, such as oxaliplatin and bevacizumab, are warranted

Conclusions

References

Ohtsu A, et al. Br J Cancer. 2000;83:141-145

Hyodo I, et al. ESMO 2006. Abstract #349P

Shirao K, et al. Cancer 2004; 100: 2355-2361

Sugimachi K, et al. Oncology. 1999;57:202-210