F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro,

P.Artru, C. Louvet, A. de Gramont

OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with

metastatic colorectal cancer (MRC). A GERCOR study.

RationaleChemotherapy-free intervals (CFI) have previously been studied in patients receiving 5FU- based therapy:Hejna et al (Br J Cancer (1998) have shown that patients can benefit from 5FU reintroduction after a CFI following 6 months of therapy.

Maughan et al (Lancet 2003) have show in a larger phase III that 3 months 5FU-based chemotherapy followed by CFI achieved the same survival than 5FU until progression.

New combination therapies have improved survival but also increased toxicity, especially the cumulative toxicities like the oxaliplatin sensory neuropathy. The need to preserve the quality of life is the clinical rationale to evaluate CFI.

Plantade et al have shown in a retrospective study presented at ASCO 2006 that patients with MCRC an benefit from CFI, especially in first-line therapy.

Grade3-4 toxicity at each cycle

0

5

10

15

20

25

1 3 5 7 9 11 13 15 17 19 21 23

cycles

% p

atie

nts

FOLFOX4

FOLFOX7

RRAANNDDOOMMIISSAATTIIOONN

FOLFOX4 until progression

FOLFOX7 x 6 cysLV5FU2 x 12 cyFOLFOX7 x6 cy

A

B

Rationale: OPTIMOX 1

Oxaliplatin Stop and Go

Better tolerance

0 25 50 75 100 125 1500.00

0.25

0.50

0.75

1.00

FOLFOX4

FOLFOX7

weeks

prob

abili

ty

20.0 months

21.6 months

p = 0,68

Same efficacy results

Tournigand, JCO 2006

RRAANNDDOOMMIISSAATTIIOONN

maintenance therapy vs chemotherapy-free interval

mFOLFOX7 x 6 cy sLV5FU2 until baseline progressionmFOLFOX7 reintroduction

mFOLFOX7 x 6 cy No maintenance until baseline progressionmFOLFOX7 reintroduction

OPTIMOX 2 Study design

A

B

OPTIMOX2 : chemotherapy-free interval

OPTIMOX1 : maintenance therapy

A

FOLFOX7 x 6 cy

A A A A A

FOLFOX7 x 6sLV5FU2

Baseline progression

FOLFOX7 x 6 cy

A A A A

FOLFOX7 x 6Chemotherapy-free interval

Baseline progression

LV 400 5-FU 3000

mFOLFOX7

Oxali 100H0 H2 H24 H48

LV 400 5-FU 3000

sLV5FU2

H0 H2 H24 H48

5FUb 400

Cycles every 14 days, dose mg/m²

CHEMOTHERAPY

OPTIMOX 1

OPTIMOX 2

A

A

Baseline Progression

t

T size

FOLFOX FOLFOX

Progression Baseline progression

Progressionat reintroduction

Chemotherapy-free Interval

Histologically proven colorectal cancer

Unresectable metastases

Mesurable or evaluable metastasis

No prior CT except adjuvant CT if ended 6 months before study entry

18 - 80 years

alk. ph.<5 UNL , platelets> 100 109, creatinin <3 UNL

WHO PS 2

No peripheral sensory neuropathy

Inclusion criteria

Randomisation using minimization technique

Stratification by • center, PS (0-1 vs 2),

• number of sites (1 vs > 1),

• age (18 - 50 vs 51-75 vs 76 - 80),

• Alk Ph. ( 3x UNL vs 3 - 5 ULN),

• adjuvant chemo or not

Initial sample size was 600, downgraded to 200 when bevacizumab was approved in France

Primary objective was duration of disease control, no formal hypothesis were done between the two arms

Statistics

Duration of Disease Control

t

T size

FOLFOX FOLFOX

PFS 1

Progression Baseline progression

PFS 2

Progressionat reintroduction

DDC = PFS 1 + PFS 2 (if no PD)

ASCO 2001, 146a

Patients Characteristics

Arm AOPTIMOX1

N = 100

Arm BOPTIMOX2

N = 102

Median age, years (range) 67 (35 - 81) 67 (32 - 80)

Male/Female 60% / 40% 59% / 41%

WHO PS 0 / 1-2 58% / 42% 59% / 41%

LDH N / > ULN / Missing 35% / 48% / 17% 30% / 45% / 25%

Colon/Rectum/Both 63% /36% / 1% 69% /26% / 5%

Prior adjuvant CT/RT (oxali) 17% (0%) 18% (2%)

Synchronous metastasis 25% 27%

Nb metastatic sites 1/ 2/Uk

46% / 51% / 3% 52% / 47% / 1%

202 patients enrolled from 12 centers

Response was evaluated at 4 and 6 cycles then every 2 months.

OPTIMOX 2 Responses

OPTIMOX1 OPTIMOX2

CR 3% 3%

PR 58% 58%

PR+CR 61% 61%Stable 27% 32%

Prog 11% 6%

NE 0% 1%Too early 11 patients 12 patients

OPTIMOX1

PD 10

no Prog. 40> 6 mths 20 (surg. 7)

>12 mths 10 (surg.5)

OPTIMOX 2 Status of the study

A

B

Median follow-up 70 weeks

Prog on maintenance 49

Reintro. 31

Line 2 18

Dead 26

Dead 35

OPTIMOX2

PD 5

no Prog. 30> 6 mths 15 (surg. 6)

>12 mths 7 (surg.5)

Prog on CFI 64

Reintro. 52

Line 2 12

OPTIMOX1N = 100

OPTIMOX2 N = 102

Nb of cycles with oxaliplatin 649 783

Nb of cycles with and without oxaliplatin

1218 783

Median nb of cycles with oxaliplatin (range)

6(1-18)

6(1-18)

Median nb of cycles with or without oxaliplatin (range)

12(1-32)

6(1-18)

OPTIMOX 2 Number of Cycles

+21%

-36 %

Response was evaluated at 4 and 6 cycles then every 2 months.

OPTIMOX 2 Responses Reintroduction 1

OPTIMOX1 OPTIMOX2N 30 45CR 0 (0%) 0 (0%)PR 4 (13%) 14 (31%)Stable 13 (43%) 11 (24%)Prog 12 (40%) 18 (40%)NE 1 (3%) 2 (5%)Too early 1 patient 6 patients

Neuropathy

Grade 1 9.7 % 2 32.2 % 3 3.2%

Grade 1 21.7 % 2 30.4 % 3 8.7 %

Grade 1 4.4 % 2 19.1 % 3 4.4 %

Grade 1 27.0 % 2 16.2 % 3 13.5 %

Optimox 1 Optimox 2

After the first reintroduction

2 months after FOLFOX

Grade 1 69.9 % 2 17.2 % 3 0%

Grade 1 71.7 % 2 17.3 % 3 0%

During C1-C6

Toxicity Grade 3-4 (%) per Patient

OPTIMOX 1 OPTIMOX 2

C1-C6 maintenance R1 C1-C6 R1

Neutropenia 17.2 6.6 3.4 11.9 6.8

Anemia 1 0 0 0 1

Thrombopenia 6.4 1.7 0 3.2 2.2

Mucitis 1 3.3 0 1 2.2

Vomiting 2.1 0 0 4.3 4.4

Diarrhea 2.1 0 0 4.3 2.2

HFS 0 3.3 0 0 0

Progression-free Survival

0 10 20 30 40 50 60 70 80 90 1000.00

0.25

0.50

0.75

1.00

optimox1 median 38 weeks

optimox2 median 30 weeks

weeks

prob

abili

ty p=.009

Progression-free Survival

8.7 months

6.9 months

Duration of Disease Control

0 10 20 30 40 50 60 70 80 90 1000.00

0.25

0.50

0.75

1.00

optimox1 median 56 weeks

optimox2 median 51 weeks

weeks

prob

abili

ty

p=.41

Duration of Disease Control

12.9 months

11.7 months

Chemotherapy-free IntervalChemotherapy-free Interval

0 10 20 30 400.00

0.25

0.50

0.75

1.00

optimox 2 n=92 median 20 weeks

weeks

prob

abili

ty

4.6 months

CFI according to Initial ResponseChemotherapy-free intervals

0 25 500.00

0.25

0.50

0.75

1.00

CR+PR N=55 median CFI 5.1 months

SD N=29 median CFI 3.9 months

weeks

prob

abili

ty

5.1 months

3.9 months

CFI according to Pc factorsChemotherapy-free Interval

0 10 20 30 400.00

0.25

0.50

0.75

1.00

Good Prog. n=30 med. 35 weeks

Poor Prog. n=57 med. 20 weeks

p=.005

weeks

prob

abili

ty

8.0 months

4.6 months

PS 2LDH ↑Alk Ph >3ULN> 1 site

PFS of Reintroduction

3.7 months

4.1 months

Progression-free Survival

0 10 20 30 400.00

0.25

0.50

0.75

1.00

optimox1 n=31 median 16 weeks

optimox2 n=51 median 18 weeks

p=.74

weeks

prob

abili

ty

Conclusions (1)Maintenance therapy improves PFS but not DDC

Median duration of chemotherapy-free interval is 20 weeks (4.6 months), 35 weeks (8 months) in patients without adverse prognostic factors

Results in the OPTIMOX 1 arm are comparable to the previous study except DDC, 12.9 vs 10.6 months, which can be explained by a higher reintroduction rate, > 60% vs 40%.

Response rate after reintroduction of FOLFOX could be higher in patients who did not receive maintenance therapy

Conclusions (2)

A break in therapy can be proposed in patients who achieved a response or a stable disease with first-line FOLFOX therapy, especially those without adverse prognostic factors

The next GERCOR study, DREAM, will evaluate maintenance therapy with targeted drugs alone.

Acknowlegments:

• Dr Lledo Gérard – Lyon

• Pr de Gramont Aimery – Paris

• Dr Mineur Laurent – Avignon

• Pr André Thierry – Paris

• Dr Bennamoun Mustapha –

Montfermeil

• Dr Mabro May – Suresnes

• Dr Carola Elisabeth – Senlis

• Dr Flesch Michel- Dijon

• Dr Ganem Gérard – Le Mans

• Dr Colin Philippe – Reims

• Dr Auby Dominique - Libourne

For the GERCOR :

• Benoist Chibaudel

• Valentine Songeur

• Nourredine Ait Rahmoune

• Nora Zeghib

• Gaelle le Guludec

• Katia Neveu

• Laurence Renaud