NO OFFENSE INTENDED

Why we need investigator-initiated trials

“Large” Randomized Sarcoma TrialsAuthor Regimen Group N= Year Pub

LeCesne AI v AHI EORTC 314 00

Santoro A v AI EORTC 424 95

Antman AD v ADI SWOG 336 93

Nielsen A v E v E EORTC 334 98

Zalupski ADb v ADi SWOG 278 91

Borden A+V v A ECOG 298 90

Baker Ad v ADC v ADAd

SWOG 272 87

Benjamin ACVD v ACVAd

SWOG 445 76

Borden A3 v Aw v AD ECOG 280 87

“Large” Randomized GIST Trials

Author Regimen Group N= Year Pub

Verweij Gleevec 400 v 800

EORTC 946 04

Demetri Gleevec

400 v 800

SWOG 750 -

Is GIST the Exception or the Rule?

• Drug with spectacular benefit

• Enrichment design

• Pent-up demand

• Prior therapy irrelevant

• Performance status irrelevant

American/European Collaboration

• United States• Canada• Denmark• The Netherlands• Belgium• Germany• Hungary• Switzerland

• Italy• France• Spain• UK• Serbia• Norway• Sweden• Slovakia• Poland

SARC MeetingASCO 2006

• Yondelis SARC trial

• Ariad 573 trial

• …..the next day

Search For Data Management Center

• The applicants

• All about CRAB

• John Crowley

• Non-profit• Founded 1997• Seattle, WA• John Crowley, CEO• > 250 trials

– Statistical design– Analysis– Management

• Services– Electronic data

capture– Patient registration

and randomization– Protocol development– Statistical support– Site monitoring

• FDA Validation

Meeting at EORTCAugust 19, 2006

• Steering committee• Data monitoring committee• European participation• Role of EORTC• Mutual support FDA/EMEA

Boston MeetingSeptember 7-8, 2006

• Issues of confidentiality

• Pre-funding agreement

• Ambitious time line

OCTOBER STORM

1 2 3 4 5 6 7

8 9 10 11

A lawyer’s advice

12

A declaration

13

A call from Spain

14

15 16

CEO call

17

Call from

J/J

18 19

A deadline passes

20

SARC,

Boston, Madrid

21

22 23

Deadline

passes

SARC proposal

24

Letter filed

25 26 27

J/J calls

28

29 30 31

JOHNSON & JOHNSON® PRODUCTS

Clear & Clean®, Aveeno®, Shower to Shower®, Stayfree®, o.b. tampons®, Monistat®, Reach® , Band-Aid® bandages, Johnson Baby®Pledge®, Vanish®, Windex®, Shout®, Drano®

Oncology drugs: Doxil, Leustatin, Procrit, Velcade

Government Business

University

Government

• Creative semantics is the key to contemporary government; it consists of talking in strange tongues lest the public learn the inevitable inconveniently early

…..George Will

• “If you are going to sin, sin against God, not the bureaucracy. God will forgive you, but the bureaucracy won’t.”

…..Hyman Rickover

University

• ACADEME, n. An ancient school where morality and philosophy were taught

• ACADEMY, n. (from academe). A modern school where football is taught

Businessmen

• “The individual who would not harm you on an individual, face-to-face basis, who is charitable, civic-minded, loving and devout, will wound you or kill behind the corporate veil”.

…..Morton Mintz

Pharma FDA Cooperative Groups

AGENT 86

GET SMART

SMART: Sarcoma Maintenance Assessed Randomized Trial

A randomized, prospective, double-blind, placebo-controlled

Phase III trial

Oral Tablet AP23573 Clinical Trial – Objectives

• Primary– Determine safety, tolerability and MTD of multiple dose schedules of

oral AP23573 studied in parallel

• Secondary

– Compare blood levels to those in the intravenous program showing anti-tumor activity

– Confirm mTOR inhibition by PD assays

– Describe anti-tumor activity

– Characterize PK parameters

Oral AP23573 Trial Status• 7 dose schedules studied in parallel

– MTD identified• Over 125 patients treated• Majority of patients with a diagnosis of sarcoma• Evidence of mTOR inhibition using pharmacodynamic assay• Many patients with prolonged stable disease

– On study 4-15+ months• Side effect profile consistent with i.v.

– Mouth sores main DLT• Final dose schedule being optimized for highest cumulative

dose and frequency of dosing together with tolerability to allow long-term use

SCHEMA

Metastatic Sarcoma Stable or Better

Following 1st or 2nd line chemo

RANDOMIZE

Oral AP 23573 Oral placebo

Inclusion Criteria

• Age 13 or >• Documented histologic dx of sarcoma• Completed 4-8 cycles of chemotherapy AND• Stable or better response (DOCUMENTED)• Completed 1ST OR 2ND Line• PS <2• Adequate organ function• NO concomitant CYP3A inhibitors

Histopathologic Exclusions• Well Diff Lipo or Fibrosarcoma

• Clear Cell sarcoma

• Extraskeletal chondrosarcoma

• Chondrosarcoma

• Alveolar soft part sarcoma

• Hemangioendothelioma

• GIST

• Embryonal Rhabdomyosarcoma

Clinical Benefit Response Rate AP23573

Subtype # pts CBR Rate

Bone sarcoma 54 16 30

LMS 57 19 33

Liposarcoma 44 13 30

Other STS 57 13 23

Total 212 29

CBR = CR, PR, SD (4 cycles)

Bone/Soft Tissue Sarcoma RationaleResponse rate (%) of single agent chemotherapy in sarcoma

Osteogenic

sarcoma

Soft tissue sarcoma

Doxorubicin 26 26

Ifosfamide 24 27

High dose mtx 25 13

Cisplatin 18 12

Cyclophosphamide 14 18

DTIC 14 18

Act-D 8 17

Response Rate of Combination Chemotherapy in Metastatic Sarcoma

Osteosarcoma

Soft tissue sarcoma

Doxorubicin/DTIC 31 19

Dox/Ctx/DTIC 24 35

Dox/Ctx/Act-D 25 40

Dox/Ifos N/A 36

Clinically Significant Progression-Free Survival

• Sarcoma relevant history– GIST imatinib– GIST sunitinib– STS Gem/Tax

• Requires validation– Specific frequency of measurement– Independent review

Steering Committee

• Jean-Yves Blay• Paolo Casali• Martine Van Glabbeke• Ian Judson• Xavier Garcia del Muro

• Robert Benjamin• John Crowley• George Demetri• Robert Maki• Denise Reinke