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1230.5 Phase II in Second Line NSCLC

Definition Phase II: BI 6727 vs. BI 6727+pemetrexed vs. pemetrexed in second line advanced NSCLCEarly stopping rule for the BI 6727 monotherapy arm

Objectives Efficacy, safety PK

Patients:

Status

Run-in phase: 12 patients treatedPhase II part: 135 planned

Run in phase completedBI 6727 MTD in combination with pem: 300 mg

Patients: 14 entered (2 SF), 12 treatedPhase II part ongoing (started 09 Sept 2009)

Arm A terminated due to lack of efficacy in late January 2011Trial recruitment on hold until approval of Amendment 3

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NSCLC Phase II: 1230.5 Trial design (2nd/3rd line)Run-in phase Exploratory randomized Phase II study

R

Volasertib 300 mg i.v (45 patients)early stopping rule after 20 patients: MET with 1PR• 1 PR/CR

or • 12 / 20 patients with SD

at 6 weeks

pemetrexed 500 mg/m2

(45 patients)

Volasertib + pemetrexed (45 patients)

Volasertib + pemetrexed

run-in cohorttotal: 12 patients

MTD: 300 mg Volasertib + Pemetrexed 500 mg/m2

Primary efficacy analysis: - Volasertib + pemetrexed vs pemetrexed: PFS comparison (one-sided log-rank test, stratified by cancer

type (non-squamous NSCLC vs. not otherwise specified [nos]) - Volasertib versus pemetrexed: median PFS and PFS rate at 3 month will be explored (calculated from KM curves with 95% CI)

Volasertib dose escalation

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Site PI Initiationdate

TotalEnteredSo far

Montreal(Noter-Dame)

Dr. Blais March30, 2009

9

Edmonton Dr. Chu April23, 2009

29

Hamilton Dr. Ellis May8, 2009

27

Montreal(McGill)

Dr. Hirsh March23, 2009

16

Toronto(PMH)

Dr. Leighl October 13, 2009

21

Ottawa Dr. Reaume September 24, 2009

11

Vancouver Dr. Sun May27, 2010

2

Kelowna Dr. Sauciuc June 14, 2010 0

Surrey Dr. Lee June 16, 2010 2

Oshawa Dr. Wierzbicki April 21, 2010 5

Calgary Dr. Krause Disc.

Nassau(Bahamas)

Dr.Turnquest June 11, 2010 1

Kitchener Dr. Callifareti August 4, 2010 2

Total 125

Canadian Recruitment by Investigator

NSCLC Phase II: 1230.5 Study Recruitment

Recruitment Curve

May

-09

Jul-0

9

Sep-0

9

Nov-0

9

Jan-

10

Mar

-10

May

-10

Jul-1

0

Sep-1

0

Nov-1

0

Jan-

11

Mar

-11

May

-11

0

20

40

60

80

100

120

140

160

180

Planned randomized CUMULATIVE new plan

Planned Cumulative randomized original plan

Actual randomized Cumulative

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NSCLC Phase II: 1230.5 Preliminary Efficacy Results

Treatment group Patients treated (n=125)

Best Response by investigator (n=105)

A (Volasertib mono) 37

4 PR5 SD

20 PD 1 NE

B (Volasertib+ Pemetrexed) 38

7 PR 16 SD 10 PD

C(Pemetrexed mono) 38

4 PR19 SD 7 PD

B(run-in phase) 12 3 PR

9 SD

*Data as of Mar 15, 2011; PR = confirmed response

Confirmed Responses

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Event Volasertib Pem + Volasertib Pemetrexed

# pts treated 35 36 36

# pts w any AE 34 (97.1%) 35 (97.2 %) 35 (97.2%)

# pts w AEs leading to disc.

2 (5.7%) 1 (2.8%) 3 (8.3%)

# pts w SAEs 7 (20.0%) 5 (13.9%) 6 (16.7%)

# pts w highest AE grade

12345

8 (22.9%)11 (31.4%)8(22.9%)4 (11.4%)3 (8.6%)*

2 (5.6%)12 (33.3%)17 (47.2 %)

3 (8.3%)0

7 (19.4%)15 (41.7%)11 (30.6%)2 (5.6%)

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NSCLC Phase II: 1230.5: Preliminary Safety Results

*Deaths due to pulmonary embolism, hepatic failure and respiratory failure

Most common AE´s regardless of Relatedness

*Data as of Mar 15, 2011

06Event (by SOC) BI6727 mg(n=35)

Pem +300 mg 6727(n=36)

Pemetrexed(n=36)

# pts w any AE 34 (97.1%) 35 (97.2 %) 35 (97.2%)

Infections & Infestations 6 (17.1%) 15 (41.7%) 19 (52.8%)

Blood & lymphatic system 11 (31.4%) 14 (38.9%) 6 (16.7%)

Metabolism & Nutritition 7 (20%) 18 (50%) 12 (33.3%)

Nervous system disorders 14 (40%) 20 (55.6%) 6 (16.7%)

Cardiac disorders 3 (8.6%) 5 (13.9%) 3 (8.3%)

Respiratory 15 (42.9%) 21 (58.3%) 18 (50%)

Gastrointestinal DisordersConstipation

DiarrhoeaVomiting

Abdominal pain

17 (48.6%)5 (14.1%)4 (11.1%)7 (20%)1 (2.9%)

29 (80.6%)11 (30.6%)10 (27.8%)13 (36.1%)

3 (8.3%)

27 (75%)6 (16.6%)8 (22.2%)5 (13.9%)2 (5.6%)

Musculoskeletal 18 (51.4%) 15 (41.7%) 11 (30.6%)

General DisordersFatigue

25 (71.4%)17 (48.6%)

27 (75.0%)23 (63.9%)

28 (77.8%)24 (66.7%)

Selected all grade AEs by SOC

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NSCLC Phase II: Amendment 3 highlights

• Trial recruitment is currently on hold pending Amendment 3 approval.– Arm A is closed to further recruitment due to a lack of efficacy,

patients given the option to remain on Arm A if receiving benefit or to leave study and receive standard of care pemetrexed

– Amendment 3 implementation will allow sites to continue recruitment of Arms B and C only

– 16 more patients to be recruited until the end of the study, 8 per arm

– Health Canada has approved Amendment 3 – Trial restart pending ethics approval at sites expected Mid May

2011

Amendment 3 highlights

• All patients must have a follow up visit 21 days (+7 days) after EOT. Thereafter patients must be followed every 12 weeks until death is documented or patient is lost to follow-up. FU may be performed by telephone call if patients are not able to visit the investigator

• While the trial data is preliminary and not all of the patients have been recruited to the study, these results are deemed to justify discontinuation of Arm A of the study. In addition no further patients are to be randomized to Arm A. However, if a patient is receiving clinical benefit from the BI 6727 monotherapy treatment as evaluated by the treating physician, the study drug may be continued after agreement with the sponsor.

• Patients in the original protocol who after 6 cycles of combination therapy were continued on BI 6727 monotherapy should continue monotherapy treatment only if the patient is receiving clinical benefit as evaluated by the treating physician. The study drug may only be continued after agreement with the sponsor.

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Amendment 3 highlights

• Follow-up visit• All patients who complete the study and are not eligible for a further cycle will have a

follow up visit at Day 21 (+ 7 days) after EOT. Additional follow up visits are every 12 weeks from the initial follow up visit until death or patient is deemed lost to follow up. The trial will be ended when sufficient events for analysis of PFS have been observed and the last patient randomized will have been followed until death or 6 months after EOT, whichever occurs first.

• At each follow-up visit, adverse events will be reported in the event that they were not recovered at the end of treatment of the last cycle or if new adverse events occurred which are considered drug related. Performance of the physical examination as well as determination of safety lab parameters is optional. The ECOG performance score will be reported. No tumor assessment is requested if the patient has progressive disease and/or has received another anti-cancer therapy.

•  • Assessments include:• physical examination (optional)• MRI or CT (if required)• clinical tumor assessment• ECOG performance score• safety labs (optional)• adverse events • vital status information• Follow-up visits may also be performed by telephone interview in case the patient is

unable to visit the investigator. In this event only ECOG, vital status and adverse events will be done by phone.

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Questions

• For the patients that were discontinued/off study meaning that they had an EOT visit done and one or more follow-up visits and that the follow-up was considered sufficient (as agreed by Behbood), should the follow-up visit every 3 months as per protocol amend.3 start with the ICF signature or do the follow-up visits be captured retrospect from the last documented study visit?

– For patients in this situation, it should be done from the time that they sign the updated ICF•  • For subjects that are discontinued/off study, have had the EOT ±  FUP visit but are in a very weakened

state and may not be able to come in to clinic will phone call updates be acceptable. All subjects alive are to be re-consented but if the patients are per the above (not able to come to clinic for ICF signature) what is the directive?

– The patient has to sign the ICF before any further information is captured even by phone. Attempts should be made for patients in such cases to have the new information in the ICF provided to them

•  • For the deceased patients (death occurred after the follow-up was considered sufficient), should a follow-

up visit be done in RDC to capture the date of death?– No. We should not be capturing data (vital status) on patients who have died and did not sign the

new ICF.

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