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BIBF 1120

BIBW 2992

Sequential BIBF 1120 + BIBW 2992

Boehringer Ingelheim

The primary objective of this trial is to estimate and compare the 12-week progression-free rate of BIBF 1120, BIBW 2992 or sequential administration of BIBF 1120 and BIBW 2992 in patients with HRPC as determined by radiographic, bone and PSA criteria.

A Multi-centre 3-arm Randomised Phase II Trial of BIBF 1120 Versus BIBW 2992 Versus Sequential Administration of BIBF 1120 and BIBW 2992 in Patients With Hormone-resistant Prostate Cancer

PFR is defined as a composite endpoint for disease progression.

If patients met one of the following criteria they were counted as having progressive disease (PD):

* Prostate serum antigen (PSA) progression according to Prostate-Specific Antigen Working Group (PSAWG) criteria
* Bone metastasis progression- development of new lesions on bone scan or development of disease-related skeletal related events (SREs)
* Disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0

PFR is defined as a composite endpoint for disease progression.

If patients met one of the following criteria they were counted as having progressive disease (PD):

* Prostate serum antigen (PSA) progression according to Prostate-Specific Antigen Working Group (PSAWG) criteria
* Bone metastasis progression- development of new lesions on bone scan or development of disease-related skeletal related events (SREs)
* Disease progression according to RECIST version 1.0

PSA response was evaluated according to the PSAWG guidelines. All patients achieving a fall in PSA of ≥50% from baseline (confirmed with a second value at least 4 weeks later) fulfilled the criteria for PSA response. The confirmatory value had to be at least 50% lower than the baseline value, but could be higher than the original drop in PSA (first PSA value).

However, the confirmatory value could not be 50% higher than the first PSA value. If it was ≥50% higher than the first PSA, another sample was taken to determine if response had been achieved.

Duration of PSA response was calculated from the time of first 50% decline in PSA (compared to baseline) until the time at which there was an increase of 50% from the PSA nadir, provided that the absolute increase was at least 5 ng/mL. The increase had to be confirmed by a second consecutive measurement that was at least 50% above the nadir. If the PSA never showed a 50% increase over the nadir value, then the patient was censored at the last PSA measurement.

Duration of PSA response expressed in median number of days.

Time to PSA progression through 48 weeks was calculated as the number of days from first administration of study drug to the first time that there was an increase of 50% from the PSA nadir, provided the absolute increase was at least 5 ng/mL.

Time is expressed in median number of days.

RECIST (version 1.0) tumour progression rate at 12, 24, 36, and 48 weeks was calculated based on the occurrence of new lesions, or an increase in the sum of the longest lesion diameters of at least 20%.

Objective response is defined as a Complete or Partial response Complete response \[CR\] for Target lesions: Disappearance of all target lesions. Complete response \[CR\] for Non- target lesions: Disappearance of all non-target lesions and normalization of tumour marker level Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Time from first observation of response (PR, CR, confirmed or unconfirmed) until progression according to RECIST (version 1.0) or death.

Duration is expressed in Median number of days.

Time from first administration of study drug until disease progression according to composite endpoint.

Time is expressed in Median number of days.

Overall survival (time to death) was calculated in days from baseline to the date of reporting of death. Time is expressed in Median number of days.

Incidence and worst intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

Changes in safety laboratory Parameters reported as adverse events

Trough plasma concentrations are defined either as pre-dose concentration of BIBF 1120 and BIBW 2992 in plasma at steady state immediately before administration of the next dose for the monotherapy treatment or as post dose concentrations taken after the dosing interval for the combination treatment

Trough plasma concentrations are defined either as pre-dose concentration of BIBF 1120 and BIBW 2992 in plasma at steady state immediately before administration of the next dose for the monotherapy treatment or as post dose concentrations taken after the dosing interval for the combination treatment (C12,14 for BIBF1120 ; C24,7 and C24,14 for BIBW2992)

C12,14: plasma concentration at 12 hours Day 14

Boehringer Ingelheim, Study Chair

250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.

BIBF 1120 Monotherapy

40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.

BIBW 2992 Monotherapy

Sequential alternating BIBF 1120 and BIBW 2992 combination therapy.

Treatment regimen:

BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28.

Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

ComBI 40

Sequential alternating BIBF 1120 and BIBW 2992 combination therapy.

Treatment regimen:

BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle.

The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged.

Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.

ComBI 70

Total

Age, Continuous

Sex: Female, Male

Treated Set: The Treated Set consisted of all patients who received at least 1 dose of study medication.

Data from the ComBI 70 group were not included in analyses of efficacy, data was available for one patient for this group for the primary outcome however is not reported to avoid reporting patient level data.

Boehringer Ingelheim Call Center

Sequential alternating BIBF 1120 and BIBW 2992 combination therapy.

Treatment regimen:

BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.

Modified full analysis set(mFAS): Patients who received at least 1 dose of study medication and for whom progression status could be determined at 12 weeks,excluding patients who discontinued treatment before 12 weeks for reasons other than PD.

Progression Free Rate (PFR) at 12 Weeks

24 weeks

48 weeks

Full analysis set (FAS), which consisted of all patients who received at least

1 dose of study medication and for whom progression status could be determined at 12 weeks.

Progression Free Rate at 24 and 48 Weeks

Response

No Response

Number of Patients Showing Prostate Serum Antigen (PSA) Response

Sequential alternating BIBF 1120 and BIBW 2992 combination therapy.

Treatment regimen:

BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21 BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28.

Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

Duration of PSA Response

Time to PSA Progression

12 weeks (N=12, 8, 7)

24 weeks (N=6, 1, 1)

36 weeks (N=3, 0, 0)

48 weeks (N=2, 0, 0)

FAS (RECIST evaluable set); RECIST evaluable set, which consisted of patients who had RECIST measurable disease at baseline.

RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks

Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks

Duration of RECIST Response

Time to Progression

Overall Survival (Time to Death)

CTCAE Grade 1

CTCAE Grade 2

CTCAE Grade 3

CTCAE Grade 4

CTCAE Grade 5

Incidence and Worst Intensity of Adverse Events With Grading According CTCAE

Alanine aminotransferase increased

Gamma-glutamyltransferase increased

Aspartate aminotransferase increased

Blood urea increased

Blood creatinine increased

Blood potassium decreased

Transaminases increased

Blood alkaline phosphatase increased

Hepatic enzyme increased

Changes in Safety Laboratory Parameters

Cpre,ss,15 (N=28, 15)

Cpre,ss,29 (N=35, 18)

Cpre,ss,57 (N=27, 12)

Pharmacokinetics (PK) data set: All patients from whom PK samples were received in the bioanalytical laboratories were included in the PK analysis.

Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy

C 12,14 (N=14)

C 24,7 (N=13)

C 24,14 (N=12)

Sequential alternating BIBF 1120 and BIBW 2992 combination therapy.

C12,14 values of BIBF 1120 BS after sequential alternating 7-days administration of 250 mg BIBF 1120 bid;

C24,7, C24,14 and C24,42 values of BIBW 2992 BS after sequential alternating 7-days administration of 40 mg BIBW 2992 qd

Combination Therapy of BIBF 1120 and BIBW 2992

Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy

Sequential alternating BIBF 1120 and BIBW 2992 combination therapy.

Treatment regimen:

BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle.

The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events (AE) reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged.

Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.

Spots Global Cancer Trial Database for sequential bibf 1120 + bibw 2992