BI836845 Plus Enzalutamide in Castrate Resistant Prostate Cancer (CRPC)

Phase 1

Completed

Conditions: Prostatic Neoplasms, Castration-Resistant

Interventions: Drug: BI 836845
Drug: Enzalutamide

Registration Number: NCT02204072

Lead Sponsor: Boehringer Ingelheim

Brief Summary: The overall aim of the trial is to investigate the safety and anti-tumour activity of an experimental drug BI 836845 taken together with the prostate cancer drug, enzalutamide, compared to enzalutamide given alone, in castrate resistant prostate cancer (CRPC) patients that have previously been treated and failed on docetaxel and abiraterone treatments. Initially, a tolerability and safety phase (phase Ib escalation) will be performed to confirm the maximum tolerated dose (MTD), or recommended doses of both BI 836845 and enzalutamide that can be taken together.

Once the MTD, or recommended phase II dose, have been determined an expansion cohort will also be explored (phase Ib expansion) in CRPC patients already taking enzalutamide and have a rise in prostate serum antigen (PSA) levels. Patients may not have received prior docetaxel or abiraterone. Patients in this cohort will receive the MTD, or recommended phase II dose, of BI 836845 and enzalutamide determined in the phase Ib escalation phase.

The randomised trial (phase II) will be an open label, parallel group study design in a 1:1 ratio to which patients will receive either BI 836845 plus enzalutamide (Arm A) at the MTD/recommended doses, or enzalutamide alone (Arm B).

In all parts of the trial safety, anti-tumour activity will be assessed, in addition to circulating tumour cells (CTC), prostate serum antigen (PSA) response and progression, and determination of Overall Survival (OS).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 120

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BI 836845 & Enzalutamide	BI 836845	-
Enzalutamide	Enzalutamide	-
BI 836845 & Enzalutamide	Enzalutamide	-

Primary Outcome Measures

Name	Time	Method
Phase Ib Escalation Part: Number of Patients With Dose Limiting Toxicities (DLTs)	From first administration of xentuzumab up to start of Cycle 2, up to 28 days.	Number of patients with DLTs were used to determine the maximum tolerated dose (MTD) in the Phase Ib escalation part. The MTD in this study was defined as the highest protocol dose level of xentuzumab in combination with enzalutamide, at which no more than 1 out of 6 patients in a cohort experienced a DLT during the MTD evaluation period.
Phase Ib Escalation Part: Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose Limiting Toxicity (DLT) During the First Treatment Course	From first administration of xentuzumab up to start of Cycle 2, up to 28 days.	Maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicity (DLT) during the first treatment course. The MTD in this study was defined as the highest protocol dose level of xentuzumab in combination with enzalutamide, at which no more than 1 out of 6 patients in a cohort experienced a DLT during the MTD evaluation period.
Phase Ib Expansion Part: Prostate Specific Antigen (PSA) Response	At Cycle 1 Day 1 before study treatment and from Cycle 3 Day 1 and Day 1 of every cycle thereafter until the end of treatment, up to 35 months.	The primary endpoint of the Phase Ib expansion part was PSA response. PSA response was defined as a decline in PSA value \>50% compared to baseline which was confirmed by the next available value occurring at least 3 weeks later. The confirmatory value had to be at least 50% lower than the baseline, but could be higher than the first PSA value taken into account for response. However the confirmatory value was not allowed to be 50% higher than this first PSA value. If it was ≥ 50% higher than the first PSA value, the next available sample was to be taken to determine if response had been achieved. The date of response was the date that the first 50% (or greater) decline was observed. Number of participants with response is reported.
Phase II Part: Progression Free Survival (PFS) Based on Investigator Assessment	From randomisation until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1269 days.	PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria) or soft tissue (based on modified RECIST 1.1) or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS (according to modified RECIST version 1.1 or PCWG2): PFS \[days\] = date of outcome - date of randomisation + 1. For patients with 'censored' as an outcome for PFS (according to modified RECIST version 1.1 or PCWG2): PFS (censored) \[days\] = date of outcome - date of randomisation + 1.

Secondary Outcome Measures

Name	Time	Method
Phase Ib Expansion Part: Progression Free Survival (PFS) Based on Investigator Assessment	From first treatment administration of any study medication until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1114 days.	PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria) or soft tissue (based on modified RECIST 1.1) or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS: (according to modified RECIST version 1.1 or PCWG2) PFS \[days\] = date of outcome - date of first treatment administration + 1. For patients with 'censored' as an outcome for PFS (according to modified RECIST version 1.1 or PCWG2): PFS (censored) \[days\] = date of outcome - date of first treatment administration + 1.
Phase Ib Expansion Part: Changes in Circulating Tumour Cells (CTC) Response - CTC Reduction From >=5 to <5 Cells Per 7.5 mL Blood for at Least One Post-baseline Time Point	Prior to study drug administration at Day 1 Cycle 1, Day 1 Cycle 2, Day 1 Cycle 3, Day 1 Cycle 5, Day 1 Cycle 7 and every 12 weeks thereafter, up to end of treatment. Up to 35 months.	Changes in circulating tumour cells (CTC) response - CTC reduction from \>=5 to \<5 cells per 7.5 mL blood for at least one post-baseline time point. Number of participants with CTC Response (yes/no) is reported.
Phase II Part: Radiological Progression Free Survival (PFS), Based on Central Review	From randomisation until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1269 days.	PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria) or soft tissue (based on modified RECIST 1.1) or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS: (according to modified RECIST version 1.1 or PCWG2) PFS \[days\] = date of outcome - date of first treatment administration + 1. For patients with 'censored' as an outcome for PFS (according to modified RECIST version 1.1 or PCWG2): PFS (censored) \[days\] = date of outcome - date of first treatment administration + 1.
Phase II Part: Overall Survival (OS)	From randomisation until radiological tumor progression or death from any cause (until cut-off date for final analysis), whichever occurred earlier, up to 1269 days.	Overall survival (OS) defined as the time from randomisation to death from any cause. Median survival time in months is reported. Overall survival at cut-off date for final analysis (24-Oct-2019) is reported.
Phase II Part: Time to Prostate Specific Antigen (PSA) Progression	At screening, at Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.	For the definition of time to PSA progression, the following rules are used: * Decline from baseline in PSA before increasing: Time to PSA progression is defined as the time from the date of randomisation until the date where a 25% or greater increase in PSA and an absolute increase of 2 ng/mL or more from baseline, is documented (which is confirmed by the next available value occurring at least 3 weeks later). * No decline from baseline in PSA: Time to PSA progression is defined as the time from the date of randomisation until the date where a 25% or greater increase in PSA and an absolute increase of 2 ng/mL or more from baseline, is documented. However, only values after 12 weeks of therapy are considered. Time to PSA progression \[days\] = date of PSA progression - date of randomisation + 1. For patients not presenting with PSA progression or being lost to follow-up: Time to PSA progression (censored) \[days\] = date of censoring - date of randomisation + 1.
Phase II Part: Maximum Decline in Prostate Specific Antigen (PSA)	At screening, at Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.	Maximum decline in (PSA) compared to baseline. The maximum decline in PSA is defined as the change in PSA between the baseline PSA value and the minimum post-baseline PSA value. The change from baseline is defined as: Change from baseline in PSA (ng/mL) = PSA value post-baseline - PSA value at baseline. Maximum decline in PSA is defined as: Maximum decline in PSA (ng/mL) = min(PSA value post-baseline) - PSA value at baseline.
Phase II Part: Percentage Change in Prostate Specific Antigen (PSA) at Week 12	At baseline and at Week 12.	Percentage change in PSA from baseline to Week 12. Percentage change in PSA from baseline to week 12 of treatment is defined as: Percentage change in PSA (%) = 100\(PSA value at week 12 - PSA value at baseline)/PSA value at baseline For this assessment, it is allowed to take a value: until one week later than week 12, in case the PSA assessment was delayed * one day earlier due to the one day window allowed by the protocol Values from assessments between day 84 and day 92 after first treatment administration will therefore be taken into account (according to the protocol schedule for visits at week 12).
Phase II Part: Prostate Specific Antigen (PSA) Response	At Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.	PSA response - defined as a decline in PSA value \>50% (which is confirmed by a second value 3 to 4 weeks apart). PSA response was defined as a decline in PSA value \>50% compared to baseline which was confirmed by the next available value occurring at least 3 weeks later. The confirmatory value had to be at least 50% lower than the baseline, but could be higher than the first PSA value taken into account for response. However the confirmatory value was not allowed to be 50% higher than this first PSA value. If it was ≥ 50% higher than the first PSA value, the next available sample was to be taken to determine if response had been achieved. Number of participants with response is reported.
Phase II Part: Circulating Tumour Cells (CTC) Reduction Defined as CTC Decline From ≥5 to <5 Cells Per 7.5 mL Blood for at Least One Post-baseline Time-point	Prior to study drug administration at Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1 and then every 12 weeks thereafter, until end of treatment. Up to 40.1 months.	CTC reduction is defined as CTC decline from ≥5 to \<5 cells per 7.5 mL blood for at least one post-baseline time-point. Patients with a CTC value \< 5 cells per 7.5mL blood at baseline, or with missing baseline values were not taken into consideration for this endpoint. Baseline value is the value collected before a patient starts treatment with trial medication. Number of participants per category is reported.
Phase II Part: Maximum Decline (%) in Circulating Tumour Cells (CTC) Counts	Prior to study drug administration at Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1 and then every 12 weeks thereafter, until end of treatment. Up to 40.1 months.	Maximum decline in CTC counts (in number of cells) compared with baseline that occurred at any point after treatment start , defined as the difference between the minimum post-baseline CTC value and the baseline CTC value. Patients with missing baseline value are considered missing for this criterion. Baseline value is the value collected before a patient starts treatment with trial medication. Positive values for maximum decline in CTC are possible in case no decline in CTC occurred. This indicates an increase in CTC.
Phase II Part: Circulating Tumour Cells (CTC) Status at Week 12	At Week 12.	CTC status (≥5 or \<5 cells per 7.5mL blood) at Week 12. Number of participants per category is reported.

Trial Locations

Locations (27): Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
NewYork-Presbyterian/Weill Cornell Medical Center
🇺🇸
New York, New York, United States
Oregon Health and Sciences University
🇺🇸
Portland, Oregon, United States
Prince of Wales Hospital
🇭🇰
Hong Kong, Hong Kong
Queen Mary Hospital
🇭🇰
Hong Kong, Hong Kong
Samsung Medical Center
🇰🇷
Seoul, Korea, Republic of
Asan Medical Center
🇰🇷
Seoul, Korea, Republic of
Erasmus MC - Daniel den Hoed
🇳🇱
Rotterdam, Netherlands
Tweesteden Ziekenhuis, locatie Tilburg
🇳🇱
Tilburg, Netherlands
National Cancer Centre Singapore
🇸🇬
Singapore, Singapore
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Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States