BI 894999 First in Human Dose Finding Study in Advanced Malignancies
- Conditions
- NeoplasmsNUT Carcinoma
- Interventions
- Drug: BI 894999
- Registration Number
- NCT02516553
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
This study is open to adults with different types of advanced cancer (solid tumours). The study is also open to patients with diffuse large B-cell lymphoma in whom previous treatment was not successful. In some countries, adolescents who are at least 15 years old and who are diagnosed with NUT carcinoma can also participate. No standard treatment exists for this rare and aggressive form of cancer.
The purpose of this study is to find out the highest dose of BI 894999 that people can tolerate.
BI 894999 is tested for the first time in humans. Participants take tablets once daily. The study also tests whether participants can tolerate BI 894999 better when taken continuously or with breaks in between.
Participants can stay in the study as long as they benefit from the treatment and can tolerate it.
The doctors also regularly check the general health of the participants.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 174
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase Ia - Schedule A: 0.2 mg BI 894999 BI 894999 Once daily continuous oral intake in 3-week cycles. Phase Ia - Schedule A: 0.5 mg BI 894999 BI 894999 Once daily continuous oral intake in 3-week cycles. Phase Ia - Schedule B: 1.5 mg BI 894999 BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL patients) BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL patients) BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ib - Schedule B: 2.5 mg BI 894999 (CRC patients) BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (mCRPC patients) BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ia - Schedule A: 1 mg BI 894999 BI 894999 Once daily continuous oral intake in 3-week cycles. Phase Ia - Schedule A: 1.5 mg BI 894999 BI 894999 Once daily continuous oral intake in 3-week cycles. Phase Ia - Schedule B: 2.5 mg BI 894999 BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ib - Schedule C: 6/3 or 7/3.5 mg BI 894999 (NC patients) BI 894999 Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. Phase Ia - Schedule A: 5 mg BI 894999 BI 894999 Once daily continuous oral intake in 3-week cycles. Phase Ia - Schedule B: 2 mg BI 894999 BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ia - Schedule C: 6/3 mg BI 894999 BI 894999 Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. Phase Ia - Schedule C: 7/3.5 mg BI 894999 BI 894999 Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL patients) BI 894999 Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (SCLC patients) BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ib - Schedule B: 2.5 mg BI 894999 (NC patients) BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ia - Schedule A: 2 mg BI 894999 BI 894999 Once daily continuous oral intake in 3-week cycles. Phase Ia - Schedule C: 5/2.5 mg BI 894999 BI 894999 Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL patients) BI 894999 Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL patients) BI 894999 Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days.
- Primary Outcome Measures
Name Time Method Phase Ia: Number of Patients With DLTs Observed in the First Cycle First treatment cycle (the first 21 days for Schedules A and B, the first 28 days for Schedule C). Number of patients with Dose Limiting Toxicities (DLTs) observed in the first treatment cycle of Phase Ia is reported.
The following drug related adverse events (AEs) qualified as DLT:
* any Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 non haematological toxicity considered related to trial medication with the following exceptions:
* inadequately treated nausea, vomiting or diarrhoea. For fatigue, if present at baseline, there had to be an increase of ≥2 grades
* electrolytes abnormalities that were corrected within 72 hours with treatment
* any haematologic AE related to the trial medication defined as follows:
* CTCAE grade ≥4 neutropenia lasting ≥ 7 days and/or complicated by infection, or
* CTCAE grade ≥4 thrombocytopenia, or
* CTCAE grade≥ 3 thrombocytopenia coupled with grade ≥ 2 of bleeding, or
* febrile neutropenia CTCAE grade 3 or higher.
* any other drug-related AE preventing the patient from taking his treatment according to the given schedule.Phase Ib: Number of Patients With DLTs Observed During the On-treatment Period Date of the first administration of study treatment until date of the last administration of study treatment + 30 days residual effect period, up to 883 days. Number of patients with Dose Limiting Toxicities (DLTs) observed during the on-treatment period of Phase Ib is reported.
The following drug related adverse events (AEs) qualified as DLT:
* any Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 non haematological toxicity considered related to trial medication with the following exceptions:
* inadequately treated nausea, vomiting or diarrhoea. For fatigue, if present at baseline, there had to be an increase of ≥2 grades
* electrolytes abnormalities that were corrected within 72 hours with treatment
* any haematologic AE related to the trial medication defined as follows:
* CTCAE grade ≥4 neutropenia lasting ≥ 7 days and/or complicated by infection, or
* CTCAE grade ≥4 thrombocytopenia, or
* CTCAE grade≥ 3 thrombocytopenia coupled with grade ≥ 2 of bleeding, or
* febrile neutropenia CTCAE grade 3 or higher.
* any other drug-related AE preventing the patient from taking his treatment according to the given schedule.
- Secondary Outcome Measures
Name Time Method Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period Date of the first administration of study treatment until date of the last administration of study treatment + 30 days residual effect period, up to 463 days. Number of patients with DLTs observed during the on-treatment period of Phase Ia is reported.
The following drug related adverse events (AEs) qualified as DLT:
* any Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 non haematological toxicity considered related to trial medication with the following exceptions:
* inadequately treated nausea, vomiting or diarrhoea. For fatigue, if present at baseline, there had to be an increase of ≥2 grades
* electrolytes abnormalities that were corrected within 72 hours with treatment
* any haematologic AE related to the trial medication defined as follows:
* CTCAE grade ≥4 neutropenia lasting ≥ 7 days and/or complicated by infection, or
* CTCAE grade ≥4 thrombocytopenia, or
* CTCAE grade≥ 3 thrombocytopenia coupled with grade ≥ 2 of bleeding, or
* febrile neutropenia CTCAE grade 3 or higher.
* any other drug-related AE preventing the patient from taking his treatment according to the given schedule.Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) 5 minutes (min) before and at 30 min, 1 hour (h), 2h, 3h, 4h, 6h, 8h and 23h55min after administration of first BI 894999 dose on Day 1 of Cycle 1. Maximum measured concentration of BI 894999 in plasma after the first dose (Cmax) for Phase 1a and Phase 1b is reported.
Phase Ia and Phase Ib: Area Under the Concentration-time Curve of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ, ss) 5 minutes (min) before and at 30 min, 1 hour (h), 2h, 3h, 4h, 6h, 8h, and at 23h55min (Schedule A) or 24h (Schedule B & C) following administration on day 14 (Schedule A & B) or day 21 (Schedule C). Area under the concentration-time curve of BI 894999 in plasma at steady state over a uniform dosing interval τ (AUCτ, ss) for Phase Ia and Ib is reported. The dosing interval is 24 hours (h) for all dose groups.
Phase Ia and Phase Ib: Objective Response (OR) Up to 15 months for Phase 1a and up to 28 months for Phase Ib. OR was defined as best overall response (BOR) of complete response (CR) or partial response (PR) with tumour assessment during treatment period for each schedule.
For DLBCL patients, a minor response according to Response Evaluation Criteria In Lymphoma 2017 (RECIL 2017) was not part of an objective response.
BOR was determined from first treatment administration until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anticancer therapy, loss to follow-up or withdrawal of consent, according to the following criteria depending on the type of cancer:
* solid tumour patients and mCRPC patients with measurable disease: CT and/ or MRI according to RECIST v1.1, every 2 cycles;
* mCRPC patients without measurable disease: bone scan and PSA level according to Prostate Cancer Clinical Trials Working Group 3, every 4 cycles;
* DLBCL patients:FDG-PET/CT scans according to RECIL 2017; every 2 cycles.Phase Ib: Progression-free Survival or (PFS) or Radiological PFS for mCRPC Patients With Non-measurable Disease by RECIST v1.1 Up to 28 months. Progression-free survival (PFS) was defined as the time from date of start of BI 894999 to the date of objective disease progression ((PD) defined as 20% increase in the sum of the longest diameter of target lesions) or death, whichever is earlier for SCLC patients, CRC patients, mCRPC patients with measurable disease by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and NC patients, with tumour assessment every 2 cycles according to RECIST v1.1 during treatment period or Radiological PFS with tumour assessment by bone scan every 4 cycles for mCRPC patients with non-measurable disease by RECIST v1.1.
For patients with 'event' as an outcome for PFS:
- PFS \[days\] = date of outcome - date of first treatment administration + 1.
For patients with 'censored' as an outcome for PFS:
- PFS (censored) \[days\] = date of outcome - date of first treatment administration + 1.
The Kaplan-Meier method was used to calculate the estimates.Phase Ia and Phase Ib: Area Under the Concentration-time Curve of BI 894999 in Plasma Over the Time Interval From 0 to 24 Hours After Administration of the First Dose (AUC0-24) 5 minutes (min) before and at 30 min, 1 hour (h), 2h, 3h, 4h, 6h, 8h and 23h55min after administration of first BI 894999 dose on Day 1 of Cycle 1. Area under the concentration-time curve of BI 894999 in plasma over the time interval from 0 to 24 hours after administration of the first dose (AUC0-24) for Phase Ia and Phase Ib is reported.
Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) 5 minutes (min) before and at 30 min, 1 hour (h), 2h, 3h, 4h, 6h, 8h, and at 23h55min (Schedule A) or 24h (Schedule B & C) following administration on day 14 (Schedule A & B) or day 21 (Schedule C). Maximum measured concentration of BI 894999 in plasma at steady state over a uniform dosing interval τ (Cmax, ss) for Phase Ia and Phase Ib is reported. The dosing interval is 24 hours (h) for all dose groups.
Phase Ib: Best Overall Response Imaging and assessment performed every 2 cycles (solid tumours patients) or 4 cycles (mCRPC patients) for the entire treatment period, up to 28 months. Best overall response (BOR) was determined from first treatment administration until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anticancer therapy, loss to follow-up or withdrawal of consent, according to the following criteria depending on the type of cancer:
* solid tumour patients and mCRPC patients with measurable disease: Computerized tomography (CT) and/ or magnetic resonance imaging (MRI) according to RECIST v1.1, every 2 cycles;
* mCRPC patients without measurable disease: bone scan and PSA level according to Prostate Cancer Clinical Trials Working Group 3, every 4 cycles.Phase Ib: Overall Survival Up to 28 months. Overall survival (OS) was defined as the time from first administration of BI 894999 until death from any cause in patients with NUT carcinoma.
For patients with 'event' as an outcome for OS:
- OS \[days\] = date of outcome - date of first treatment administration + 1.
For patients with 'censored' as an outcome for OS:
- OS (censored) \[days\] = date of outcome - date of first treatment administration + 1.
The Kaplan-Meier method was used to calculate the estimates.Phase Ib: Prostate Specific Antigen (PSA) Response in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC) Up to 93 days. PSA response was defined as a decline in PSA value ≥50% from baseline (which is confirmed by a second value 3 to 4 weeks apart).
Trial Locations
- Locations (16)
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
UNIV UZ Gent
🇧🇪Gent, Belgium
HOP Timone
🇫🇷Marseille, France
HOP Saint-Louis
🇫🇷Paris, France
Brussels - HOSP Jules Bordet
🇧🇪Anderlecht, Belgium
Brussels - UNIV Saint-Luc
🇧🇪Bruxelles, Belgium
INS Gustave Roussy
🇫🇷Villejuif, France
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
UZ Leuven
🇧🇪Leuven, Belgium
Universitätsklinikum Tübingen
🇩🇪Tübingen, Germany
HOP Hôtel-Dieu
🇫🇷Nantes, France
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of