Neoplasms, NUT Carcinoma
Conditions
Keywords
NUT midline carcinoma
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.
Interventions
DRUGBI 894999
film-coated tablets
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For all patients * Age 18 years or older at the time of signature of the informed consent. * Life expectancy of at least 12 weeks after the start of the treatment according to the investigator's judgement * Male or female patients. Women of childbearing potential\* must be ready and able to use highly effective methods of birth control per ICH M3(R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. For women of childbearing potential using a contraceptive pill, an additional barrier method is necessary due to the potential CYP3A4 inducing effect of BI894999. Male patients having a partner of childbearing potential must use condoms and ensure their partner is using a highly effective method of birth control as described above, during the trial and for at least three months after the end of the trial \* Any female who has experienced menarche and does not meet the criteria for women not of childbearing potential as described below. Women not of childbearing potential are defined as: women who are postmenopausal (12 months with no menses without an alternative medical cause) or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy). \- Written informed consent consistent with ICH-GCP and local legislation For patients with solid tumours * Patients with a histologically or cytologically confirmed diagnosis of an advanced unresectable and/or metastatic, malignant solid tumour, who have failed conventional treatment or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies * Age ≥ legal age to be adult for the given country at the time of signature of the informed consent. For NC patients, age 15 years or older at the time of signature of the informed consent ( in Germany and South Korea, only legally adult patients may be included * Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0 or 1 at the time of screening. A score of 2 is allowed for NUT carcinoma patients * Recovery of therapy-related toxicities from previous chemotherapy, tyrosine kinase inhibitors, hormone therapy, immunotherapy, antibodies, vaccine therapy, or radiotherapy to CTCAE ≤ grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 2) * Life expectancy of at least 12 weeks after the start of the treatment according to the investigator's judgement * Male or female patients. Women of childbearing potential\* must be ready and able to use highly effective methods of birth control per ICH M3(R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. For women of childbearing potential using a contraceptive pill, an additional barrier method is necessary due to the potential CYP3A4 inducing effect of BI894999. Male patients having a partner of childbearing potential must use condoms and ensure their partner is using a highly effective method of birth control as described above, during the trial and for at least three months after the end of the trial treatment * Written informed consent consistent with ICH-GCP and local legislation. For adolescent NC patients aged 15 years to \< legal adult age, written assent of the patient and written informed consent of the parents (both or one according to national regulation) or legal guardian of the adolescent * Written informed consent for tumour biopsies in the escalation phase Ia * Optional for those patients until extension of the MTD cohort, * Optional for the patients in the extension of MTD cohort at the same time points as described below for the expansion phase. For these patients in the extension of the MTD cohort, if they have an accessible lesion for biopsy, they will be offered optional consent for tumour biopsies * In addition, all patients included in the expansion Phase Ib must: * Have been diagnosed with one of the four types of tumours selected: * small cell lung cancer (SCLC) * metastatic castrate resistant prostate cancer (mCRPC) * colorectal cancer (CRC) * NUT carcinoma (NC) (for which the midline origin is not a prerequisite) * Have failed conventional treatments or who are not amenable to standard therapies (per criterion 1) that specifically include for: * SCLC: a platinum-based therapy (previous treatment with topotecan is not mandatory) * mCRPC: a hormonal agent (abiraterone, enzalutamide, or apalutamide) and a taxane (docetaxel or cabazitaxel) * CRC: fluoropyrimidine, oxaliplatin and irinotecan, bevacizumab for patients eligible to this treatment and an anti-epidermal growth factor receptor (EGFR) in RAS (Rat Sarcoma Virus) wild type metastatic CRC. * Have measurable disease (radiated lesions and lesions used for biopsy do not qualify as target lesions), according to RECIST 1.1 (R09-0262) (for NC patients only nonmeasurable disease is acceptable); or according to PCWG3 (R17-3377) for the mCRPC cohort (see point 5 of inclusion criteria below, specific to mCRPC patients) * Have progressive disease within the last 6 months, according to RECIST 1.1 (R09-0262) or according to PCWG3 (R17-3377) for the mCRPC cohort (see point 5 of inclusion criteria below, specific to mCRPC patients). NC patients do not need to show progression per RECIST 1.1 (for example, if newly diagnosed). * Have a tumour lesion accessible for biopsies (pre- and at steady state under treatment in Cycle 1, ideally from the same anatomic lesion) (except for mCRPC patients having only bone metastases or for patients with therapeutic INR because of treatment with a vitamin K antagonist or a novel oral anticoagulant. Biopsies are optional for NC patients * Give written informed consent for two tumour biopsies, one at screening and one after start of treatment, between Day 8 and Day 11 of Cycle 1 (or between day 3 and day 8 if the day of biopsy in Cycle 1 needs to be moved as explained in Section 3.1) (when applicable) * In addition, all patients in the mCRPC expansion cohort of Phase Ib must have: * Histologically or cytologically confirmed adenocarcinoma of the prostate * Radiographic evidence of metastatic prostate cancer (stage M1 or D2). Distant metastases evaluable by bone scan, CT scan, or MRI within 28 days before the start of study treatment. * PSA ≥ 5 ng/mL (if no measurable disease by RECIST 1.1) * Prior surgical or chemical castration with a serum testosterone of \<50 ng/dL (\< 1.7 nmol/L) by luteinizing hormone releasing level hormone (LHRH) agonist or antagonist, or by abiraterone or by enzalutamide or apalutamide. If the actual method of castration is LHRH agonist or antagonist, the patient must be willing to continue the use of LHRH agonist or antagonist during protocol treatment. * Progressive disease defined as at least one of the following: * Progressive measurable disease: using conventional solid tumour criteria RECIST 1.1 * Bone scan progression: at least two new lesions on bone scan plus a rising PSA as described in point c below * Increasing PSA level: at least two consecutive rising PSA values over a reference value (PSA no.1) taken at least 1 week apart. A third PSA (PSA no. 3) is required to be \> than PSA no. 2; if not, a fourth PSA (PSA no. 4) is required to be \> to PSA no. 2 In patients with DLBCL * Patients with histologically confirmed DLBCL who have failed 2 or more lines of systemic therapy including an anti-CD-20 therapy and an anthracycline or who are not amenable to standard therapies but have an indication for therapy as per investigator's judgement. Standard therapies may also include but are not limited to CAR-T cells therapy, depending on approved therapies in the country where the patient is treated * ECOG Performance Status 0, 1 or 2 at the time of screening * Measurable disease (radiated lesions do not qualify as target lesions) according to according to RECIL 2017 on the CT scan part of the FDG/PET-CT scan * Recovery of therapy-related toxicities from previous anti-lymphoma therapy to CTCAE \<= grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 2) * written informed consent for tumour biopsies (optional) * Further inclusion criteria apply
Exclusion criteria
For all patients: * Inability to swallow tablets * Additional other serious illness, concomitant non-oncological disease (e.g. active infectious disease including an active infection with SARS-CoV-2 confirmed by a PCR test or had one in the prior 6 weeks or active hepatitis (Hep) B infection as defined by positive Hep B DNA test, active Hep C infection as defined by positive Hep C RNA test and human immunodeficiency virus (HIV) infection (positive result in established HIV diagnostic assay), or ongoing toxicity from prior therapies considered by the investigator to potentially compromise patient's safety in this trial * Serum creatinine greater than 1.5 mg/dL (\>132 µmol/L, SI unit equivalent) * Women who are pregnant, nursing, or who plan to become pregnant while in the trial * Treatment with other investigational drugs or participation in another clinical interventional trial within the past four weeks or within five times the half-life of the previous investigational drug, whichever is shorter, before start of therapy or concomitant with this trial * Patients unable to comply with the protocol * Patients who are actively abusing alcohol or drugs. Since no alcohol or drug testing is required per protocol, it is at the investigator's discretion to determine abuse. For patients with solid tumours: * Additional other serious illness , concomitant non-oncological disease (e.g. active infectious disease or known chronic Hepatitis B/Hepatitis C infection and HIV), or ongoing toxicity from prior therapies considered by the investigator to potentially compromise patient's safety in this trial * History or presence of cardiovascular abnormalities deemed clinically relevant by the investigator such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to study entry.Left Ventricular Ejection Fraction (LVEF) less than 50% at baseline * Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the last 28 days before the start of treatment with BI 894999 * Absolute neutrophil count less than 1500/mm\^3 * Platelet count less than 100 000/mm\^3 * Bilirubin greater than 1.5 mg/dL (\>26 µmol/L, SI unit equivalent) (except known Gilbert's syndrome, accepted up to 2 mg/dL or up to 34.2 µmol/L in this case) * Aspartate amino transferase (AST) and/or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (if related to liver metastases, greater than five times the upper limit of normal) * Treatment with other investigational drugs or participation in another clinical interventional trial within the past four weeks (past two weeks for NC patients) or within five times the half-life of the previous investigational drug, whichever is the shorter, before start of therapy or concomitant with this trial * Systemic anti-cancer therapy within four weeks (past two weeks for NC patients) or five times the half-life of the drug, whichever is shorter. Radiotherapy given for curative intent or other than palliative radiotherapy within the past four weeks before start of therapy or concomitantly with this trial. This These restrictions does not apply to LHRH agonists or antagonists, steroids (given at a stable dose in the last four weeks) used for palliative intent, bisphosphonates, and denosumab and to palliative radiotherapy (no wash out required) For patients with DLBCL: * Patient is eligible for curative salvage high dose therapy followed by stem cell transplant. * Primary central nervous system (CNS) lymphoma or known CNS involvement * Prior allogeneic bone marrow or stem cell transplant * High-dose therapy with stem cell support \<3 months prior to visit 1 * AST or ALT \>2.5 x upper limit of normal (CTCAE grade 2 or higher) * Total bilirubin \>1.5 x upper limit of normal (CTCAE grade 2 or higher) * Absolute neutrophil count \<1.0 x 10\^9/L(without growth factor support) * Platelets \<100 x 10\^9/L (without transfusions) * Significant concurrent medical disease or condition which according to the investigator's judgement would either compromise patient safety or interfere with the evaluation of the safety of the test drug, e.g. symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within 6 months prior to study entry, cardiac arrhythmia requiring therapy with the exception of extra systoles or minor conduction abnormalities * Chronic or ongoing infection requiring treatment at the time of enrolment or within the previous two weeks, e.g. active infectious disease or known Hepatitis B/Hepatitis C infection, HIV * Systemic anti-DLBCL therapy within the past two weeks or five times the half-life of the drug, whichever is shorter (palliative radiotherapy and agents used for palliative reasons for example steroids and bisphosphonates, are allowed) * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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: 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 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 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 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). |
| 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. |
Countries
Belgium, France, Germany, South Korea, Spain, United States
Participant flow
Recruitment details
This was an open label, Phase Ia/Ib dose finding study with BI 894999 orally administered once a day in patients with advanced malignancies with repeated administration in patients with clinical benefit.
Pre-assignment details
For Phase Ib - Schedule B SCLC, Phase Ib - Schedule B mCRPC, DMC decided on 28Nov2018 to lower the dose of SCLC and mCRPC due to safety concern, thus patients treated prior the decision received 2.5mg BI 894999 and patients treated after the decision received 2mg . For Phase Ib - Schedule C NC, the dose was lowered since DMC reclaimed the MTD as 6/3mg on 08Jul2020 after 1 patient already treated with 7/3.5mg, so the first patient in NC and all the following patients were treated with 6/3mg.
Participants by arm
| Arm | Count |
|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 0.2 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule A was a continuous daily intake in cycles of 21 days. | 2 |
| Phase Ia - Schedule A: 0.5 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 0.5 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule A was a continuous daily intake in cycles of 21 days. | 2 |
| Phase Ia - Schedule A: 1 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 1 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule A was a continuous daily intake in cycles of 21 days. | 3 |
| Phase Ia - Schedule A: 1.5 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 1.5 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule A was a continuous daily intake in cycles of 21 days. | 6 |
| Phase Ia - Schedule A: 2 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 2 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule A was a continuous daily intake in cycles of 21 days. | 6 |
| Phase Ia - Schedule A: 5 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 5 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule A was a continuous daily intake in cycles of 21 days. | 2 |
| Phase Ia - Schedule B: 1.5 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 1.5 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule B was a continuous intake for 14 days followed by one week off treatment in cycles of 21 days. | 6 |
| Phase Ia - Schedule B: 2 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 2 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule B was a continuous intake for 14 days followed by one week off treatment in cycles of 21 days. | 6 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally 2.5 mg of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule B was a continuous intake for 14 days followed by one week off treatment in cycles of 21 days. | 13 |
| Phase Ia - Schedule C: 5/2.5 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally once daily on Day 1 and on Day 15 of each cycle a loading dose of 5 milligram (mg) of BI 894999, followed by six days daily intake of the maintenance dose of 2.5 mg of BI 894999 once daily, followed by one week off, repeated every two weeks in cycles of 28 days (Schedule C). The loading and the maintenance dose were administered in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. | 4 |
| Phase Ia - Schedule C: 6/3 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally once daily on Day 1 and on Day 15 of each cycle a loading dose of 6 milligram (mg) of BI 894999, followed by six days daily intake of the maintenance dose of 3 mg of BI 894999 once daily, followed by one week off, repeated every two weeks in cycles of 28 days (Schedule C). The loading and the maintenance dose were administered in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. | 15 |
| Phase Ia - Schedule C: 7/3.5 mg BI 894999 Adult patients with a confirmed diagnosis of advanced, unresectable and/or metastatic malignant solid tumours who had failed conventional treatment or for whom no therapy of proven efficacy existed or who were not amenable to standard therapies were administered orally once daily on Day 1 and on Day 15 of each cycle a loading dose of 7 milligram (mg) of BI 894999, followed by six days daily intake of the maintenance dose of 3.5 mg of BI 894999 once daily, followed by one week off, repeated every two weeks in cycles of 28 days (Schedule C). The loading and the maintenance dose were administered in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. | 12 |
| Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) Adult patients with histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL) were administered orally 1.5 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule B was a continuous intake for 14 days followed by one week off treatment in cycles of 21 days. | 8 |
| Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) Adult patients with histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL) were administered orally 2 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule B was a continuous intake for 14 days followed by one week off treatment in cycles of 21 days. | 4 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) Adult patients with histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL) were administered orally 2.5 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule B was a continuous intake for 14 days followed by one week off treatment in cycles of 21 days. | 2 |
| Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) Adult patients with histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL) were administered orally once daily on Day 1 and on Day 15 of each cycle a loading dose of 4 milligram (mg) of BI 894999, followed by six days daily intake of the maintenance dose of 2 mg of BI 894999 once daily, followed by one week off, repeated every two weeks in cycles of 28 days (Schedule C). The loading and the maintenance dose were administered in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. | 2 |
| Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL Patients) Adult patients with histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL) were administered orally once daily on Day 1 and on Day 15 of each cycle a loading dose of 5 milligram (mg) of BI 894999, followed by six days daily intake of the maintenance dose of 2.5 mg of BI 894999, followed by one week off, repeated every two weeks in cycles of 28 days (Schedule C). The loading and the maintenance dose were administered in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. | 2 |
| Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (SCLC Patients) This arm included adult patients diagnosed with small cell lung cancer (SCLC). SCLC patients were initialy administered 2.5 mg of BI 894999. BI 894999 administration was performed in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water according to Schedule B (continuous intake for 14 days followed by one week off treatment in cycles of 21 days).
The Data Monitoring Committee decided on 28 November 2018 to lower the 2.5 mg BI 894999 dose due to safety concerns to 2mg, therefore patients treated before the decision were administered 2.5mg, and patients treated after the decision were administered 2mg. | 12 |
| Phase Ib - Schedule B: 2.5 mg BI 894999 (CRC Patients) Adult patients diagnosed with colorectal cancer (CRC) were administered orally 2.5 milligram (mg) of BI 894999. BI 894999 administration was performed in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water according to Schedule B (continuous intake for 14 days followed by one week off treatment in cycles of 21 days). | 14 |
| Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (mCRPC Patients) This arm included adult patients diagnosed with metastatic castrate resistant prostate cancer (mCRPC).
MCRPC patients were initialy administered 2.5 mg of BI 894999. BI 894999 administration was performed in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water according to Schedule B (continuous intake for 14 days followed by one week off treatment in cycles of 21 days).
The Data Monitoring Committee decided on 28 November 2018 to lower the 2.5 mg BI 894999 dose due to safety concerns to 2mg, therefore patients treated before the decision were administered 2.5mg, and patients treated after the decision were administered 2mg. | 11 |
| Phase Ib - Schedule B: 2.5 mg BI 894999 (NC Patients) Adult patients diagnosed with NUT carcinoma (NC) were administered orally 2.5 milligram (mg) of BI 894999 once daily, in the morning, after an overnight fast, 1 hour before breakfast with at least 250 milliliter (mL) of water. Schedule B was a continuous intake for 14 days followed by one week off treatment in cycles of 21 days. The 2.5 mg dose could be reduced to 2 mg in case of adverse events. | 20 |
| Phase Ib - Schedule C: 6/3 or 7/3.5 mg BI 894999 (NC Patients) This arm included adult patients diagnosed with NUT carcinoma (NC). The DMC reclaimed the maximum tolerated dose (MTD) as 6/3mg on 08 July 2020 after 1 patient was already treated with 7/3.5mg, so the first patient in NC and all the following patients were treated with 6/3mg.
Patients in were administered orally once daily on Day 1 and on Day 15 of each cycle a loading dose of 6 milligram (mg) of BI 894999, followed by six days intake of the maintenance dose of 3 mg of BI 894999 once daily, followed by one week off, repeated every two weeks in cycles of 28 days (Schedule C). | 22 |
| Total | 174 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 | FG019 | FG020 | FG021 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Dose limiting toxicity | 0 | 0 | 0 | 0 | 3 | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 2 | 0 | 0 |
| Overall Study | Other Adverse Events | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 3 | 2 | 0 | 1 | 0 | 0 | 0 | 2 | 1 | 2 | 2 | 1 |
| Overall Study | other reasons than listed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 |
| Overall Study | Progressive disease | 2 | 2 | 3 | 5 | 3 | 0 | 5 | 5 | 11 | 3 | 10 | 8 | 8 | 2 | 2 | 2 | 1 | 9 | 12 | 7 | 16 | 18 |
| Overall Study | Refused to continue trial medication | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ia - Schedule A: 5 mg BI 894999 | Phase Ia - Schedule B: 1.5 mg BI 894999 | Phase Ia - Schedule B: 2 mg BI 894999 | Phase Ia - Schedule B: 2.5 mg BI 894999 | Phase Ia - Schedule C: 5/2.5 mg BI 894999 | Phase Ia - Schedule C: 6/3 mg BI 894999 | Phase Ia - Schedule C: 7/3.5 mg BI 894999 | Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) | Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) | Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) | Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) | Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL Patients) | Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (SCLC Patients) | Phase Ib - Schedule B: 2.5 mg BI 894999 (CRC Patients) | Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (mCRPC Patients) | Phase Ib - Schedule B: 2.5 mg BI 894999 (NC Patients) | Phase Ib - Schedule C: 6/3 or 7/3.5 mg BI 894999 (NC Patients) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.5 Years STANDARD_DEVIATION 10.6 | 69.5 Years STANDARD_DEVIATION 2.1 | 46.7 Years STANDARD_DEVIATION 9.3 | 57.5 Years STANDARD_DEVIATION 11.9 | 53.5 Years STANDARD_DEVIATION 18.1 | 54.5 Years STANDARD_DEVIATION 26.2 | 60.7 Years STANDARD_DEVIATION 10.8 | 61.5 Years STANDARD_DEVIATION 13 | 64.5 Years STANDARD_DEVIATION 7.5 | 63.3 Years STANDARD_DEVIATION 12.8 | 59.7 Years STANDARD_DEVIATION 12 | 62.5 Years STANDARD_DEVIATION 6.5 | 71.4 Years STANDARD_DEVIATION 10.9 | 78.8 Years STANDARD_DEVIATION 9 | 68.5 Years STANDARD_DEVIATION 2.1 | 68.5 Years STANDARD_DEVIATION 2.1 | 79.0 Years STANDARD_DEVIATION 9.9 | 63.5 Years STANDARD_DEVIATION 7.3 | 66.2 Years STANDARD_DEVIATION 6.3 | 69.7 Years STANDARD_DEVIATION 4.1 | 44.4 Years STANDARD_DEVIATION 13.9 | 40.5 Years STANDARD_DEVIATION 16.5 | 58.6 Years STANDARD_DEVIATION 15.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 3 Participants | 6 Participants | 5 Participants | 2 Participants | 6 Participants | 6 Participants | 13 Participants | 4 Participants | 14 Participants | 10 Participants | 2 Participants | 4 Participants | 2 Participants | 2 Participants | 1 Participants | 8 Participants | 8 Participants | 9 Participants | 17 Participants | 17 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 5 Participants | 2 Participants | 3 Participants | 4 Participants | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 5 Participants | 2 Participants | 3 Participants | 4 Participants | 27 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 3 Participants | 6 Participants | 6 Participants | 2 Participants | 6 Participants | 6 Participants | 13 Participants | 4 Participants | 15 Participants | 12 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 0 Participants | 7 Participants | 9 Participants | 8 Participants | 14 Participants | 16 Participants | 140 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 6 Participants | 0 Participants | 3 Participants | 1 Participants | 4 Participants | 2 Participants | 5 Participants | 7 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 5 Participants | 6 Participants | 0 Participants | 5 Participants | 8 Participants | 61 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 4 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants | 9 Participants | 2 Participants | 10 Participants | 5 Participants | 7 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 7 Participants | 8 Participants | 11 Participants | 15 Participants | 14 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk | EG021 affected / at risk | EG022 affected / at risk | EG023 affected / at risk | EG024 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 3 | 1 / 6 | 1 / 6 | 0 / 2 | 1 / 6 | 1 / 6 | 2 / 13 | 0 / 4 | 2 / 15 | 1 / 12 | 0 / 8 | 0 / 4 | 0 / 2 | 1 / 2 | 0 / 2 | 0 / 3 | 1 / 9 | 0 / 14 | 0 / 10 | 0 / 1 | 5 / 20 | 2 / 21 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 3 / 3 | 6 / 6 | 6 / 6 | 2 / 2 | 6 / 6 | 6 / 6 | 12 / 13 | 4 / 4 | 15 / 15 | 12 / 12 | 8 / 8 | 4 / 4 | 2 / 2 | 2 / 2 | 2 / 2 | 3 / 3 | 9 / 9 | 14 / 14 | 10 / 10 | 1 / 1 | 20 / 20 | 21 / 21 | 1 / 1 |
| serious Total, serious adverse events | 1 / 2 | 2 / 2 | 0 / 3 | 3 / 6 | 2 / 6 | 1 / 2 | 3 / 6 | 3 / 6 | 6 / 13 | 2 / 4 | 8 / 15 | 8 / 12 | 3 / 8 | 2 / 4 | 2 / 2 | 1 / 2 | 0 / 2 | 2 / 3 | 3 / 9 | 8 / 14 | 8 / 10 | 1 / 1 | 15 / 20 | 12 / 21 | 1 / 1 |
Outcome results
Primary
Phase Ia: Number of Patients With DLTs Observed in the First Cycle
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.
Time frame: First treatment cycle (the first 21 days for Schedules A and B, the first 28 days for Schedule C).
Population: Maximum Tolerated Dose (MTD) Evaluation Set (MTDS): Included all patients in the treated set (TS) of Phase 1a who were not replaced for the MTD determination.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 0 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 0 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 0 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 0 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 3 Participants |
| Phase Ia - Schedule A: 5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 2 Participants |
| Phase Ia - Schedule B: 1.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 1 Participants |
| Phase Ia - Schedule B: 2 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 0 Participants |
| Phase Ia - Schedule B: 2.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 2 Participants |
| Phase Ia - Schedule C: 5/2.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 0 Participants |
| Phase Ia - Schedule C: 6/3 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 2 Participants |
| Phase Ia - Schedule C: 7/3.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 4 Participants |
| Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 1 Participants |
| Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 1 Participants |
| Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 2 Participants |
| Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 0 Participants |
| Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed in the First Cycle | 0 Participants |
Primary
Phase Ib: Number of Patients With DLTs Observed During the On-treatment Period
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.
Time frame: 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.
Population: For Phase Ib - Schedule B SCLC, Phase Ib - Schedule B mCRPC, DMC decided on 28Nov2018 to lower the dose of SCLC and mCRPC due to safety concern, thus patients treated prior the decision received 2.5mg BI 894999 and patients treated after the decision received 2mg. For Phase Ib - Schedule C NC, the dose was lowered since DMC reclaimed the MTD as 6/3mg on 08Jul2020 after 1 patient already treated with 7/3.5mg, so the first patient in NC and all the following patients were treated with 6/3mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Number of Patients With DLTs Observed During the On-treatment Period | 3 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Number of Patients With DLTs Observed During the On-treatment Period | 2 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ib: Number of Patients With DLTs Observed During the On-treatment Period | 7 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ib: Number of Patients With DLTs Observed During the On-treatment Period | 2 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ib: Number of Patients With DLTs Observed During the On-treatment Period | 3 Participants |
Secondary
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)
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.
Time frame: 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).
Population: Pharmacokinetic (PK) analysis Set (PKS): Included all patients in the treated set (TS) who have at least one evaluable PK parameters.~In phase Ib, solid tumor patients (SCLC, mCRPC, CRC and NC) are combined by dose level (2 or 2.5mg) as data of all solid tumor patients were needed since no differences were expected, but the NC patients alone were differentiated in an additional subgroup as it was the initial indication for BI 894999.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | 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) | 10.3 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 72.6 |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | 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) | 17.9 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 46.4 |
| Phase Ia - Schedule A: 1 mg BI 894999 | 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) | 54.6 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 40.4 |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | 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) | 76.4 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 26.6 |
| Phase Ia - Schedule A: 2 mg BI 894999 | 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) | 119 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 90.3 |
| Phase Ia - Schedule A: 5 mg BI 894999 | 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) | NA nanomole *hour/Liter (nmol*h/)L | — |
| Phase Ia - Schedule B: 1.5 mg BI 894999 | 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) | 62.6 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 49.2 |
| Phase Ia - Schedule B: 2 mg BI 894999 | 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) | 81.1 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 32.1 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 | 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) | 87.0 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 28.3 |
| Phase Ia - Schedule C: 5/2.5 mg BI 894999 | 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) | 144 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 46.4 |
| Phase Ia - Schedule C: 6/3 mg BI 894999 | 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) | 176 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 37 |
| Phase Ia - Schedule C: 7/3.5 mg BI 894999 | 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) | 226 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 63.2 |
| Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) | 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) | 70.3 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 38.5 |
| Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) | 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) | 120 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 19.6 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) | 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) | NA nanomole *hour/Liter (nmol*h/)L | — |
| Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) | 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) | NA nanomole *hour/Liter (nmol*h/)L | — |
| Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL Patients) | 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) | NA nanomole *hour/Liter (nmol*h/)L | — |
| Phase Ib - Schedule B: BI 894999 2 mg (Solid Tumours Including NC) | 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) | NA nanomole *hour/Liter (nmol*h/)L | — |
| Phase Ib - Schedule B: 2.5 mg BI 894999 (NC Patients) | 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) | 73.6 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 58.2 |
| Phase Ib - Schedule B: BI 894999 2.5 mg (Solid Tumours Including NC) | 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) | 94.9 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 43.9 |
| Phase Ib - Schedule C: BI 894999 6/3 mg (NC Patients) | 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) | 125 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 50.4 |
| Phase Ib - Schedule C: BI 894999 6/3 mg (NC Patients) | 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) | 149 nanomole *hour/Liter (nmol*h/)L | Geometric Coefficient of Variation 56.7 |
Secondary
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)
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.
Time frame: 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.
Population: Pharmacokinetic (PK) analysis Set (PKS): Included all patients in the treated set (TS) who have at least one evaluable PK parameters.~In phase Ib, solid tumor patients (SCLC, mCRPC, CRC and NC) are combined by dose level (2 or 2.5mg) as data of all solid tumor patients were needed since no differences were expected, but the NC patients alone were differentiated in an additional subgroup as it was the initial indication for BI 894999.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | 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) | 4.36 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 21.1 |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | 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) | 6.43 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 2.78 |
| Phase Ia - Schedule A: 1 mg BI 894999 | 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) | 20.5 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 16.8 |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | 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) | 34.0 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 69.4 |
| Phase Ia - Schedule A: 2 mg BI 894999 | 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) | 64.9 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 71 |
| Phase Ia - Schedule B: 1.5 mg BI 894999 | 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) | 27.7 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 81.5 |
| Phase Ia - Schedule B: 2 mg BI 894999 | 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) | 44.8 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 34.8 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 | 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) | 51.5 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 41.7 |
| Phase Ia - Schedule C: 5/2.5 mg BI 894999 | 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) | 123 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 37.6 |
| Phase Ia - Schedule C: 6/3 mg BI 894999 | 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) | 212 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 45.5 |
| Phase Ia - Schedule C: 7/3.5 mg BI 894999 | 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) | 230 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 27.3 |
| Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) | 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) | 31.7 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 33.4 |
| Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) | 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) | 48.0 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 26.9 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) | 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) | 53.3 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 6.91 |
| Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) | 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) | 138 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 7.52 |
| Phase Ib - Schedule C: BI 894999 7/3.5 mg (NC Patients) | 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) | NA nanomole * hour /Liter (nmol*h/L) | — |
| Phase Ib - Schedule B: BI 894999 2 mg (Solid Tumours Including NC) | 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) | 39.2 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 38.8 |
| Phase Ib - Schedule B: 2.5 mg BI 894999 (NC Patients) | 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) | 56.9 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 58.6 |
| Phase Ib - Schedule B: BI 894999 2.5 mg (Solid Tumours Including NC) | 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) | 67.6 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 50.9 |
| Phase Ib - Schedule C: BI 894999 6/3 mg (NC Patients) | 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) | 214 nanomole * hour /Liter (nmol*h/L) | Geometric Coefficient of Variation 6.01 |
Secondary
Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax)
Maximum measured concentration of BI 894999 in plasma after the first dose (Cmax) for Phase 1a and Phase 1b is reported.
Time frame: 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.
Population: Pharmacokinetic (PK) analysis Set (PKS): Included all patients in the treated set (TS) who have at least one evaluable PK parameters.~In phase Ib, solid tumor patients (SCLC, mCRPC, CRC and NC) are combined by dose level (2 or 2.5mg) as data of all solid tumor patients were needed since no differences were expected, but the NC patients alone were differentiated in an additional subgroup as it was the initial indication for BI894999.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 0.393 nanomole/L (nmol/L) | Geometric Coefficient of Variation 35.6 |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 0.569 nanomole/L (nmol/L) | Geometric Coefficient of Variation 46.2 |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 1.75 nanomole/L (nmol/L) | Geometric Coefficient of Variation 31.6 |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 3.79 nanomole/L (nmol/L) | Geometric Coefficient of Variation 84 |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 7.39 nanomole/L (nmol/L) | Geometric Coefficient of Variation 56 |
| Phase Ia - Schedule A: 5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 16.2 nanomole/L (nmol/L) | Geometric Coefficient of Variation 68 |
| Phase Ia - Schedule B: 1.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 3.00 nanomole/L (nmol/L) | Geometric Coefficient of Variation 155 |
| Phase Ia - Schedule B: 2 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 3.93 nanomole/L (nmol/L) | Geometric Coefficient of Variation 50.2 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 4.48 nanomole/L (nmol/L) | Geometric Coefficient of Variation 46.6 |
| Phase Ia - Schedule C: 5/2.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 12.0 nanomole/L (nmol/L) | Geometric Coefficient of Variation 85.1 |
| Phase Ia - Schedule C: 6/3 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 19.4 nanomole/L (nmol/L) | Geometric Coefficient of Variation 58.4 |
| Phase Ia - Schedule C: 7/3.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 21.0 nanomole/L (nmol/L) | Geometric Coefficient of Variation 48.3 |
| Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 2.98 nanomole/L (nmol/L) | Geometric Coefficient of Variation 34.9 |
| Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 4.49 nanomole/L (nmol/L) | Geometric Coefficient of Variation 36 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 4.75 nanomole/L (nmol/L) | Geometric Coefficient of Variation 0.595 |
| Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 13.9 nanomole/L (nmol/L) | Geometric Coefficient of Variation 12.8 |
| Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | NA nanomole/L (nmol/L) | — |
| Phase Ib - Schedule C: BI 894999 7/3.5 mg (NC Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | NA nanomole/L (nmol/L) | — |
| Phase Ib - Schedule B: BI 894999 2 mg (Solid Tumours Including NC) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 4.10 nanomole/L (nmol/L) | Geometric Coefficient of Variation 37.8 |
| Phase Ib - Schedule B: 2.5 mg BI 894999 (NC Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 4.88 nanomole/L (nmol/L) | Geometric Coefficient of Variation 50.1 |
| Phase Ib - Schedule B: BI 894999 2.5 mg (Solid Tumours Including NC) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 6.01 nanomole/L (nmol/L) | Geometric Coefficient of Variation 59.6 |
| Phase Ib - Schedule C: BI 894999 6/3 mg (NC Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax) | 18.8 nanomole/L (nmol/L) | Geometric Coefficient of Variation 55.8 |
Secondary
Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss)
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.
Time frame: 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).
Population: Pharmacokinetic (PK) analysis Set (PKS): Included all patients in the treated set (TS) who have at least one evaluable PK parameters.~In phase Ib, solid tumor patients (SCLC, mCRPC, CRC and NC) are combined by dose level (2 or 2.5mg) as data of all solid tumor patients were needed since no differences were expected, but the NC patients alone were differentiated in an additional subgroup as it was the initial indication for BI894999.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 0.697 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 59.8 |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 1.26 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 24.9 |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 4.06 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 61.7 |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 5.25 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 60.1 |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 11.6 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 54.4 |
| Phase Ia - Schedule A: 5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | NA nanomole/Liter (nmol/L) | — |
| Phase Ia - Schedule B: 1.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 4.75 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 46.9 |
| Phase Ia - Schedule B: 2 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 5.62 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 27.7 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 6.94 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 42 |
| Phase Ia - Schedule C: 5/2.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 11.4 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 56.1 |
| Phase Ia - Schedule C: 6/3 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 13.1 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 41.8 |
| Phase Ia - Schedule C: 7/3.5 mg BI 894999 | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 17.1 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 63.6 |
| Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 5.48 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 32.7 |
| Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 7.67 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 8.44 |
| Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | NA nanomole/Liter (nmol/L) | — |
| Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | NA nanomole/Liter (nmol/L) | — |
| Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | NA nanomole/Liter (nmol/L) | — |
| Phase Ib - Schedule B: BI 894999 2 mg (Solid Tumours Including NC) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | NA nanomole/Liter (nmol/L) | — |
| Phase Ib - Schedule B: 2.5 mg BI 894999 (NC Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 6.51 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 70 |
| Phase Ib - Schedule B: BI 894999 2.5 mg (Solid Tumours Including NC) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 7.68 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 45.4 |
| Phase Ib - Schedule C: BI 894999 6/3 mg (NC Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 10.4 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 59.4 |
| Phase Ib - Schedule C: BI 894999 6/3 mg (NC Patients) | Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss) | 11.2 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 60.1 |
Secondary
Phase Ia and Phase Ib: Objective Response (OR)
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.
Time frame: Up to 15 months for Phase 1a and up to 28 months for Phase Ib.
Population: For Phase Ib - Schedule B SCLC, Phase Ib - Schedule B mCRPC, DMC decided on 28Nov2018 to lower the dose of SCLC and mCRPC due to safety concern, thus patients treated prior the decision received 2.5mg BI 894999 and patients treated after the decision received 2mg. For Phase Ib - Schedule C NC, the dose was lowered since DMC reclaimed the MTD as 6/3mg on 08Jul2020 after 1 patient already treated with 7/3.5mg, so the first patient in NC and all the following patients were treated with 6/3mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 1 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 1 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule A: 5 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule B: 1.5 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 1 Participants |
| Phase Ia - Schedule B: 2 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule B: 2.5 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule C: 5/2.5 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule C: 6/3 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule C: 7/3.5 mg BI 894999 | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Objective Response (OR) | 1 Participants |
| Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL Patients) | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ib - Schedule C: BI 894999 7/3.5 mg (NC Patients) | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ib - Schedule B: BI 894999 2 mg (Solid Tumours Including NC) | Phase Ia and Phase Ib: Objective Response (OR) | 0 Participants |
| Phase Ib - Schedule B: 2.5 mg BI 894999 (NC Patients) | Phase Ia and Phase Ib: Objective Response (OR) | 1 Participants |
| Phase Ib - Schedule B: BI 894999 2.5 mg (Solid Tumours Including NC) | Phase Ia and Phase Ib: Objective Response (OR) | 1 Participants |
| Phase Ib - Schedule C: BI 894999 6/3 mg (NC Patients) | Phase Ia and Phase Ib: Objective Response (OR) | 2 Participants |
Secondary
Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period
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.
Time frame: 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.
Population: Included all patients in Phase 1a who were dispensed study treatment and were documented to have taken at least one dose of the study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 0 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 0 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 0 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 2 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 4 Participants |
| Phase Ia - Schedule A: 5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 2 Participants |
| Phase Ia - Schedule B: 1.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 1 Participants |
| Phase Ia - Schedule B: 2 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 0 Participants |
| Phase Ia - Schedule B: 2.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 3 Participants |
| Phase Ia - Schedule C: 5/2.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 1 Participants |
| Phase Ia - Schedule C: 6/3 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 3 Participants |
| Phase Ia - Schedule C: 7/3.5 mg BI 894999 | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 4 Participants |
| Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 1 Participants |
| Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 2 Participants |
| Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 2 Participants |
| Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 1 Participants |
| Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL Patients) | Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period | 2 Participants |
Secondary
Phase Ib: Best Overall Response
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.
Time frame: Imaging and assessment performed every 2 cycles (solid tumours patients) or 4 cycles (mCRPC patients) for the entire treatment period, up to 28 months.
Population: For Phase Ib - Schedule B SCLC, Phase Ib - Schedule B mCRPC, DMC decided on 28Nov2018 to lower the dose of SCLC and mCRPC due to safety concern, thus patients treated prior the decision received 2.5mg BI 894999 and patients treated after the decision received 2mg. For Phase Ib - Schedule C NC, the dose was lowered since DMC reclaimed the MTD as 6/3mg on 08Jul2020 after 1 patient already treated with 7/3.5mg, so the first patient in NC and all the following patients were treated with 6/3mg.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Best Overall Response | Complete response | 0 Participants |
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Best Overall Response | Partial response | 0 Participants |
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Best Overall Response | Stable disease | 1 Participants |
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Best Overall Response | Progressive disease | 8 Participants |
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Best Overall Response | Not evaluable | 3 Participants |
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Best Overall Response | Not assessed | 0 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Best Overall Response | Not evaluable | 2 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Best Overall Response | Not assessed | 0 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Best Overall Response | Complete response | 0 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Best Overall Response | Stable disease | 2 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Best Overall Response | Progressive disease | 10 Participants |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Best Overall Response | Partial response | 0 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ib: Best Overall Response | Progressive disease | 4 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ib: Best Overall Response | Not evaluable | 4 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ib: Best Overall Response | Complete response | 0 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ib: Best Overall Response | Stable disease | 2 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ib: Best Overall Response | Partial response | 1 Participants |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ib: Best Overall Response | Not assessed | 0 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ib: Best Overall Response | Progressive disease | 9 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ib: Best Overall Response | Partial response | 1 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ib: Best Overall Response | Stable disease | 7 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ib: Best Overall Response | Not assessed | 0 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ib: Best Overall Response | Not evaluable | 3 Participants |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ib: Best Overall Response | Complete response | 0 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ib: Best Overall Response | Not evaluable | 5 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ib: Best Overall Response | Stable disease | 6 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ib: Best Overall Response | Partial response | 1 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ib: Best Overall Response | Not assessed | 0 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ib: Best Overall Response | Progressive disease | 9 Participants |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ib: Best Overall Response | Complete response | 1 Participants |
Secondary
Phase Ib: Overall Survival
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.
Time frame: Up to 28 months.
Population: Patients in NC Schedules B and C in Phase Ib dose expansion and after approval of protocol version 11.0 and gave consent to the collection of overall survival status.~For Phase Ib - Schedule C: 6/3 or 7/3.5 mg BI 894999 (NC patients) arm, the dose was lowered since DMC reclaimed the MTD as 6/3mg on 08Jul2020 after 1 patient already treated with 7/3.5mg, so the first patient in NC and all the following patients were treated with 6/3mg.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Overall Survival | 6.6 Weeks |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Overall Survival | 15.4 Weeks |
Secondary
Phase Ib: Progression-free Survival or (PFS) or Radiological PFS for mCRPC Patients With Non-measurable Disease by RECIST v1.1
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.
Time frame: Up to 28 months.
Population: For Phase Ib - Schedule B SCLC, Phase Ib - Schedule B mCRPC, DMC decided on 28Nov2018 to lower the dose of SCLC and mCRPC due to safety concern, thus patients treated prior the decision received 2.5mg BI 894999 and patients treated after the decision received 2mg. For Phase Ib - Schedule C NC, the dose was lowered since DMC reclaimed the MTD as 6/3mg on 08Jul2020 after 1 patient already treated with 7/3.5mg, so the first patient in NC and all the following patients were treated with 6/3mg.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Progression-free Survival or (PFS) or Radiological PFS for mCRPC Patients With Non-measurable Disease by RECIST v1.1 | 5.6 Weeks |
| Phase Ia - Schedule A: 0.5 mg BI 894999 | Phase Ib: Progression-free Survival or (PFS) or Radiological PFS for mCRPC Patients With Non-measurable Disease by RECIST v1.1 | 5.6 Weeks |
| Phase Ia - Schedule A: 1 mg BI 894999 | Phase Ib: Progression-free Survival or (PFS) or Radiological PFS for mCRPC Patients With Non-measurable Disease by RECIST v1.1 | 11.9 Weeks |
| Phase Ia - Schedule A: 1.5 mg BI 894999 | Phase Ib: Progression-free Survival or (PFS) or Radiological PFS for mCRPC Patients With Non-measurable Disease by RECIST v1.1 | 6.9 Weeks |
| Phase Ia - Schedule A: 2 mg BI 894999 | Phase Ib: Progression-free Survival or (PFS) or Radiological PFS for mCRPC Patients With Non-measurable Disease by RECIST v1.1 | 7.8 Weeks |
Secondary
Phase Ib: Prostate Specific Antigen (PSA) Response in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)
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).
Time frame: Up to 93 days.
Population: mCRPC Schedule B in Phase Ib dose expansion (mCRPC): Included all mCRPC patients in the treated set who were treated in Phase Ib with Schedule B.~For Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (mCRPC patients), DMC decided on 28Nov2018 to lower the dose of mCRPC due to safety concern, thus patients treated prior the decision received 2.5mg BI 894999 and patients treated after the decision received 2mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase Ia - Schedule A: 0.2 mg BI 894999 | Phase Ib: Prostate Specific Antigen (PSA) Response in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC) | 0 Participants |