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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02516553




Registration number
NCT02516553
Ethics application status
Date submitted
27/07/2015
Date registered
6/08/2015
Date last updated
6/12/2021

Titles & IDs
Public title
BI 894999 First in Human Dose Finding Study in Advanced Malignancies
Scientific title
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
Secondary ID [1] 0 0
2015-001111-12
Secondary ID [2] 0 0
1367.1
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms 0 0
NUT Carcinoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - BI 894999
Treatment: Drugs - BI 894999
Treatment: Drugs - BI 894999

Experimental: arm A - once daily continuous oral intake in 3-week cycles

Experimental: arm B - once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles

Experimental: arm C - one week on followed by one week off treatment, repeated every two weeks in 4-week cycles


Treatment: Drugs: BI 894999
day 1 to day 21 in 3-week cycles

Treatment: Drugs: BI 894999
day 1 to day 14 followed by a week off in 3-week cycles in schedule B

Treatment: Drugs: BI 894999
one week on followed by one week off treatment, repeated every two weeks in 4-week cycles
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
In phase Ib: Number of patients experiencing DLTs from start of treatment until end of treatment (in all cycles) as assessed approximately every 3 weeks after Cycle 2 (at the end of each new cycle) in order to determine the recommended phase II dose
Timepoint [1] 0 0
average of 12 months
Primary outcome [2] 0 0
In phase Ia: Number of patients with DLT observed in the first cycle (first 21 days) for Schedules A and B, first 28 days for Schedule C), to meet objective of assessing MTD for each schedule in solid tumour patients & in schedule B in the DLBCL cohort
Timepoint [2] 0 0
Up to 4 weeks
Secondary outcome [1] 0 0
efficacy endpoint in phases Ia and Ib: Objective response (OR), defined as CR or PR with tumour assessment during treatment period for each schedule
Timepoint [1] 0 0
every 6 weeks, average of 4 months
Secondary outcome [2] 0 0
efficacy endpoint in phase Ib: Progression-free Survival (PFS) or radiological PFS
Timepoint [2] 0 0
average of 5 months
Secondary outcome [3] 0 0
efficacy endpoint in phase Ib: Best overall response with an evaluation of approximately every 2 cycles (6 weeks if no delays) during the entire treatment period
Timepoint [3] 0 0
every 6 weeks, average of 4 months
Secondary outcome [4] 0 0
In both phases: Cmax,ss after single dose and at steady state, as measured during the first cycle (3 weeks) for Schedules A and B, the first 4 weeks for Schedule C)
Timepoint [4] 0 0
up to 4 weeks
Secondary outcome [5] 0 0
In both phases: AUC0-24 after single dose and at steady state, as measured during the first cycle (3 weeks) for Schedules A and B, the first 4 weeks for Schedule C)
Timepoint [5] 0 0
up to 4 weeks
Secondary outcome [6] 0 0
In both phases: AUC tau, ss after single dose and at steady state, as measured during the first cycle (3 weeks) for Schedules A and B, the first 4 weeks for Schedule C)
Timepoint [6] 0 0
up to 4 weeks
Secondary outcome [7] 0 0
Phase Ia: Number of patients experiencing DLTs from start of treatment until end of treatment (in all cycles) for each of the schedules (A, B and C) in patients with solid tumours and in schedule B in the DLBCL cohort
Timepoint [7] 0 0
average of 12 months
Secondary outcome [8] 0 0
In both phases: Cmax after single dose and at steady state, as measured during the first cycle (3 weeks) for Schedules A and B, the first 4 weeks for Schedule C)
Timepoint [8] 0 0
up to 4 weeks
Secondary outcome [9] 0 0
efficacy endpoint in phase Ib: Prostate Specific Antigen (PSA) response (decline in PSA value =50% from baseline) in patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)
Timepoint [9] 0 0
average of 12 months
Secondary outcome [10] 0 0
Overall survival in patients with NUT Carcinoma (NC)
Timepoint [10] 0 0
Up to 29 months

Eligibility
Key inclusion criteria
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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 exclusion criteria apply

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/07/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
23/11/2021
Sample size
Target
Accrual to date
Final
174
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
United States of America
State/province [2] 0 0
New York
Country [3] 0 0
United States of America
State/province [3] 0 0
Ohio
Country [4] 0 0
United States of America
State/province [4] 0 0
Texas
Country [5] 0 0
Belgium
State/province [5] 0 0
Anderlecht
Country [6] 0 0
Belgium
State/province [6] 0 0
Bruxelles
Country [7] 0 0
Belgium
State/province [7] 0 0
Gent
Country [8] 0 0
Belgium
State/province [8] 0 0
Leuven
Country [9] 0 0
France
State/province [9] 0 0
Marseille
Country [10] 0 0
France
State/province [10] 0 0
Nantes
Country [11] 0 0
France
State/province [11] 0 0
Paris
Country [12] 0 0
France
State/province [12] 0 0
Villejuif
Country [13] 0 0
Germany
State/province [13] 0 0
Tübingen
Country [14] 0 0
Korea, Republic of
State/province [14] 0 0
Seoul
Country [15] 0 0
Spain
State/province [15] 0 0
Barcelona
Country [16] 0 0
Spain
State/province [16] 0 0
Madrid

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Boehringer Ingelheim
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT02516553
Trial related presentations / publications
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Boehringer Ingelheim
Address 0 0
Boehringer Ingelheim
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02516553