BI 894999 First in Human Dose Finding Study in Advanced Malignancies

NCT02516553 | Completed Phase 1 Results

• 2 other identifiers: 1367.12015-001111-12
• Study Type: interventional
• Target: 174
• Locations: 6 countries
• Sites: 16

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.

Conditions

Neoplasms; NUT Carcinoma

Keywords

NUT midline carcinoma

Outcome Measures

Primary Outcomes (2)

• 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.

  First treatment cycle (the first 21 days for Schedules A and B, the first 28 days for Schedule C).

• 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.

  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.

Secondary Outcomes (10)

• 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.

• 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.

• 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.

• 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).

• 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).

Study Arms (22)

Phase Ia - Schedule A: 0.2 mg BI 894999

EXPERIMENTAL

Once daily continuous oral intake in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule A: 0.5 mg BI 894999

EXPERIMENTAL

Once daily continuous oral intake in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule A: 1 mg BI 894999

EXPERIMENTAL

Once daily continuous oral intake in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule A: 1.5 mg BI 894999

EXPERIMENTAL

Once daily continuous oral intake in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule A: 2 mg BI 894999

EXPERIMENTAL

Once daily continuous oral intake in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule A: 5 mg BI 894999

EXPERIMENTAL

Once daily continuous oral intake in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule B: 1.5 mg BI 894999

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule B: 2 mg BI 894999

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule B: 2.5 mg BI 894999

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule C: 5/2.5 mg BI 894999

EXPERIMENTAL

Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days.

Drug: BI 894999

Phase Ia - Schedule C: 6/3 mg BI 894999

EXPERIMENTAL

Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days.

Drug: BI 894999

Phase Ia - Schedule C: 7/3.5 mg BI 894999

EXPERIMENTAL

Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days.

Drug: BI 894999

Phase Ia - Schedule B: 1.5 mg BI 894999 (DLBCL patients)

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL patients)

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule B: 2.5 mg BI 894999 (DLBCL patients)

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ia - Schedule C: 4/2 mg BI 894999 (DLBCL patients)

EXPERIMENTAL

Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days.

Drug: BI 894999

Phase Ia - Schedule C: BI 894999 5/2.5 mg (DLBCL patients)

EXPERIMENTAL

Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days.

Drug: BI 894999

Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (SCLC patients)

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ib - Schedule B: 2.5 mg BI 894999 (CRC patients)

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ib - Schedule B: 2 or 2.5 mg BI 894999 (mCRPC patients)

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ib - Schedule B: 2.5 mg BI 894999 (NC patients)

EXPERIMENTAL

Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles.

Drug: BI 894999

Phase Ib - Schedule C: 6/3 or 7/3.5 mg BI 894999 (NC patients)

EXPERIMENTAL

Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days.

Drug: BI 894999

Interventions

BI 894999 DRUG

film-coated tablets

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: 1.5 mg BI 894999 (DLBCL patients); Phase Ia - Schedule B: 2 mg BI 894999; Phase Ia - Schedule B: 2 mg BI 894999 (DLBCL patients); Phase Ia - Schedule B: 2.5 mg BI 894999; 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: 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 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 or 2.5 mg BI 894999 (mCRPC patients); Phase Ib - Schedule B: 2.5 mg BI 894999 (CRC 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)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (16)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10021, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Brussels - HOSP Jules Bordet

Anderlecht, 1070, Belgium

Location

Brussels - UNIV Saint-Luc

Brussels, 1200, Belgium

Location

UNIV UZ Gent

Ghent, 9000, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

HOP Timone

Marseille, 13385, France

Location

HOP Hôtel-Dieu

Nantes, 44000, France

Location

HOP Saint-Louis

Paris, 75475, France

Location

INS Gustave Roussy

Villejuif, 94800, France

Location

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Related Publications (1)

• Schoffski P, Machiels JP, Rottey S, Sadrolhefazi B, Musa H, Marzin K, Awada A. Phase Ia dose-escalation trial with the BET protein inhibitor BI 894999 in patients with advanced or metastatic solid tumours. Eur J Cancer. 2023 Sep;191:112987. doi: 10.1016/j.ejca.2023.112987. Epub 2023 Jul 11.

  PMID: 37556913 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Neoplasms

Interventions

BI 894999

Limitations and Caveats

This trial was closed in accordance with protocol-defined criteria for stopping the trial following assessments of futility. Trial was completed as described in protocol.

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Study Officials

• Boehringer Ingelheim

  Boehringer Ingelheim

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2015
• First Posted: August 6, 2015
• Study Start: July 8, 2015
• Primary Completion: November 23, 2021
• Study Completion: November 23, 2021
• Last Updated: April 15, 2024
• Results First Posted: April 15, 2024

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: After all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication.
• Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by both the independent review panel and the sponsor, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a 'Data Sharing Agreement'.

Locations

FR (4); KR (1); US (4); BE (4); ES (2); DE (1)