Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Carcinoma

Breast Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Breast Diseases

Skin Diseases

Patients receive ZEN003694 PO QD on days 1-28 or 5 days on and 2 days off, and abemaciclib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo imaging evaluation, blood sample collection and tumor biopsy throughout the study.

Abemaciclib

BET Bromodomain Inhibitor ZEN-3694

Biopsy

Biospecimen Collection

Diagnostic Imaging

Site Public Contact

Robert Hsu

Jia Luo

Liza C. Villaruz

Sarina A. Piha-Paul

This phase I trial tests the safety, side effects, and best dose of a ZEN003694 when given together with abemaciclib in treating patients with NUT carcinoma, breast cancer or other solid tumors that have spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that overproduce BET protein. Abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ZEN003694 and abemaciclib may help shrink or stabilize cancer in patients with NUT carcinoma, breast cancer or other solid tumors.

PRIMARY OBJECTIVE:

I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of BET bromodomain inhibitor ZEN-3694 (ZEN003694) and abemaciclib.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. Determine the preliminary rates of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), time to response (TTR) and duration of response (DoR) for the combination of ZEN003694 and abemaciclib in participants utilizing Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

III. Evaluate the pharmacokinetic (PK) profile of the combination.

EXPLORATORY OBJECTIVE:

I. Explore potential biomarker indicators of response and resistance in tumor tissue and blood samples.

OUTLINE: This is a dose-escalation study of BET bromodomain inhibitor ZEN-3694 followed by a dose expansion study.

Patients receive ZEN003694 orally (PO) once daily (QD) on days 1-28 or 5 days on and 2 days off, and abemaciclib PO twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo imaging evaluation, blood sample collection and tumor biopsy throughout the study.

After completion of study treatment, patients are followed up for 30 days, every 3 months for 2 years, and then every 6 months for 3 years.

Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors

A Phase 1 Study of BET Bromodomain Inhibitor ZEN003694 in Combination With the CDK4/6 Inhibitor Abemaciclib in Patients With NUT Carcinoma, Breast Cancer and Other Solid Tumors

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

An internal pipeline will be used to perform quality control and data pre-processing. Burrows-Wheeler Aligner will be used for read mapping against the hg19 map using default parameters.

The toxicity of the combination will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v). 5.0 criteria.

Safety will be reported with descriptive statistics. Toxicity will be graded according to National Cancer Institute CTCAE, v5.0. Toxicities will be summarized by maximum grade and by treatment arm. Incidence rate of each toxicity will be reported with 95% exact confidence intervals.

Will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease.

Clinical benefit is defined as CR, PR or SD \>= 24 weeks according to Response Evaluation Criteria in Solid Tumors 1.1. CBR will be reported with 90% exact confidence intervals.

Designed the PK sampling to enable simultaneous estimation of individual pharmacokinetic parameters of abemaciclib, ZEN003694, and their respective metabolites using nonlinear mixed effects modeling. Will compare the ratio of observed/historical 90% confidence interval of abemaciclib exposure.

Will compare exposures of abemaciclib and abemaciclib metabolites to TK activity at cycle 1 day 15 and beyond and also change in TK activity versus clinical outcomes.

National Cancer Institute (NCI)

Once daily continuous oral intake in 3-week cycles.

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

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.

BI 894999

Boehringer Ingelheim

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.

BI 894999 First in Human Dose Finding Study in Advanced Malignancies

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

After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement".

Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

The data shared are the raw clinical study data sets.

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.

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.

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.

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.

Maximum measured concentration of BI 894999 in plasma after the first dose (Cmax) for Phase 1a and Phase 1b is reported.

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.

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.

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.

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.

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.

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.

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).

Treated Set (TS): Included all patients who were dispensed study treatment and were documented to have taken at least one dose of the study treatment.

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.

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 0.5 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.

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 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.

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 1.5 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.

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 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.

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 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.

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 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.

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 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.

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 2.5 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.

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 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.

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 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.

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 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.

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

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.

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 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.

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 2.5 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.

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 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.

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 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.

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

Adult patients diagnosed with small cell lung cancer (SCLC) were administered 2.5 milligram (mg) of BI 894999 once daily. 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).

Phase Ib - Schedule B: 2.5 mg BI 894999 (SCLC Patients)

Adult patients diagnosed with small cell lung cancer (SCLC) were administered orally 2 milligram (mg) of BI 894999 once daily. 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).

Phase Ib - Schedule B: 2 mg BI 894999 (SCLC 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).

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

Adult patients diagnosed with metastatic castrate resistant prostate cancer (mCRPC) were administered orally 2.5 milligram (mg) of BI 894999 once daily. 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).

Phase Ib - Schedule B: 2.5 mg BI 894999 (mCRPC Patients)

Adult patients diagnosed with metastatic castrate resistant prostate cancer (mCRPC) were administered orally 2 milligram (mg) of BI 894999 once daily. 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).

Phase Ib - Schedule B: 2 mg BI 894999 (mCRPC 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.

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

Adult patients diagnosed with NUT carcinoma (NC) 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).

Phase Ib - Schedule C: BI 894999 6/3 mg (NC Patients)

Adult patients diagnosed with NUT carcinoma (NC) 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 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.

Phase Ib - Schedule C: BI 894999 7/3.5 mg (NC Patients)

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

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

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

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

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

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.

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.

Boehringer Ingelheim, Call Center

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 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.

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.

Phase Ia: Number of Patients With DLTs Observed in the First Cycle

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.

Phase Ib: Number of Patients With DLTs Observed During the On-treatment Period

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.

Phase Ia: Number of Patients With DLTs Observed During the On-treatment Period

Adult patients diagnosed with one of the following cancer types small cell lung cancer (SCLC); metastatic castrate resistant prostate cancer (mCRPC); NUT carcinoma (NC) 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.

Phase Ib - Schedule B: BI 894999 2 mg (Solid Tumours Including NC)

Adult patients diagnosed with one of the following cancer types small cell lung cancer (SCLC); metastatic castrate resistant prostate cancer (mCRPC); colorectal cancer (CRC); NUT carcinoma (NC) were administered orally 2.5 milligram (mg) of BI 894999, 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.

Phase Ib - Schedule B: BI 894999 2.5 mg (Solid Tumours Including NC)

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.

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)

Adult patients diagnosed with NUT carcinoma (NC) who 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 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.

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.

Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma After the First Dose (Cmax)

Adult patients diagnosed with NUT carcinoma (NC) who were administered during the first cycle 2.5 milligram (mg) BI 894999 according to Schedule B and then the dosage was decreased at steady state to 2 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.

Phase Ib - Schedule B: 2 mg BI 894999 (NC Patients Only)

Adult patients diagnosed with one of the following cancer types small cell lung cancer (SCLC); metastatic castrate resistant prostate cancer (mCRPC); colorectal cancer (CRC); NUT carcinoma (NC) who were administered orally 2.5 milligram (mg) of BI 894999, 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.

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)

Adult patients diagnosed with NUT carcinoma (NC) were administered during the first cycle 2.5 milligram (mg) BI 894999 according to Schedule B and then the dosage was decreased at steady state to 2 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.

Adult patients diagnosed with NUT carcinoma (NC) who 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).

Phase Ia and Phase Ib: Maximum Measured Concentration of BI 894999 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax, ss)

Phase Ia and Phase Ib: Objective Response (OR)

Phase Ib: Progression-free Survival or (PFS) or Radiological PFS for mCRPC Patients With Non-measurable Disease by RECIST v1.1

Complete response

Partial response

Stable disease

Progressive disease

Not evaluable

Not assessed

Phase Ib: Best Overall Response

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.

Phase Ib: Overall Survival

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.

Phase Ib: Prostate Specific Antigen (PSA) Response in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Patients will be assigned escalated dose according to BOIN design. The starting dose is 5 mg orally once a day for 7 consecutive days followed by 14 days of rest.

EP31670 (also known as NEO2734) is a first-in-class dual BET and CBP/p300 inhibitor.

EP31670

Judy Chiao, MD

Atish Choudhury, MD

Jia Luo, MD

Rabia Khan

Sarina A Piha-Paul, MD

Chi Westerhold

Michael Schweizer, MD

A Phase 1, first-in-human study of EP31670, a dual BET and CBP/p300 inhibitor in patients with targeted advanced solid tumors.

EP31670 (also known as NEO2734) is a first-in-class dual BET and CBP/p300 inhibitor which has demonstrated antitumor activity in in vitro and in vivo models of human cancer. This Phase I open-label, multi-center, dose-escalation study will assess the safety and determine the maximum tolerated dose of EP31670 administered orally in patients with castration-resistant prostate cancer, NUT midline carcinoma and other targeted advanced solid tumors.

Dose escalation/de-escalation will follow rules by employing the Bayesian optimal interval (BOIN) method.

Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors

A Phase 1 Study of EP31670, a Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors

MTD is the highest dose level at which ≤30% of patients experienced DLTs during cycle 1.

DLT is any of the following adverse events (AEs) that occur during cycle 1.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors	NCT05372640	Breast Carcinom... Malignant Solid... NUT Carcinoma	Abemaciclib BET Bromodomain... Biopsy Biospecimen Col... Diagnostic Imag...	12 Years -	National Cancer Institute (NCI)
BI 894999 First in Human Dose Finding Study in Advanced Malignancies	NCT02516553	Neoplasms NUT Carcinoma	BI 894999	18 Years -	Boehringer Ingelheim
Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors	NCT05488548	Castrate Resist... NUT Carcinoma	EP31670	18 Years -	Epigenetix, Inc.
Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors	NCT05372640	Breast Carcinom... Malignant Solid... NUT Carcinoma	Abemaciclib BET Bromodomain... Biopsy Biospecimen Col... Diagnostic Imag...	12 Years -	National Cancer Institute (NCI)
Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors	NCT05372640	Breast Carcinom... Malignant Solid... NUT Carcinoma	Abemaciclib BET Bromodomain... Biopsy Biospecimen Col... Diagnostic Imag...	12 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for nut carcinoma