A Study to Find the Best Dose of BI 905711 in Combination With Chemotherapy and to Test Whether This Dose Helps People With Advanced Gastrointestinal Cancers

Study Overview
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Brief Summary
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This study is open to adults with advanced colorectal cancer or with advanced pancreatic cancer. The study has 2 parts. In the first part, participants with colorectal cancer get a medicine called BI 905711 combined with chemotherapy and bevacizumab. The purpose of the first part is to find the highest BI 905711 dose participants can tolerate. In the second part, participants with colorectal cancer or pancreatic cancer get BI 905711 combined with chemotherapy. Some participants also get bevacizumab. The second part tests whether BI 905711 makes tumours shrink. Participants get BI 905711, chemotherapy and bevacizumab about every 2 weeks as an infusion into a vein. Participants can stay in the study as long as they benefit from treatment and can tolerate it. The doctors regularly check the health of the participants and note any health problems that could have been caused by the study treatment. The doctors also monitor the size of the tumour.

Official Title
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A Phase Ia/Ib, Open Label, Multicentre, Dose Escalation Study of BI 905711 in Combination With Chemotherapy Followed by Expansion Cohorts in Patients With Advanced Gastrointestinal Cancers

Conditions
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Gastrointestinal Cancer, Metastatic

Intervention / Treatment
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* Drug: BI 905711
* Drug: FOLFIRI
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent in accordance with International Council of Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial. Of legal adult age (according to local legislation) at screening. Histologically or cytologically confirmed, advanced unresectable or metastatic colorectal adenocarcinoma. Colorectal adenocarcinoma (CRC): Patients who have Progressive disease (PD) after prior oxaliplatin-based first line therapy or within 6 months after the end of oxaliplatin-based adjuvant therapy. Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Life expectancy ≥ 3 months in the opinion of the investigator. Availability and willingness to provide tumor tissue (fresh biopsy or archival) for biomarker analysis. Only non-significant risk procedures per the investigator's judgment will be used to obtain any biopsies specified in this study. In case a fresh tumor biopsy cannot be obtained, the recruitment of the patient may proceed on a case-by-case basis after agreement between the investigator and BI. In such a case, an archived tumor tissue specimen must be submitted. Adequate hepatic, pancreatic, renal and bone marrow functions as defined by all of the below: Total bilirubin ≤ 1.5 x institutional upper level of normal (ULN). Alanine transaminase (ALT) and Aspartate transaminase (AST) ≤2.5 x institutional ULN or ≤5 x institutional ULN for patients with known liver metastases. Serum creatinine ≤1.5x institutional ULN. If creatinine is > 1.5 x ULN, patient is eligible if concurrent creatinine clearance ≥ 50 ml/min (≥ 0.05L/min) (measured or calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or Japanese version of CKD-EPI formula for Japanese patients). Absolute neutrophil count (ANC) ≥ 1.5 x 1^9/L, ≥ 1.5 x 10^3/μL, or ≥ 1500/mm^3 Platelets ≥ 100 x 10^9/L, ≥ 100 x 10^3/μL, or ≥ 100 x 10^3/mm^3 Hemoglobin (Hb) ≥ 8.5 g/dl, ≥ 85 g/L, or ≥ 5.3 mmol/L (without transfusion within previous week) Serum lipase ≤ 1.5 institutional ULN (Only for CRC cohort); >1.5 - 2.0 x ULN or asymptomatic >2.0 - 5.0 x ULN if related to Pancreatic Ductal Adenocarcinoma (PDAC) (Only for PDAC cohort) Further inclusion criteria apply. Exclusion criteria: Any prior irinotecan-based therapy in the metastatic setting. Previous systemic anti-cancer therapy within the specified timeframe from the last dose intake to the first dose of trial treatment as follows: Any non-investigational drug, including anti-angiogenic agents (bevacizumab or ramucirumab or aflibercept) and anti-EGFR antibodies (cetuximab or panitumumab), within 14 days. Any investigational drug or other antibodies including immune checkpoint inhibitors, within 28 days. Currently enrolled in another investigational device or drug trial. Patients who are in follow-up/observation for another clinical trial are eligible. Radiation therapy within 4 weeks prior to start of treatment. However, palliative radiotherapy for symptomatic metastasis is allowed if completed within 2 weeks prior to start of treatment. Any serious concomitant disease or medical condition affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal (GI) tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, and in the judgment of the Investigator, would make the patient inappropriate for entry into the trial. Known pathological condition of GI tract, liver and pancreas, excluding the disease under study, that may interfere with assessment of drug safety or may increase the risk of toxicity: inflammatory bowel disease chronic pancreatitis other serious GI pathological conditions by judgment of the investigator e.g. autoimmune disease with GI involvement, unexplained active diarrhea CTCAE v5.0 grade ≥ 2. Known history of human immunodeficiency virus (HIV) infection. Any of the following laboratory evidence of hepatitis virus infection. Test results obtained in routine diagnostics are acceptable if done within 14 days before the informed consent date: Positive results of hepatitis B surface (HBs) antigen Presence of HBc antibody together with hepatitis B virus deoxyribonucleic acid (HBV-DNA) Presence of hepatitis C ribonucleic acid (RNA) Further exclusion criteria.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1a non randomized, Phase 1b randomized.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a: BI 905711 + FOLFIRI + Bevacizumab<br>Phase 1a: Dose escalation in colorectal adenocarcinoma (CRC) | Drug: BI 905711<br>* BI 905711<br>Drug: FOLFIRI<br>* FOLFIRI<br>Drug: Bevacizumab<br>* Bevacizumab<br>|
| Experimental: Phase 1b: BI 905711 + FOLFIRI<br>Phase 1b: Dose Expansion: Single arm cohort in 2nd line Pancreatic Ductal Adenocarcinoma (PDAC) | Drug: BI 905711<br>* BI 905711<br>Drug: FOLFIRI<br>* FOLFIRI<br>|
| Experimental: Phase 1b: BI 905711 + FOLFIRI + Bevacizumab<br>Phase 1b: Dose Expansion: Randomized cohort in 2nd line colorectal adenocarcinoma (CRC); Arm A. | Drug: BI 905711<br>* BI 905711<br>Drug: FOLFIRI<br>* FOLFIRI<br>Drug: Bevacizumab<br>* Bevacizumab<br>|
| Experimental: Phase 1b: FOLFIRI + Bevacizumab<br>Phase 1b: Dose Expansion: Randomized cohort in 2nd line colorectal adenocarcinoma (CRC); Arm B. | Drug: FOLFIRI<br>* FOLFIRI<br>Drug: Bevacizumab<br>* Bevacizumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being equal or above 33% during the MTD evaluation period |  | Up to 28 days. | 
| Phase 1a: Number of patients with DLTs in the MTD evaluation period |  | Up to 28 days. | 
| Phase 1b: Confirmed objective response (OR) as assessed by the investigator | Confirmed objective response (OR) as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in patients with measurable disease, defined as the best overall response of complete response (CR) or partial response (PR), from the first administration of trial medication until the earliest of progressive disease (PD), death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. | Up to 13 months. | 
| Phase 1b: Number of patients with DLTs during the MTD evaluation period assessed in the first 6 patients | In safety run-in part of Pancreatic Ductal Adenocarcinoma (PDAC) cohort. | Up to 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Cmax: Maximum measured plasma concentration of BI 905711 during the first cycle |  | Up to 14 days. | 
| Phase 1a: Cmax: Maximum measured plasma concentration of BI 905711 after multiple cycles |  | Up to 13 months. | 
| Phase 1a: AUC0-t2: Area under the concentration-time curve in plasma of BI 905711 during the first cycle |  | Up to 14 days. | 
| Phase 1a: AUC0-t2: Area under the concentration time-curve in plasma of BI 905711 after multiple cycles |  | Up to 13 months. | 
| Phase 1b: Progression Free Survival (PFS) | Progression-Free Survival (PFS) defined from date of start of treatment to the date of disease progression or death, whichever is earlier as assessed by the investigator according to RECIST 1.1. | Up to 13 months. | 
| Phase 1b: Radiological (CT Scan) tumor shrinkage | Radiological (CT Scan) tumor shrinkage, defined as the difference between the minimum post-baseline sum of longest diameters of target lesions and the baseline sum of longest diameters of the same set of target lesions according to RECIST 1.1. | Up to 13 months. | 
| Phase 1b: Duration of objective response (OR) | The duration of OR is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively documented (taking as reference for PD the smallest measurements recorded on study) according to RECIST 1.1. | Up to 13 months. | 
| Phase 1b: Disease control, defined as complete response (CR), partial response (PR), or stable disease (SD) lasting at least 16 weeks according to RECIST 1.1 | Disease control, defined as CR, PR, or stable disease (SD) lasting at least 16 weeks according to RECIST 1.1 from the start of treatment until the earliest of PD, death or last evaluable tumor assessment and before start of subsequent anti-cancer therapy. | Up to 13 months. | 
| Phase 1b: Cmax: Maximum measured plasma concentration of BI 905711 during the first cycle |  | Up to 14 days. | 
| Phase 1b: Cmax: Maximum measured plasma concentration of BI 905711 after multiple cycles |  | Up to 13 months. | 
| Phase 1b: AUC0-t2: Area under the concentration-time curve of BI 9057 during the first treatment cycle |  | Up to 14 days. | 
| Phase 1b: AUC0-t2: Area under the concentration-time curve of BI 9057 after multiple cycles |  | Up to 13 months. |