A Study to Find a Safe and Effective Dose of BI 905711 in Patients With Advanced Gastrointestinal Cancer

NCT04137289 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 1412-00012018-003268-29
• Study Type: interventional
• Target: 110
• Locations: 8 countries
• Sites: 18

Brief Summary

Phase 1a - Explore safety and establish the maximum tolerated dose (MTD)/recommended dose levels for phase Ib expansion phase of BI 905711 based on the frequency of patients experiencing dose limiting toxicities (DLTs) during the MTD evaluation period. The MTD evaluation period is defined as the first two treatment cycles (from first dose administration until the day preceding the third dose administration or end of REP in case of discontinuation before start of Cycle 3). Phase 1a - Explore pharmacokinetics/pharmacodynamics, and efficacy to guide the determination of a potentially effective dose range for phase Ib in the absence of MTD. Phase 1b - Evaluate efficacy and safety of BI 905711 at a potentially effective dose range and determine the Recommended Phase 2 Dose (RP2D)

Conditions

Gastrointestinal Neoplasms; Cholangiocarcinoma; Pancreatic Neoplasms

Outcome Measures

Primary Outcomes (4)

• Maximum Tolerated Dose (MTD) of BI 905711 in Phase 1a

  Maximum tolerated dose (MTD) was defined as the highest dose with less than 25% risk of the true drug limiting dose (DLT) rate being equal to or above 33% during the MTD evaluation period. The MTD was to be considered reached if one of the following criteria was fulfilled: the posterior probability of the true DLT rate in the target interval (0.16, 0.33) of the MTD is above 0.5 or at least 15 patients have been treated in phase 1a, of which at least 6 were at the MTD.

  From cycle 1 Day 1 until the second administration of study treatment (two 14-day treatment cycles).

• Number of Patients With Dose-limiting Toxicity (DLT) During the MTD Evaluation Period in Phase 1a

  Number of patients with dose-limiting toxicity (DLT) during the MTD evaluation period is reported.

  From cycle 1 Day 1 until the day before cycle 3 Day 1 (two 14-day treatment cycles).

• Confirmed Objective Response (OR) for Phase 1a and Phase 1b Combined

  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 is reported. This was defined as the best overall response of complete response (CR) or partial response (PR), where best overall response was the best response recorded from the start of the study treatment until the earliest of disease progression, death, or last evaluable tumor assessment and before start of subsequent anticancer therapy.

  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 48 weeks.

• Progression-free Survival (PFS)

  This was evaluated per RECIST 1.1 criteria for target lesions and assessed by CT scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. Overall response at each time point was evaluated by target lesion, non-target lesions and new lesions together, according to RECIST 1.1. Objective response (OR) was defined as best overall response of confirmed CR or confirmed PR according to RECIST 1.1.

  From the first administration of trial medication until tumor progression or death, whichever occurred first, up to 48 weeks.

Secondary Outcomes (12)

• Maximum Measured Plasma Concentration (Cmax) of BI 905711 During the First Cycle in Phase 1a

  Within 5 minutes (min) before start of BI 905711 infusion and at 30 min, 7 hours (hrs), 24 hrs, 48 hrs, 168 hrs and 336 hrs after BI 905711 infusion in cycle 1.

• Maximum Measured Plasma Concentration (Cmax) of BI 905711 During the Third Cycle in Phase 1a

  Cycle 3: Within 5 minutes (min) before start of BI 905711 infusion and at 30 min, 7 hours (hrs), 24 hrs, 48 hrs, 168 hrs and 336 hrs after BI 905711 infusion.

• Area Under the Concentration-time Curve (AUC0-336) of BI 905711 During the First Cycle in Phase 1a

  Within 5 minutes (min) before start of BI 905711 infusion and at 30 min, 7 hours (hrs), 24 hrs, 48 hrs, 168 hrs and 336 hrs after BI 905711 infusion in cycle 1 .

• Area Under the Concentration-time Curve (AUC0-336) of BI 905711 During the Third Cycle in Phase 1a

  Cycle 3: Within 5 minutes (min) before start of BI 905711 infusion and at 30 min, 7 hours (hrs), 24 hrs, 48 hrs, 168 hrs and 336 hrs after BI 905711 infusion.

• Maximum Measured Plasma Concentration (Cmax) of BI 905711 During the First Cycle in Phase 1b

  Within 5 minutes (min) before start of BI 905711 infusion and at 30 min, 7 hours (hrs), 24 hrs, 48 hrs, 168 hrs and 336 hrs after infusion in cycle 1. For 0.6 mg/kg QW only, there was no 336 hrs timepoint as the next drug was already given after 168 hrs.

Study Arms (9)

BI 905711 0.02 mg/kg, Q2W

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.02 milligram/kilogram (mg/kg) of BI 905711 intravenously as a powder for solution for infusion, on Day 1 of each 14-day cycle treatment, once every two weeks.

Drug: BI 905711

BI 905711 0.06 mg/kg, Q2W

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.06 mg/kg of BI 905711 intravenously as a powder for solution for infusion, on Day 1 of each 14-day cycle treatment, once every two weeks.

Drug: BI 905711

BI 905711 0.2 mg/kg, Q2W

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.2 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks.

Drug: BI 905711

BI 905711 0.6 mg/kg, Q2W

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.6 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks. Participants in both the dose escalation and dose expansion phases at this dose were pooled together for baseline analysis.

Drug: BI 905711

BI 905711 0.6 mg/kg, QW

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.6 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every week for 3 weeks and then 1 week off (3 weeks on, 1 week off).

Drug: BI 905711

BI 905711 1.2 mg/kg, Q2W

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 1.2 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks. Participants in both the dose escalation and dose expansion phases at this dose were pooled together for baseline analysis.

Drug: BI 905711

BI 905711 2.4 mg/kg, Q2W

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 2.4 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks. Participants in both the dose escalation and dose expansion phases at this dose were pooled together for baseline analysis.

Drug: BI 905711

BI 905711 3.6 mg/kg, Q2W

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 3.6 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks.

Drug: BI 905711

BI 905711 4.8 mg/kg, Q2W

EXPERIMENTAL

Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 4.8 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks.

Drug: BI 905711

Interventions

BI 905711 DRUG

BI 905711

BI 905711 0.02 mg/kg, Q2W; BI 905711 0.06 mg/kg, Q2W; BI 905711 0.2 mg/kg, Q2W; BI 905711 0.6 mg/kg, Q2W; BI 905711 0.6 mg/kg, QW; BI 905711 1.2 mg/kg, Q2W; BI 905711 2.4 mg/kg, Q2W; BI 905711 3.6 mg/kg, Q2W; BI 905711 4.8 mg/kg, Q2W

Eligibility Criteria

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

You may qualify if:

• \- a. Phase Ia (dose escalation only)
• Histologically or cytologically confirmed, advanced unresectable or metastatic gastrointestinal cancers of following histologies:
• Colorectal adenocarcinoma
• Gastric adenocarcinoma
• Esophageal adenocarcinoma
• Pancreatic adenocarcinoma
• Cholangiocarcinoma and gallbladder carcinoma
• Small intestine adenocarcinoma b. Phase Ib (expansion phase)
• Histologically or cytologically confirmed, advanced unresectable or metastatic colorectal adenocarcinoma.
• Patient who has failed all available conventional therapies known to confer clinical benefit for their disease based on local approved standards. For patients with colorectal cancer, prior treatment with regorafenib or TAS-102 is optional.
• Phase Ia (dose escalation) only: Patient with either measurable or non-measurable/non-evaluable disease.
• Phase Ia (expanded cohort) and Phase Ib (expansion phase) only: At least one target lesion that can be accurately measured per RECIST v.1.1
• Availability and willingness to provide an archived tumor tissue specimen and undergo tumor biopsy before treatment. Pre-treatment fresh tumor biopsy collections for biomarker analyses are considered optional in phase Ia and mandatory in phase Ib. Only nonsignificant 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 due to before mentioned reasons an archived tumor tissue specimen obtained within ≤6 months of screening must be submitted. In case the patient undergoes baseline tumor biopsy, an archived tumor tissue specimen must be submitted regardless of the date of collection.
• Adequate hepatic, renal and bone marrow functions as defined by all of the below:
• Total bilirubin ≤ 1.5 x institutional Upper Level of Normal (ULN) (≤ 3 x institutional ULN for patient with Gilbert's syndrome)

You may not qualify if:

• Previous systemic anti-cancer therapy within the specified timeframe from the last dose intake to the first dose of trial treatment as shown below:
• Any non-investigational drug, including anti-angiogenic antibodies (bevacizumab or ramucirumab) and anti-EGFR antibodies (cetuximab or panitumumab), within 14 days.
• Any investigational drug or other antibodies including immune checkpoint inhibitors, within 28 days.
• 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 but must be discussed with the sponsor.
• 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. Any history of stroke or myocardial infarction within 6 months prior to screening.
• 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 grade ≥2 according to CTCAE v5.0.
• Known history of human immunodeficiency virus 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 HBV-DNA
• Presence of hepatitis C RNA
• Active concomitant malignancies, other than the one treated in this trial.

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (18)

Yale Cancer Center

New Haven, Connecticut, 06511, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10022, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

START South Texas Accelerated Research Therapeutics, LLC

San Antonio, Texas, 78229, United States

Location

Brussels - UNIV Saint-Luc

Brussels, 1200, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Beijing Cancer Hospital

Beijing, 100142, China

Location

The Sixth Affiliated Hospital of Sun Yat-sen University

Guangzhou, 510655, China

Location

HOP Jean Minjoz

Besançon, 25030, France

Location

CTR Leon Berard

Lyon, 69373, France

Location

HOP la Milétrie

Poitiers, 86021, France

Location

CTR Eugène Marquis

Rennes, 35042, France

Location

Universitätsklinikum Mannheim GmbH

Mannheim, 68167, Germany

Location

National Cancer Center Hospital East

Chiba, Kashiwa, 277-8577, Japan

Location

Korea University Anam Hospital

Seoul, 02841, South Korea

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Clínico de Valencia

Valencia, 46010, Spain

Location

Related Publications (1)

• Garcia-Martinez JM, Wang S, Weishaeupl C, Wernitznig A, Chetta P, Pinto C, Ho J, Dutcher D, Gorman PN, Kroe-Barrett R, Rinnenthal J, Giragossian C, Impagnatiello MA, Tirapu I, Hilberg F, Kraut N, Pearson M, Kuenkele KP. Selective Tumor Cell Apoptosis and Tumor Regression in CDH17-Positive Colorectal Cancer Models using BI 905711, a Novel Liver-Sparing TRAILR2 Agonist. Mol Cancer Ther. 2021 Jan;20(1):96-108. doi: 10.1158/1535-7163.MCT-20-0253. Epub 2020 Oct 9.

  PMID: 33037135 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Gastrointestinal Neoplasms; Cholangiocarcinoma; Pancreatic Neoplasms

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases

Limitations and Caveats

Based on available preliminary data from Phase 1 clinical studies (1412-0001 and 1412-0003), the decision was made to terminate the BI 905711 (TRAILR2/CDH17) development program. This decision was not related to any safety concerns or unfavorable benefit/risk balance, but to the lack of predictive biomarkers and the limited efficacy, particularly in the context of the evolving treatment landscape for advanced colorectal cancer (CRC) and other gastrointestinal (GI) cancers.

Results Point of Contact

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

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Publication Agreements

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

Study Design

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

Model Details: Phase 1a: Dose escalation (non randomised) Phase 1b: Dose expansion (randomised)

Study Record Dates

• First Submitted: October 22, 2019
• First Posted: October 24, 2019
• Study Start: March 11, 2020
• Primary Completion: July 26, 2023
• Study Completion: November 27, 2023
• Last Updated: March 25, 2025
• Results First Posted: March 25, 2025

Record last verified: 2025-03

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

CN (2); FR (4); ES (3); KR (1); JP (1); BE (2); DE (1); US (4)