A Study to Test Different Doses of BI 3011441 in Japanese People With Different Types of Advanced Cancer (NRAS/KRAS Mutation Positive)

A Phase I Open-label Trial of BI 3011441 in Japanese Patients With NRAS/KRAS Mutation Positive Advanced, Unresectable or Metastatic Refractory Solid Tumours

This study is open to Japanese adults with different types of advanced cancer that are positive for NRAS/KRAS mutations. This is a study in people for whom previous treatment was not successful or no standard treatment exists.

The purpose of this study is to find the highest dose of BI 3011441 that Japanese people with advanced cancer can tolerate. BI 3011441 is a medicine that may turn off a signal by NRAS/KRAS that makes tumours grow.

Participants take BI 3011441 as capsules once a day. Participants can stay in the study as long as they benefit from treatment and can tolerate it. The doctors collect information on any health problems of the participants.

Study Overview

• Status: Completed
• Conditions: Solid Tumors, KRAS Mutation
• Intervention / Treatment: Drug: BI 3011441

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba, Kashiwa, Japan, 277-8577
    • National Cancer Center Hospital East
  • Tokyo, Chuo-ku, Japan, 104-0045
    • National Cancer Center Hospital
  • Tokyo, Koto-ku, Japan, 135-8550
    • Japanese Foundation for Cancer Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Must be at least 20 years of age at screening.
• Signed and dated written informed consent in accordance with Good Clinical Practice(GCP) and local legislation prior to admission to the trial.
• Pathologically documented, locally-advanced or metastatic malignancy with previously identified activating Neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) or Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation based on local test.
• Provision of archival tumor tissue, if available, to confirm retrospectively NRAS or KRAS mutation status and for biomarker assessment.
• Willingness to undergo pre- and on-treatment tumour biopsies for pharmacodynamics and biomarker assessment. Patients can be enrolled without tumour biopsy upon agreement between the Investigator and the Sponsor if tumour biopsy is not feasible (Apply only to study site which agreed to conduct biopsy).
• Must have either progressed despite appropriate prior standard therapies or for whom no standard therapy exists for their tumour type and disease stage
• Must have at least one target lesion that can be measured per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1
• Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Further inclusion criteria apply.

Exclusion Criteria:

• Previous anticancer chemotherapy within 3 weeks of the first administration of trial drug. Previous anticancer hormonal treatment or anticancer immunotherapy within 2 weeks of the first administration of trial drugs.

• Radiotherapy within 4 weeks prior to first administration of BI 3011441 except as follows

  • Palliative radiotherapy to regions other than the chest is allowed up to 2 weeks prior to start of treatment
  • Single dose palliative radiotherapy for symptomatic metastasis within 2 weeks prior to start of treatment may be allowed but must be discussed with the sponsor.
• Major surgery within 4 weeks prior to start of treatment or scheduled during the projected course of the trial
• Previous treatment with a Rat sarcoma (RAS), Mitogen-activated protein kinase (MAPK) targeting agent
• Previous treatment with any investigational agent(s) or targeted treatment within 4 weeks (28 days) prior to start of trial drug or concurrent participation in another clinical trial with an investigational device or drug.
• Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient's ability to comply with the study or interfere with the evaluation of the efficacy and safety of the study medications
• Patients who have a history or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment or central serous retinopathy; for example, predisposing factors of RVO or central serous retinopathy include uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes.

• Patients who have visible retinal pathology that is considered a risk factor for RVO or central serous retinopathy as assessed by ophthalmic examination, such as:

  • Evidence of new optic disc cupping
  • Evidence of new visual field defects
  • Intraocular pressure >21 mm Hg History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of ≥2, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator; Myocardial infarction within 6 months prior to start of treatment. Uncontrolled hypertension is defined as: Blood pressure (BP) measured in a rested and relaxed condition, where systolic BP >=140 mmHg, or diastolic BP >= 90 mmHg, with or without medication.

Further exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 4 mg BI 3011441; The patients were administered 4 milligram (mg) BI 3011441 soft capsule once daily during 4 weeks with water limited to a maximum of 100 milliliters (mL) per capsules, taken without food, at least 1 hour before a meal or 1 hour after a meal. Patients continued the treatment until undue drug toxicity, disease progression, or withdrawal of consent, whichever occurred first.	Drug: BI 3011441; BI 3011441
Experimental: 6 mg BI 3011441; The patients were administered 6 milligram (mg) BI 3011441 soft capsule once daily during 4 weeks with water limited to a maximum of 100 milliliters (mL) per capsules, taken without food, at least 1 hour before a meal or 1 hour after a meal. Patients continued the treatment until undue drug toxicity, disease progression, or withdrawal of consent, whichever occurred first.	Drug: BI 3011441; BI 3011441
Experimental: 8 mg BI 3011441; The patients were administered 8 milligram (mg) BI 3011441 soft capsule once daily during 4 weeks with water limited to a maximum of 100 milliliters (mL) per capsules, taken without food, at least 1 hour before a meal or 1 hour after a meal. Patients continued the treatment until undue drug toxicity, disease progression, or withdrawal of consent, whichever occurred first.	Drug: BI 3011441; BI 3011441

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With DLTs in the MTD Evaluation Period	Number of participants with Dose limiting toxicities (DLT) occurring during the first treatment cycle (first 4 weeks). DLT was defined as any of the following adverse events related to the treatment: Haematologic toxicities:; Neutropenia Grade 4 lasting for >7 days days without documented infection; Neutropenia Grade ≥3 with documented infection; Grade ≥3 febrile neutropenia; Grade 4 neutropenia defined as life-threatening consequences or urgent intervention indicated; Grade 5 neutropenia defined as a fatal neutropenia; Grade 3 thrombocytopenia associated with bleeding	First treatment cycle, the first 28 days following the start of trial medication.
Maximum Tolerated Dose (MTD) of BI 3011441 Monotherapy	Maximum tolerated dose (MTD) of BI 3011441 monotherapy. The MTD was defined as the highest dose with less than 25% risk of the true dose-limiting toxicity (DLT) rate being equal or above 0.33 (EWOC criterion) during the MTD evaluation period. The analysis of the MTD was based on a Bayesian 2-parameter logistic regression model (BLRM) with overdose control.	First treatment cycle, the first 28 days following the start of trial medication.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With DLTs During the Entire On-treatment Period	Number of participants with Dose limiting toxicities (DLT) occurring during the first treatment cycle (first 4 weeks). DLT was defined as any of the following adverse events related to the treatment: Haematologic toxicities:; Neutropenia Grade 4 lasting for >7 days days without documented infection; Neutropenia Grade ≥3 with documented infection; Grade ≥3 febrile neutropenia; Grade 4 neutropenia defined as life-threatening consequences or urgent intervention indicated; Grade 5 neutropenia defined as a fatal neutropenia; Grade 3 thrombocytopenia associated with bleeding	From first BI 3011441 intake until last BI 3011441 intake + 30 days of Residual effect period (REP), up to 373 days.
Number of Patients With Grade ≥3 Treatment-related Adverse Events	Number of participants with Grade ≥3 treatment-related adverse events is reported. The severity of AEs were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The CTCAE grades are Grade 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).	From first BI 3011441 intake until last BI 3011441 intake + 30 days of Residual effect period (REP), up to 373 days.
Number of Patients With Treatment Related Adverse Events	Number of participants with drug-related adverse events (AEs) analysed as investigator defined drug-related AEs is presented. Medical judgment was used to determine the relationship between the AEs and the study medication, considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant medication, concomitant diseases and relevant history.	From first BI 3011441 intake until last BI 3011441 intake + 30 days of Residual effect period (REP), up to 373 days.
Area Under the Concentration-time Curve of BI 3011441 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)	Area under the concentration-time curve of BI 3011441 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.	Cycle 1: Day 1: Within 5 minutes (min) before and 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h and optionally 12h. and Day 2 : Within 5 minutes (min) before dosing on Day 2.
Area Under the Concentration-time Curve of BI 3011441 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point at Steady State (AUC0-tz,ss)	Area under the concentration-time curve of BI 3011441 in plasma over the time interval from 0 to the last quantifiable data point at steady state (AUC0-tz,ss) is reported.	Cycle 1: Day 15: Within 5 minutes (min) before drug administration on Day 15, and 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h and optionally 12h. and Day 16 : Within 5 minutes (min) before dosing on Day 16.
Maximum Measured Concentration of BI 3011441 in Plasma After First Dose (Cmax)	Maximum measured concentration of BI 3011441 in plasma (Cmax) is reported.	Cycle 1: Day 1: Within 5 minutes (min) before and 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h and optionally 12h. and Day 2 : Within 5 minutes (min) before dosing on Day 2.
Maximum Measured Concentration of BI 3011441 in Plasma at Steady State (Cmax,ss)	Maximum measured concentration of BI 3011441 in plasma at steady state (Cmax,ss) is reported. PK samples were collected at the following timepoints.	Cycle 1: Day 15: Within 5 minutes (min) before drug administration on Day 15, and 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h and optionally 12h. and Day 16 : Within 5 minutes (min) before dosing on Day 16.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2021
• Primary Completion (Actual): October 13, 2022
• Study Completion (Actual): October 20, 2022

Study Registration Dates

• First Submitted: February 3, 2021
• First Submitted That Met QC Criteria: February 5, 2021
• First Posted (Actual): February 8, 2021

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: April 26, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: 1469-0002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents, except for the following exclusions:

1. studies in products where Boehringer Ingelheim is not the license holder;
2. studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials;
3. studies conducted in a single center or targeting rare diseases (because of limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datasharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No