A Study to Find a Safe and Effective Dose of BI 1701963 Alone and in Combination With BI 3011441 in Patients With Advanced Cancer and a Certain Mutation (Kirsten Rat Sarcoma Viral Oncogene Homologue [KRAS])

A Phase I Open-label Dose Escalation Trial of BI 1701963 as Monotherapy and in Combination With BI 3011441 in Patients With KRAS Mutated Advanced or Metastatic Solid Tumours

This is a study in adults with advanced cancer (solid tumours including non-small cell lung cancer and colorectal cancer) in whom previous chemotherapy was not successful. People who have a tumour with a KRAS mutation can participate in the study. A KRAS mutation makes cancer grow faster.

The study tests 2 medicines called BI 1701963 and BI 3011441. BI 1701963 and BI 3011441 prevent activation of KRAS.

The purpose of this study is to find out the highest dose of BI 1701963 alone and in combination with BI 3011441 the participants can tolerate. Another purpose is to check whether BI 1701963 in combination with BI 3011441 is able to make tumours shrink.

Participants can stay in the study as long as they benefit from treatment and can tolerate it. During this time, they get tablets of BI 1701963 and capsules of BI 3011441 once daily. The doctors regularly monitor the size of the tumour. Doctors also regularly record any unwanted effects and check participants' health.

Study Overview

• Status: Completed
• Conditions: Solid Tumors, KRAS Mutation
• Intervention / Treatment: Drug: BI 1701963; Drug: BI 3011441

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Aichi, Nagoya, Japan, 464-8681
    • Aichi Cancer Center Hospital
  • 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
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Previously-identified activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation in tumour tissue or blood prior to screening. Activating mutations may include but are not limited to: KRAS mutations in expressed region (exon) 2 (G12, G13), exon 3 (A59, Q61) and exon 4 (K117, A146).
• Provision of archival tumour tissue, if available, to confirm retrospectively KRAS mutation status and for biomarker assessment
• At least one target lesion that can be measured per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. In patients who only have one target lesion, and a biopsy of the lesion is required, the baseline imaging must be performed at the earliest two weeks after the biopsy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening

• Adequate organ function at screening as follows:

  • Absolute neutrophil count (ANC) ≥1.5 x 109/L; hemoglobin ≥9.0 g/dL; platelets ≥100 x 109/L without the use of haematopoietic growth factors or recent transfusion
  • Total bilirubin ≤1.5 times the upper limit of normal (ULN), or ≤4 x ULN for patients who are known to have Gilbert's syndrome.
  • Creatinine ≤1.5 x ULN. If creatinine is >1.5 x ULN, patient is eligible if concurrent glomerular filtration rate (GFR) ≥50 mL/min (measured or calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula).
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 x ULN if no demonstrable liver metastases, or ≤ 5 x ULN if transaminase elevation is attributable to liver metastases.
• Age ≥18 years of age, or over the legal age of consent as required by local legislation at informed consent.
• Recovery from any previous therapy related toxicity to Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤1 at Cycle 1 Day 1 (except for alopecia, stable sensory neuropathy must be CTCAE Grade ≤2 and except for amenorrhea/menstruation related disorders of any grade) before the first dose.
• Signed and dated written informed consent in accordance with Good Clinical Practice (GCP) and local legislation prior to admission to the trial.

Further inclusion criteria apply.

Exclusion Criteria:

• Previous anticancer chemotherapy or anticancer immunotherapy within 3 weeks of the first administration of trial drug. Previous anticancer hormonal treatment within 2 weeks of the first administration of trial drugs.
• Previous treatment with Rat sarcoma (RAS), Mitogen-activated protein kinase (MAPK) or Son of Sevenless 1 (SOS1) targeting agents

• Radiotherapy within 4 weeks prior to start of treatment 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 (major according to the investigator's assessment) performed within 4 weeks prior to start of treatment or planned during the projected course of the trial, e.g. hip replacement.
• Previous treatment with any investigational agent(s) or targeted treatment within 28 days prior to start of treatment.
• Known history of hypersensitivity to any of the excipients of BI 1701963 tablets
• History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New-York-Heart-Assocation (NYHA) classification of ≥3, unstable angina or poorly controlled arrhythmia which are considered 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.
• Left ventricular ejection fraction (LVEF) <50 %. Further exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part B with Combination therapy dose escalation	Drug: BI 1701963; BI 1701963; Drug: BI 3011441; BI 3011441
Experimental: Part C with Combination therapy dose confirmation	Drug: BI 1701963; BI 1701963; Drug: BI 3011441; BI 3011441
Experimental: Part D with Combination therapy dose expansion	Drug: BI 1701963; BI 1701963; Drug: BI 3011441; BI 3011441
Experimental: Part A monotherapy: BI 1701963 400 mg; 4 tablets of 100 milligrams (mg) of BI 1701963 (daily dosage: 400 mg) were administered orally once daily over 28-day (4-week) treatment cycles continuously. Patients KRAS mutated advanced or metastatic solid tumours continued treatment with the study drug as long as they were deriving clinical benefit or until undue drug toxicity or withdrawal of consent, whichever occurred first.	Drug: BI 1701963; BI 1701963
Experimental: Part A monotherapy: BI 1701963 600 mg; 1 tablet of 100 milligrams (mg) and 2 tablets of 250 mg of BI 1701963 (daily dosage: 600 mg) were administered orally once daily over 28-day (4-week) treatment cycles continuously. Patients KRAS mutated advanced or metastatic solid tumours continued treatment with the study drug as long as they were deriving clinical benefit or until undue drug toxicity or withdrawal of consent, whichever occurred first.	Drug: BI 1701963; BI 1701963

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with dose-limiting toxicities (DLTs) in the Maximum tolerated dose (MTD) evaluation period in monotherapy (Part A)	The number of patients with dose-limiting toxicities (DLTs) in the Maximum tolerated dose (MTD) evaluation period, i.e. first treatment cycle, in monotherapy (Part A) was reported.	From first dose until end of first treatment cycle, up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax) of BI 1701963 after the first dose in monotherapy (Part A)	The maximum plasma concentration (Cmax) of BI 1701963 after the first dose in monotherapy (Part A) was reported.	At 5 minutes before and at 30min, 1 hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h55min after the first administration of study drug.
Area under the plasma concentration-time curve over the time interval from 0 to the last quantifiable data point (AUC0-tz) of BI 1701963 after the first dose in monotherapy (Part A)	The area under the plasma concentration-time curve over the time interval from 0 to the last quantifiable data point (AUC0-tz) of BI 1701963 after the first dose in monotherapy (Part A) was reported.	At 5 minutes before and at 30min, 1 hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h55min after the first administration of study drug.
Maximum plasma concentration at steady state (Cmax,ss) of BI 1701963 after multiple doses in monotherapy (Part A)	The maximum plasma concentration at steady state (Cmax,ss) of BI 1701963 after multiple doses in monotherapy (Part A) was reported. The steady state was reach by Day 15.	At 5 minutes (min) before and at 30min, 1 hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h55min after dosing on Day 15 of first cycle.
Area under the concentration-time curve at steady state over the uniform dosing interval τ (AUCτ,ss) of BI 1701963 after multiple doses in monotherapy (Part A)	The area under the concentration-time curve at steady state over the uniform dosing interval τ (24 hours) (AUCτ,ss) of BI 1701963 after multiple doses in monotherapy (Part A) was reported. The steady state was reach by Day 15.	At 5 minutes (min) before and at 30min, 1 hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h55min after dosing on Day 15 of first cycle.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2021
• Primary Completion (Actual): January 18, 2022
• Study Completion (Actual): January 18, 2022

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: April 6, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): December 21, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: 1432-0006

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