Clinical trial NCT04973163: A Study to Test Different Doses of BI 1823911 Alone and Combined With Other Medicines in People With Different Types of Advanced Cancer With KRAS Mutation
Official title: A Phase Ia/Ib, Open-label, Multicentre Dose-escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of BI 1823911 as a Monotherapy and in Combination With Other Anti-cancer Therapies in Patients With Advanced or Metastatic Solid Tumours Expressing KRAS G12C Mutation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Solid Tumors, KRAS Mutation
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2021-07-22
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The following parts will be included in this trial:

* First: Monotherapy Arm
* After confirmation of safety: Combination Therapy Arm

Each arm consists of three parts (dose escalation (A), dose confirmation (B), and dose expansion (C)).
Primary purpose: TREATMENT

Brief summary: This study is open to adults with different types of advanced or metastatic cancer (including lung cancer, colorectal cancer, pancreatic cancer, and bile duct cancer). This study is for people for whom previous treatment was not successful or no treatment exists.

People who have a tumour with a KRAS mutation can participate in the study. A KRAS mutation makes tumours grow faster. BI 1823911 and BI 1701963 are medicines that may turn off KRAS, each in a different way. In this study, BI 1823911 is given to people for the first time.

The purpose of this study is to find the highest dose of BI 1823911 that people can tolerate when taken alone and together with BI 1701963. The most suitable dose is used to find out whether BI 1823911 alone and in combination with BI 1701963 can make tumours shrink.

Participants can stay in the study as long as they benefit from treatment and can tolerate it.

During this time, participants take tablets of BI 1823911 alone or in combination with BI 1701963 once a day. The doctors regularly monitor the size of the tumour. Doctors also regularly record any unwanted effects and check participant's health.


Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed diagnosis of locally advanced or metastatic solid tumours, e.g. adenocarcinoma of the lung, colorectal cancer, pancreatic cancer or cholangiocarcinoma. Non-small cell lung cancer (NSCLC) patients with mixed histology are eligible if adenocarcinoma is the predominant histology.
* Documented disease progression despite appropriate prior standard therapies or for whom no standard therapy exists for their tumour type and disease stage.
* KRAS mutation status: Kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation in tumour tissue or blood based on previously performed local testing using a validated test.
* Provision of archival tumour tissue, if available, to confirm retrospectively KRAS G12C 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 (radiated lesions do not qualify as target lesions). In patients who only have one target lesion, and a biopsy of the lesion is required, the baseline imaging must be performed before the biopsy or at the earliest two weeks after the biopsy.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate organ function as follows:

  * Absolute neutrophil count (ANC) ≥1.5 x 10\^9/L (equivalent values: ≥ 1.5 x 10³/μL or ≥ 1500/mm³); hemoglobin ≥9.0 g/dL (equivalent values: ≥ 90 g/L or ≥ 5.6 mmol/L); platelets ≥100 x 10\^9/L (equivalent values: ≥ 100 x 10³/μL or ≥ 100 x 10³/mm³) without the use of haematopoietic growth factors.
  * 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 creatinine clearance ≥50 mL/min (equivalent value: 0.84mL/s) (measured or calculated by Cockcroft-Gault formula).
  * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 x ULN, for patients with liver metastases ≤5 x ULN.
* Age ≥18 years of age, or over the legal age of consent as required by local legislation.

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 drug.
* Previous treatment with Rat Sarcoma (RAS), Mitogen-activated protein kinase (MAPK) or Son of sevenless 1 (SOS1) targeting agents (only for monotherapy Parts A, B, and C).
* Radiotherapy within 2 weeks prior to start of treatment, provided recovery from related toxicity.
* 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 or 5 half-lives, whichever is shorter.
* Known history of hypersensitivity to any of the excipients of BI 1823911 tablets, or any contraindication to Midazolam (for Monotherapy Part B only).
* History or presence of cardiovascular abnormalities such as congestive heart failure New York Heart Association (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 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.

Primary outcomes:
measure: Dose escalation (Part A) - Monotherapy and combination therapy: Number of patients experiencing Dose limiting toxicities (DLTs) during the Maximum tolerated dose (MTD) evaluation period for BI 1823911 in monotherapy and in each combination
timeFrame: up to 28 days
measure: Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Objective response (OR) defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR)
timeFrame: up to 39 months
Secondary outcomes:
measure: Dose escalation (Part A) - Monotherapy and combination therapy: Number of patients experiencing DLTs during all treatment cycles for BI 1823911 in monotherapy and in each combination
timeFrame: up to 39 months
measure: Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Objective response (OR)
timeFrame: up to 39 months
measure: Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Duration of OR
timeFrame: up to 39 months
measure: Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Tumour shrinkage (in millimetres)
timeFrame: up to 39 months
measure: Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Progression-free survival (PFS) rate
timeFrame: at month 6
measure: All study parts: Number of patients with adverse events during the on-treatment period
timeFrame: up to 39 months
measure: All study parts, BI 1823911: Maximum concentration (Cmax)
timeFrame: up to 24 hours
measure: All study parts, BI 1823911: Steady state concentration (Css)
timeFrame: up to 24 hours
measure: All study parts, BI 1823911: Area under the plasma concentration-time curve from time zero to time t (AUCτ)
timeFrame: up to 24 hours
measure: All study parts, BI 1823911: Area under the plasma concentration-time curve at steady state (AUCss)
timeFrame: up to 24 hours
measure: All study parts, BI 1701963: Maximum concentration (Cmax)
timeFrame: up to 24 hours
measure: All study parts, BI 1701963: Steady state concentration (Css)
timeFrame: up to 24 hours
measure: All study parts, BI 1701963: Area under the plasma concentration-time curve from time zero to time t (AUCτ)
timeFrame: up to 24 hours
measure: All study parts, BI 1701963: Area under the plasma concentration-time curve at steady state (AUCss)
timeFrame: up to 24 hours
Other outcomes:
Locations:
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Anderlecht/Brussels-Capital
country: Belgium
facility: Brussels - HOSP Jules Bordet
city: Edegem/Antwerpen
country: Belgium
facility: Edegem - UNIV UZ Antwerpen
city: Gent/Oost-Vlaanderen
country: Belgium
facility: UNIV UZ Gent
city: Leuven/Vlaams-Brabant
country: Belgium
facility: UZ Leuven
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Manchester
country: United Kingdom
facility: The Christie
Study officials:
References: