A Study to Test Different Doses of BI 1701963 in Combination With Irinotecan in People With Advanced Bowel Cancer With Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Mutation

Study Overview
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Brief Summary
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This study is open to adults with advanced bowel cancer (colorectal cancer) with a KRAS mutation. This is a study in people for whom previous treatment was not successful and surgery is not a treatment option. The purpose of this study is to find the highest dose of BI 1701963 that people with bowel cancer can tolerate when taken together with a medicine called irinotecan. The study also tests whether BI 1701963 in combination with irinotecan is able to make tumours shrink. BI 1701963 may help to turn off KRAS. Activating KRAS mutations make tumours grow. Irinotecan is a medicine to treat bowel cancer. Participants can stay in the study as long as they benefit from treatment and can tolerate it. During this time, participants take BI 1701963 as tablet once a day and get irinotecan as infusion every two weeks. The doctors regularly monitor the size of the tumour. The doctors also collect information on any health problems of the participants.

Official Title
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A Phase 1 Open-label Dose Escalation Trial of BI 1701963 in Combination With Irinotecan in KRAS Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer (CRC)

Intervention / Treatment
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* Drug: BI 1701963
* Drug: Camptosar®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have a confirmed activating KRAS mutation in CRC tumour tissue by local test. Activating mutations include but are not limited to: KRAS mutations in exon 2 (G12, G13), exon 3 (A59, Q61) and exon 4 (K117, A146) Patients must have a histological or cytological diagnosis of CRC Patients must have received at least first-line chemotherapy (oxaliplatin/ 5-Fluorouracil (5-FU)/ capecitabine et al treatment failure) for unresectable locally advanced or metastatic CRC Must have at least one target lesion that can be accurately measured per RECIST version 1.1 Must have Eastern Cooperative Oncology Group score of 0 or 1 Must show adequate organ function defined as all of the following: Absolute neutrophil count (ANC) ≥1.5 x 109/L; haemoglobin ≥9.0 g/dL; platelets ≥100 x 109/L without the use of hematopoietic growth factors within 4 weeks of start of Trial medication. Total bilirubin ≤1.5 x Upper Limited 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) ≥30 mL/min (measured or calculated by CKD-EPI formula) Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤3 x ULN if no demonstrable liver metastases, or otherwise ≤5 x ULN For patients participating in the combination dose escalation and expansion parts (Part B and C), must be eligible to receive treatment with irinotecan in accordance with the local label including Summary of Product Characteristics (SmPC), U.S. PI or Chinese Label Must be at least 18 years of age at screening Must have recovered from any previous therapy related toxicity to CTCAE grade ≤1 before the first dose (except for alopecia; stable sensory neuropathy must be CTCAE grade ≤2) Signed and dated written informed consent in accordance with good clinical practice and local legislation prior to admission to the trial further inclusion criteria apply Exclusion Criteria: Previous anticancer chemotherapy, anticancer immunotherapy, and/or other anticancer biologic therapy within 3 weeks of the first administration of trial drug. Previous anticancer hormonal therapy within 2 weeks of first administration of trial drug Previous treatment with a RAS, Mitogen-activated protein kinase (MAPK) or Son of Sevenless 1 (SOS1) targeting agent For patients participating in the combination dose escalation and expansion parts (Part B and C only): Previous treatment with irinotecan Radiotherapy within 4 weeks 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 Association (NYHA) classification of ≥3, 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 Left ventricular ejection fraction (LVEF) <50% Congenital long QT prolongation syndrome or mean resting corrected QT interval (QTcF) >470 msec further exclusion criteria apply

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: Parallel Assignment
Interventional Model Description: Trial consists of three parts: Monotherapy safety run-in part (Part A), combination dose escalation part (Part B), combination therapy expansion part (Part C). A randomization will be included for the expansion therapy part (Part C) because the same patient population will be recruited to two different dose levels at the same time.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Expansion dose 1<br>Part C: Combination therapy expansion part | Drug: BI 1701963<br>* Tablet<br>Drug: Camptosar®<br>* Solution for infusion<br>|
| Experimental: Expansion dose 2<br>Part C: Combination therapy expansion part | Drug: BI 1701963<br>* Tablet<br>Drug: Camptosar®<br>* Solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) based on the number of dose limiting toxicities (DLTs) in the MTD evaluation period | Combination dose escalation part (Part B) | 28 days | 
| Number of patients experiencing DLTs in the MTD evaluation period | Combination dose escalation part (Part B) | 28 days | 
| Objective Response (OR) according to RECIST version 1.1 | Combination therapy expansion part (Part C) | 28 days per treatment cycle. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with DLTs in the first treatment cycle | Monotherapy safety run-in part (Part A) | 28 days | 
| Maximum measured concentration of BI 1701963 in plasma (Cmax) | Monotherapy safety run-in part (Part A) | 28 days per treatment cycle. | 
| Area under the concentration time curve of BI 1701963 in plasma over the time interval from 0 to the last quantifiable plasma concentration (AUC0-tz) | Monotherapy safety run-in part (Part A) | 28 days per treatment cycle. | 
| Area under the concentration-time curve of BI 1701963 in plasma over the dosing interval τ at steady state (AUCτ(,ss)) | Monotherapy safety run-in and combination dose escalation part (Part A+B) | 28 days per treatment cycle. | 
| Maximum measured concentration of BI 1701963 in plasma at steady state over a uniform dosing interval tau (Cmax,ss) | Monotherapy safety run-in and combination dose escalation part (Part A+B) | 28 days per treatment cycle. | 
| Duration of objective response (DOR) | Combination therapy expansion part (Part C) | 28 days per treatment cycle. | 
| Tumour shrinkage (in millimetres) | Combination therapy expansion part (Part C) | 28 days per treatment cycle. | 
| Progression-free survival (PFS) | Combination therapy expansion part (Part C) | Up to 6 months. | 
| Number of patients experiencing grade ≥3 treatment-related AEs during the entire treatment period | Combination therapy expansion part (Part C) | 28 days per treatment cycle. |