MC# 21-27 - 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

  • Agent(s): BI 1701963 & BI 1823911
  • Disease Type(s): Solid Tumor
  • Phase(s): I
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): KRAS, KRAS G12C, SOS1

Mechanism of Action

  • BI 1701963 selectively targets and binds to SOS1, preventing the interaction of SOS1 with KRAS.  This prevents activation of downstream RAF/MEK/ERK signaling pathway by GTP-loaded KRAS.  This inhibits mutant KRAS-dependent signaling and may inhibit growth and survival of KRAS-expressing tumor cells.
  • BI 1823911 is an orally administered, small-molecule inhibitor of KRASG12C.


In this study, the sponsor and investigators want to learn:

  • How much of the study drug 1 can be given with an acceptable level of side effects
  • The effects of the study drug (good and bad)
  • How much of the study drug is absorbed into the blood and how fast it is removed
  • How proteins that indicate the status of your disease are affected with use of the study drug
  • If research tests can be used in the future to predict who will benefit from BI 1823911
  • If the study drug prevents or delays tumor growth
Inclusion Criteria
  1. Pathologically confirmed diagnosis of locally advanced or metastatic solid tumours, e.g. adenocarcinoma of the lung, colorectal cancer, pancreatic cancer or cholangiocarcinoma. NSCLC patients with mixed histology are eligible if adenocarcinoma is the predominant histology
  2. Documented disease progression despite appropriate prior standard therapies or for whom no standard therapy exists for their tumour type and disease stage
  3. 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
  4. Provision of archival tumour tissue, if available, to confirm retrospectively KRAS G12C mutation status and for biomarker assessment
  5. At least one target lesion that can be measured per 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.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  7. Adequate organ function as follows:
    1. Absolute neutrophil count (ANC) ≥1.5 x 109/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 109/L (equivalent values: ≥ 100 x 103/μL or ≥ 100 x 103/mm3) without the use of haematopoietic growth factors or transfusion
    2. 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
    3. 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 CKD-EPI formula).
    4. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 x ULN, for patients with liver metastases ≤5 x ULN
  8. Age ≥18 years of age, or over the legal age of consent as required by local legislation
  9. Recovery from any previous therapy related toxicity to CTCAE Grade ≤1 at C1 Day 1 (except for alopecia, stable sensory neuropathy must be CTCAE Grade ≤2)
  10. Signed and dated written informed consent in accordance with GCP and local legislation prior to admission to the trial
  11. Male or female patients.  Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly, prior to trial entry and for the duration of trial participation and for a minimum time-period after treatment has ended, i.e. at least 4 months for BI 1823911 and BI 1701963.  A list of contraception methods meeting these criteria is provided in the patient information.  Women of childbearing potential who are not surgically sterilized must have a negative serum pregnancy test completed during the Screening period.
Exclusion Criteria

All Parts

  1. 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.
  2. Previous treatment with RAS, MAPK or SOS1 targeting agents (only for monotherapy Parts A, B, and C)
  3. Radiotherapy within 2 weeks prior to start of treatment, provided recovery from related toxicity
  4. 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
  5. 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
  6. Known history of hypersensitivity to any of the excipients of BI 1823911 tablets, or any contraindication to Midazolam (for Monotherapy Part B only)
  7. History or presence of cardiovascular abnormalities such as congestive heart failure 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 as defined as: Blood pressure measured in a rested and relaxed condition, where systolic BP >=140 mmHg, or diastolic BP >= 90 mmHg, with or without medication.
  8. Left ventricular ejection fraction (LVEF) <50%
  9. Congenital long QT prolongation syndrome
  10. Mean resting corrected QT interval (QTcF) >470 msec
  11. Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient’s ability to comply with the trial or interfere with the evaluation of the efficacy and safety of the trial medications
  12. Previous or concomitant malignancies at other sites, except effectively treated:
    • Non-melanoma skin cancers,
    • Carcinoma in situ of the cervix,
    • Ductal carcinoma in situ,
    • Other malignancy that has been in remission for more than 3 years and is considered to be cured
  13. Leptomeningeal carcinomatosis
  14. Presence or history of uncontrolled or symptomatic brain metastases, unless considered stable by the Investigator and local therapy was completed.  Use of corticosteroids is allowed if the dose was stable for at least 2 weeks.  Inclusion of patients with newly identified brain metastasis/es at screening will be allowed if patients are asymptomatic.
    • Patients who have resected brain metastases, or have received radiation therapy that finished at least 4 weeks (whole brain radiation) or 2 weeks (stereotactic body radiotherapy) prior to treatment of the trial are considered eligible if they meet all of the following criteria:
      • Residual neurological symptoms CTCAE Grade ≤2,
      • Are taking stable doses of dexamethasone, if applicable,
      • Follow-up magnetic resonance imaging (MRI) shows no new lesions
  15. Known or suspected interstitial lung disease / interstitial pneumonitis or history of it
  16. Known active hepatitis B infection (defined as presence of Hep B sAg and/or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier
  17. Active infectious disease which puts the patient at increased risk in the opinion of the Investigator
  18. Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the trial drug (e.g. nausea, uncontrolled vomiting, Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the Investigator
  19. History of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED)
  20. Concurrent participation in another clinical trial with an investigational device or drug
  21. Concomitant use of strong CYP3A4 inhibitors or inducers.  Concomitant use of highly sensitive substrates of CYP3A4 and CYP3A4 substrates with narrow therapeutic index as well as sensitive P-gp substrates with narrow therapeutic index. In addition, any moderate CYP3A4 inhibitors and inducers are not permitted during monotherapy part B in Cycle 1 from day -8 until day 8 and in Cycle 1 from day 21 until Cycle 2 day 1 addressing food effect and DDIs.
  22. Women who are pregnant, nursing, or who plan to become pregnant while in the trial or within 6 months after the last dose of trial treatment
  23. Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial
  24. Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the Investigator’s opinion, makes the patient an unreliable trial participant)

Combination Therapy Arm

  1. Hypersensitivity to any of the excipients of the respective combination partner(s) (based on the treatment allocated)
  2. Concomitant use of sensitive CYP2C9 substrates with narrow therapeutic index


  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info:

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Re: MC# 21-27