MC# 21-25

Whole Trial

1. Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or metastatic non-haematologic malignancy.  Patient must have measurable or evaluable lesions (according to RECIST 1.1).
2. Eastern Cooperative Oncology Group score of 0 or 1
3. Availability and patient willingness to provide a sample of tumour for confirmation of the patient´s HER2 status.  This sample can be archival material obtained at any time prior to study enrollment.
4. Patient willing to undergo a fresh tumour biopsy prior to first treatment and also 5-7h after any treatment with BI 1810631 during cycle 1 (except biopsies of brain metastases) for pharmacodynamic assessments
5. Adequate organ function defined as all of the following:
   • Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L (≥ 1.5 x 103/µL) (≥ 1500/mm³); haemoglobin ≥ 9.0 g/dL (≥ 90 g/L) (≥ 5.6 mmol/L); platelets ≥ 100 x 10⁹/L (100 x 10³/µL) (100 x 10³/mm³) without the use of hematopoietic growth factors within 4 weeks of start of trial medication
   • Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), except for patients with Gilbert’s syndrome: total bilirubin ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN
   • Creatinine ≤ 1.5 x ULN.  If creatinine is > 1.5 x ULN, patient is eligible if concurrent creatinine clearance ≥ 50 mL/min (measured or calculated by Chronic Kidney Disease  Epidemiology (CKD-EPI) formula or Japanese version of CKD-EPI formula for Japanese patients).
   • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN if no demonstrable liver metastases, or otherwise ≤ 5 x ULN if transaminase elevation is attributable to liver metastases
   • Alkaline Phosphatase < 5 x ULN
6. Recovered from any previous therapy-related toxicity to ≤ CTCAE Grade 1 at start of treatment (except for alopecia, stable sensory neuropathy and hypothyroidism (patients on thyroid replacement therapy) which must be ≤ CTCAE Grade 2)
7. Life expectancy of at least 12 weeks at the start of treatment in the opinion of the investigator
8. At least 18 years of age at the time of consent or over the legal age of consent in countries where that is greater than 18 years
9. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial
10. Male or female patients.  Women of childbearing potential (WOCBP)1 and men who are 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.  A list of contraception methods meeting these criteria is provided in the patient information and in the Clinical Trial Protocol.

Phase Ia

11. Patients with a documented diagnosis of HER2 aberration: overexpression OR gene amplification OR non-synonymous somatic mutation OR gene rearrangement involving HER2 or NRG1
12. Patient who has failed conventional treatment or for whom no therapy of proven efficacy exists or who is not eligible for established treatment options.  Patient must have exhausted, or not be a suitable candidate for, available treatment options known to prolong survival for their disease.

Phase Ib

13. Patient with documented HER2 Exon20 insertion-mutation positive NSCLC as per central lab results (see section 6.2.1 for further details)
14. Patient who had received, in the advanced/metastatic setting, at least one line of systemic therapy that includes a platinum-based combination chemotherapy.  Patients with NSCLC harboring additionally genomic aberrations for which approved targeted therapy is available such as but not limited to non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS re-arrangement, and BRAF V600E mutation, must have received prior treatment with an approved targeted therapy.

1. Major surgery (major according to the investigator’s assessment) performed within 4 weeks prior to first trial treatment or planned within 6 months after screening
2. Previous or concomitant malignancies other than the one treated in this trial within the last 2 years, except;
   1. effectively treated non-melanoma skin cancers
   2. effectively treated carcinoma in situ of the cervix
   3. effectively treated ductal carcinoma in situ
   4. other effectively treated malignancy that is considered cured by local treatment
3. Treatment with a systemic anti-cancer therapy or investigational drug within 21 days or 5 half-lives (whichever is shorter) of the first treatment with the study medication
4. 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
5. Use of concomitant medications that are narrow therapeutic index drugs that are substrates of P-gp or BCRP (e.g. digoxin, dabigatran etexilate)
6. Treatment with strong CYP3A4 inhibitors as specified
7. Treatment with strong CYP3A inducers as specified
8. Treatment with Proton Pump Inhibitors (PPIs) or Potassium-competitive acid blockers (PCAB).  Patients on these therapies may switch to antiacid or H2antagonists at the discretion of the investigator.
9. Previous treatment with any HER2 TKI (for phase Ib pretreated NSCLC only)
10. Radiotherapy within 2 weeks prior to first study treatment except as follows;
    1. Palliative radiotherapy to regions other than the chest is allowed up to 1 week prior to first study treatment
11. 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 safety and efficacy of the test drug
12. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of ≥ III or IV, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator.  Myocardial infarction within 6 months prior to first study treatment.
13. Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
14. Mean resting corrected QT interval (QTcF) >470 msec
15. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval
16. Ejection fraction (EF) <50% or the lower limit of normal of the institutional standard.  Only in cases where the investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition scan).  A historic measurement of EF no older than 6 months prior to first administration of trial drug can be accepted provided that there is clinical evidence that the patient’s cardiac disease has not significantly worsened since this measurement in the opinion of the investigator or of the treating physician or both.
17. Women who are pregnant, nursing, or who plan to become pregnant during the trial or within 30 days after the last dose of trial treatment
18. Presence or history of uncontrolled or symptomatic brain, subdural metastases or leptomeningeal disease, unless considered stable by the investigator and local therapy was completed.  Use of corticosteroids is allowed if the dose is decreasing or was stable for at least 1 week.  Inclusion of patients with newly identified brain metastasis/es at screening will be allowed if patients are asymptomatic and stable by the investigator and immediate CNS treatment is unlikely to be required.
19. Active hepatitis B or C infection which in the opinion of the investigator may interfere with participation in the trial or known history of human immunodeficiency virus (HIV) infection.
20. Known history of allergy to the trial drug, or any excipients of the trial drug
21. Active alcohol or drug abuse in the opinion of the investigator that would limit the ability of the patient to comply with the protocol requirements
22. 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)
23. Known pre-existing interstitial lung disease / pneumonitis