Klinische Studien Radar

Medical conditions

1. Patients harbouring concurrent actionable driver mutations with locally approved targeted therapies (e.g., MET amplification) will be excluded.

2. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.

3. Clinically significant abnormalities of glucose metabolism as defined by any of the following:

   • Fasting glucose ≥7.0 mmol/L (126 mg/dL) or 2 hours after glucose solution intake, blood glucose ≥11.1 mmol/L (200 mg/dL).
   • HbA1c ≥8.0% (63.9 mmol/mol) at screening. Note: for any patient with evidence of impaired glucose control or insulin resistance refer to the Capivasertib Toxicity Management Guidelines.

4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection (e.g. patients receiving treatment for infection) including hepatitis C and human immunodeficiency virus (HIV), or active uncontrolled hepatitis B virus (HBV) infection, or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice) .

   • Screening for chronic conditions is not required.

5. Spinal cord compression, leptomeningeal metastasis, or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.

6. Any of the following cardiac criteria:

   • Mean resting corrected QTc >470 msec, obtained from triplicate electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value.

   • History of QT prolongation associated with other medications that required discontinuation of that medication.

   • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block and second-degree heart block.

   • Medical history significant for arrhythmia (e.g., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study based on the Investigator judgement with cardiologist consultation recommended.

   • Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities including:

     • Hypokalaemia|* ≥ CTCAE Grade 2.
     • Heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
     • Correction of electrolyte abnormalities should be documented prior to first dose.

   • Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) Grade 2.

7. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥2 years before the first dose of investigational product (IP) and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease.

8. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment except for alopecia and grade 2 prior platinum-therapy related neuropathy. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the Investigator may be included (e.g., hearing loss).

9. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of IP.

10. Any other disease, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.

    Prior/concomitant therapy

11. Prior or current treatment with a third-generation EGFR-TKI other than Osimertinib.

12. Prior or current treatment with any PI3K/AKT pathway inhibitors, including but not limited to: Capivasertib or other AKT inhibitors, PI3K inhibitors, or agents targeting key nodes in this pathway (e.g., PTEN-modulating therapies).

13. Concurrent use of herbal or natural products intended as treatment or prophylaxis for any type of cancer.

14. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study intervention or has not recovered from side effects of such therapy.

15. Major surgery or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted thoracoscopic surgery (VATS) are permitted.

16. Systemic therapy: Prior exposure to any anti-cancer agents other than those specified in the protocol (e.g. hormonal therapy such as luteinizing hormone releasing hormone \[LHRH\] agonists) without appropriate washout period before enrolment, for example, enrolment within 3 half-lives of a small molecule anti-cancer agent, or within 4 weeks for any antibody-based anticancer agents.

17. Participants currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers (at least 3-week prior), moderate inducers (at least 2-week prior) or strong inhibitors of CYP3A4 (at least 2-week prior). All participants must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer or inhibitor effects on CYP3A4. Any concomitant medication that may interfere with Osimertinib safety and efficacy based on the prescribing information of Osimertinib and local clinical guidelines.

    Prior/concurrent clinical study experience

18. Participation in another clinical study with a study intervention or investigational medicinal device administered in the 4 weeks prior to first dose of study intervention or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.

    Other exclusions

19. History of hypersensitivity to active or inactive excipients of Capivasertib or Osimertinib or drugs with a similar chemical structure or class.

20. Women who are currently pregnant (confirmed with positive pregnancy test) or breast-feeding or planning to become pregnant.

21. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).