Adverse change in the risk/benefit.

A phase 1, first-in-human, open-label study to evaluate the safety, tolerability, PK, and efficacy of the novel ALK inhibitor TPX-0131 in pretreated subjects with ALK+ advanced or metastatic non-small cell lung cancer (NSCLC).

Phase 1 Dose Escalation: To evaluate the overall safety profile, efficacy of TPX-0131 in pretreated subjects with ALK+ advanced or metastatic NSCLC.

Inclusion Criteria:

• Age ≥ 18 (or as required by local regulation).
• Histological or cytological confirmation of advanced/metastatic ALK+ NSCLC.
• Pretreated with up to three prior lines of an ALK TKI treatment, including at least one prior line of a second or third-generation ALK TKI (alectinib, brigatinib, ensartinib, or lorlatinib) in Phase 1.
• ECOG performance status ≤ 1.
• Existence of measurable or evaluable disease (according to Response evaluation criteria in solid tumors [RECIST v1.1] criteria).
• Subjects with asymptomatic CNS metastases and/or asymptomatic leptomeningeal carcinomatosis are eligible.
• Adequate organ function.

Exclusion Criteria:

• Major surgery within four weeks of the start of TPX-0131 treatment.

• Clinically significant cardiovascular disease

• Any of the following cardiac criteria:

  • Mean resting corrected QT interval (QTc) > 470 msec obtained from three ECGs and any factors that increase the risk of QTc prolongation or arrhythmic events
  • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG

• Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity).

• Gastrointestinal disease or other malabsorption syndromes that would impact drug absorption.

• Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.

• Subjects with current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow therapeutic indices.