A Phase 1/2 dose escalation and expansion study of TRI-611 in ALK-positive NSCLC

Prior treatment

• Participant taking any medication on the prohibited medication list unless they can be transferred to other medications prior to first dose
• Major surgery (excluding placement of vascular access) < 28 days of the first dose of IMP
• A female of childbearing potential who has a positive pregnancy test prior to initiating study treatment, female who is breast feeding, male of reproductive potential who is expecting to father children within the projected duration of the study through 6 months after the last dose of study treatment, or male or female who is not willing to use a highly effective form of contraception from Screening through 6 months after last dose. Note: All females will be considered to be of childbearing potential unless they are postmenopausal (have amenorrhea for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing)
• Participant receives any other concurrent anticancer treatment or investigational agent.
• Radiotherapy to a large field or including a vital organ (including whole brain radiotherapy or stereotactic radiosurgery to brain) within 14 days before the first dose of IMP. Participants who received radiotherapy to a focal site of disease that did not include a vital organ (such as a limb) within 7 days before the first dose of IMP are eligible.

Other illness

• Past medical history of drug induced interstitial lung disease or any evidence of clinically active interstitial lung disease requiring steroid treatment
• Known hypersensitivity to TRI-611 or any of its ingredients.
• NSCLC with histologic transformation to small cell lung cancer.
• CNS metastases or spinal cord compression that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a participant requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks preceding treatment. Asymptomatic CNS and leptomeningeal disease are allowed and, when measurable, should be captured as target lesions.
• History of another primary malignancy that has been diagnosed or required therapy within 3 years prior to initiation of study treatment. However, the following categories of participants with prior malignancy are eligible to participate: a. Participants with early stage basal/squamous cell skin cancer or non-invasive or in situ carcinomas that have undergone definitive treatment at any time b. Participants who remain cancer free at least 3 years before enrollment

Lab values

• Tumor harbors any additional driver alterations known to be a mechanism of resistance to ALK TKI. At a minimum, local tests must include MET, EGFR, KRAS and BRAF. Tumor mutation profile may be determined locally via a Sponsor-approved testing methodology (NGS is preferred), using tumor tissue and/or ctDNA in plasma.
• Any other prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s or Sponsor’s opinion, could affect the safety of the participant; alter the absorption (have had prior surgery [eg, gastric bypass surgery, gastrectomy] or gastrointestinal dysfunction), distribution, metabolism, or excretion of the IMP; or impair the assessment of study results.
• Insufficient wash-out period since receipt of the last dose of prior anticancer therapy (including investigational ones) to first dose of TRI-611: a. ALK-targeted TKI: ≥ 7 days or ≥ 5 half-lives, whichever is shorter Note: Among the following ALK TKIs - lorlatinib, alectinib, brigatinib, ceritinib, crizotinib, and ensartinib - both certinib and crizotinib require approximately 9 days to achieve coverage of 5 half-lives; washout of ≥ 7 days required. b. Any checkpoint inhibitor (cytotoxic T-lymphocyte associated protein 4 [CTLA4], programmed cell death protein 1 [PD-1], programmed death ligand 1 [PD-L1]) or other antibody therapy (including ALK-targeted antibodies or bi specific antibodies): ≥ 28 days or a minimum of their dosing interval if shorter than 4 weeks (eg, agents administered every 2 weeks would require a 2-week wash-out) c. All others, including investigational agents: ≥ 28 days or ≥ 5 × half-lives, whichever is shorter, with a minimum of 7 days in all circumstances
• Have active, uncontrolled infection (viral, bacterial, or fungal), including tuberculosis, symptomatic active hepatitis B or C, active AIDS-related illness (or a current cluster of differentiation 4 [CD4] count < 350 cells/µL), or coronavirus disease (COVID-19) infection (positive COVID-19 test by polymerase chain reaction) requiring systemic therapy. Controlled infections, including HIV and “cured” hepatitis C (no active fever, no evidence of systemic inflammatory response syndrome) that are stable on antiviral treatment continued as clinically indicated while on study are not exclusionary.
• Have clinically significant, uncontrolled, cardiovascular disease including: a. Congestive heart failure Grade III or IV according to the New York Heart Association classification; b. Myocardial infarction or unstable angina within the previous 6 months; c. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg; diastolic blood pressure ≥100 mmHg) despite adequate treatment prior to first dose of IMP; d. Clinically significant, uncontrolled arrhythmias, including bradyarrhythmia that may cause QT prolongation (eg, Type II second degree heart block or third-degree heart block), or other baseline arrhythmias that might interfere with interpretation of ECG on study (eg, bundle branch block); e. Mean resting QT interval corrected for heart rate (QTc) interval using the Fridericia formula (QTcF) >470 msec (as calculated per institutional standards) obtained from 3 ECGs ≥1 minute apart or history of family history of congenital long QT syndrome; f. Left ventricular ejection fraction < 40% by echocardiogram or radionuclide test; and/or g. Cerebral vascular accident/stroke within the previous 6 months.

• ≥18 years of age at the time of signing the informed consent
• Willing and able to adhere to the study visit schedule and other protocol requirements
• Participant must provide informed consent to participate in the study.
• Pathologically confirmed, locally advanced unresectable, or metastatic NSCLC harboring an ALK fusion: a. ALK fusion status must be determined by a locally approved companion diagnostic test. b. Tumor mutation profile may be determined locally via a Sponsor-approved testing methodology (NGS is preferred), using tumor tissue and/or ctDNA in plasma.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Prior anticancer treatment – protocol includes a table with the details.
• Measurable disease per RECIST v1.1.
• Able to provide a tumor sample for central analysis (a tumor block [formalin-fixed, paraffin-embedded] is preferred, or 11 to 14 unstained slides), obtained from a lesion progressing during or after the last line of therapy received before study entry unless not technically feasible or safe; in which case, the Sponsor will accept the most recent archived sample available. NOTE: For PD subcohorts only, participants for whom it has been deemed feasible and safe per the Investigator, will undergo both a baseline and an on-treatment core biopsy. Samples will be collected and sent for central analysis.
• All toxicity resulting from prior cancer therapies must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v6.0 Grade ≤ 1 or pre-therapy baseline, with the exception of alopecia, pre-existing Grade ≤ 2 neuropathy, and laboratory parameters outlined below.
• Adequate hematological, renal, and hepatic function: a. Absolute neutrophil count (ANC) ≥ 1.0 × 10^9 /L b. Platelet count ≥ 75 × 10^9 /L;); c. Hemoglobin ≥9.0 g/dL, transfusion is allowed to meet eligibility (transfusion > 14 days prior to first dose of IMP allowed); d. Alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN; if liver metastases are present, ≤ 5.0 × ULN); e. Aspartate aminotransferase (AST) ≤ 2.5 × ULN (if liver metastases are present, ≤ 5.0 × ULN); f. Total bilirubin ≤ 1.5 × ULN (participants with known Gilbert’s Syndrome may enroll with 3 × ULN provided that direct bilirubin is ≤ 1.5 mg/dL); g. Calculated creatinine clearance≥ 60 mL/min to be calculated per Cockcroft-Gault formula; h. Prothrombin time and/or International Normalized Ratio (INR) and partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as the coagulation tests results are within the intended therapeutic range
• Able to swallow an oral medication