Phase 1/2 Dose-Escalation and Expansion Study of Oral ALK Molecular Glue Degrader TRI-611 in Advanced ALK‑Positive Non‑Small Cell Lung Cancer

Trial ID: 2025-524418-27-00
Protocol: TRI-611-101
Sponsor: Triana Biomedicines Inc.

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Diseases & Conditions

Non-small cell lung cancer Non-small cell lung cancer metastatic

Objectives

The primary objective is to characterize the safety and tolerability of TRI‑611 monotherapy to support selection of the recommended Phase 2 dose or maximum tolerated dose and to evaluate antitumor activity using RECIST v1.1, thereby informing dose selection and therapeutic potential in patients with advanced ALK‑positive NSCLC. Secondary objectives include: evaluation of the pharmacokinetic profile of TRI‑611 and correlation of drug exposure with safety assessments; confirmation of antitumor activity by RECIST v1.1; assessment of central nervous system antitumor activity using modified RECIST v1.1 in participants with baseline CNS metastases; analysis of treatment‑induced modulation of ALK expression in pharmacodynamic subcohorts; further characterization of safety and tolerability; investigation of additional measures of antitumor activity; and repeated evaluation of CNS response with mRECIST v1.1.

Participants

One participant was enrolled, comprising adult patients (≥18 years) with advanced ALK-positive NSCLC. Both male and female individuals were eligible, and inclusion of vulnerable subjects was permitted. Eligible participants required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, measurable disease per RECIST v1.1, and adequate hematologic, renal, and hepatic function as defined by protocol‑specified laboratory thresholds. Additional requirements included confirmed ALK fusion status by a locally approved companion diagnostic test, ability to swallow oral medication, and provision of a tumor sample for central analysis. Prior anticancer therapy‑related toxicities had to have resolved to ≤ grade 1 (with specified exceptions). The selection was based on pathologic confirmation of locally advanced unresectable or metastatic disease and adherence to the outlined inclusion criteria.

Plans and Procedures

The study is a combined Phase 1/2, open‑label, dose‑escalation and expansion trial evaluating the oral ALK molecular glue degrader TRI‑611 in participants with advanced ALK‑positive non‑small cell lung cancer (NSCLC). Participants undergo an initial screening visit to confirm eligibility, including assessment of ALK fusion status, performance status, organ function, and provision of a tumor sample for central analysis. Eligible subjects receive a single oral dose of TRI‑611 on Day 1 of Cycle 1, followed by continuous daily dosing in subsequent cycles; dose levels are escalated according to a predefined schema until the maximum tolerated dose or recommended Phase 2 dose is identified. Safety and pharmacokinetic assessments are performed at each scheduled study visit, typically occurring every 3 weeks, with radiographic tumor assessments conducted per RECIST v1.1 at baseline and every 6 weeks thereafter to evaluate antitumor activity. The trial continues until disease progression, unacceptable toxicity, withdrawal of consent, or completion of the planned treatment period, after which an end‑of‑study visit is performed to collect final safety, efficacy, and biomarker data. Participant involvement may extend up to 24 months of treatment, and the overall study recruitment period spans from July 2026 to June 2031.

Treatment

The investigational product is TRI-611, supplied as an oral tablet. The formulation is designated for administration by the oral route; specific dose levels and dosing frequency are defined within the dose‑escalation schema of the protocol and may be adjusted during the study to identify the recommended Phase 2 dose and/or maximum tolerated dose.

No comparator, placebo, or standard‑of‑care therapy is incorporated as a treatment arm in this Phase 1/2 study; participants receive TRI-611 monotherapy only.

Dosing is performed under controlled conditions with each dose recorded in the study eCRF. Compliance is assessed by pill count at each clinic visit and by review of participant dosing diaries. Any deviations from the prescribed schedule are documented and reported according to protocol‑specified safety monitoring procedures. The study population consists of individuals with advanced ALK-positive NSCLC.

Efficacy

Efficacy will be evaluated by assessing antitumor activity according to RECIST v1.1. The primary efficacy parameters include objective response rate (ORR) and depth of response (DofR). Secondary efficacy parameters comprise duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression‑free survival (PFS), overall survival (OS), central nervous system (CNS) ORR, CNS DOR, and time to intracranial progression. Changes in ALK protein levels in tumor tissue will be compared between baseline and on‑treatment samples.

Radiographic assessments will be performed using standard imaging modalities (e.g., CT or MRI) and evaluated centrally according to RECIST v1.1 criteria. Tumor tissue analyses for ALK protein expression will be conducted using validated laboratory methods on collected biopsies. All efficacy data will be analyzed descriptively and, where appropriate, with time‑to‑event statistical methods to estimate PFS, OS, and intracranial progression endpoints.

Inclusion and Exclusion Criteria

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Inclusion Criteria

≥18 years of age at the time of signing the informed consent
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
Willing and able to adhere to the study visit schedule and other protocol requirements
Participant must provide informed consent to participate in the study.

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Exclusion Criteria

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.
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.
Participant receives any other concurrent anticancer treatment or investigational agent.
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
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.
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.
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
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.
Participant taking any medication on the prohibited medication list unless they can be transferred to other medications prior to first dose
Past medical history of drug induced interstitial lung disease or any evidence of clinically active interstitial lung disease requiring steroid treatment
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)
Known hypersensitivity to TRI-611 or any of its ingredients.
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.