THIO Sequenced With Cemiplimab in Advanced NSCLC

The THIO-101 study evaluates the safety and efficacy of different doses of THIO sequenced with fixed dose of cemiplimab (referred to as investigational products [IP]) in subjects with advanced NSCLC who progressed, discontinued due to toxicity, or relapsed after receiving prior therapy with an anti-PD-1/PD-L1 agent.

This study is a Phase 2, open-label, multicenter study comprised of 4 parts:

• Part A (Completed enrolment, N=10): Modified 3+3 design safety lead-in study of THIO 360 mg per cycle (120 mg on Days 1-3, sequenced with cemiplimab).
• Part B (Completed enrolment, N=69): Randomized, dose-finding, Simon's 2-stage design, 3-arm study (THIO 60 mg, THIO 180 mg, or THIO 360 mg per cycle; all dose levels sequenced with cemiplimab), with optional extension cohort(s).
• Revised Part C (Planned; N= 37 to 48)
• Part D (Planned; N=100): Single-arm Efficacy cohort evaluating the efficacy and safety of THIO 180 mg per cycle sequenced with cemiplimab as third-line treatment in patients with advanced/metastatic NSCLC.

This study aims to establish THIO followed by cemiplimab as a potential treatment regimen in a high unmet medical need setting.

A Safety Review Committee (SRC) will monitor subject safety during the study and will make recommendations to the Sponsor regarding enrollment, eg, de-escalating dose in Part A, proceeding to Part B, expanding an arm in Part B, opening Part C, and Part D of the study based on emerging data from prior study parts.

In each study part, on Cycle 1, Day 1, eligible subjects initiate treatment with THIO (at doses described for each study part below) as intravenous (IV) infusion, once daily, on Days 1-3 of every 3-week cycle (Q3W) followed by a fixed dose of cemiplimab (350 mg IV) on Day 5 Q3W. The only exception is the randomized Arm 2 of Part C, where subjects will be receiving single agent THIO (without sequential cemiplimab). Study treatment may continue until PD, occurrence of an unacceptable toxicity, withdrawal of consent, death, or two years on treatment, whichever occurs first.

The initial radiographic imaging for baseline assessment is to be conducted by the investigator up to 28 days before the first dose of THIO for tumor evaluation and measurements. The on-treatment radiographic assessments are to be performed every 2 cycles (every 6 weeks, ± 7 days) during the first year of treatment, and then every 3 cycles (every 9 weeks, ± 14 days) during the second year of treatment until documented PD, initiation of a new anti-cancer treatment, or completion of follow-up, whichever occurs first. The radiographic scans are to be assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and/or iRECIST until PD, initiation of a new anti-cancer treatment, or end of the study, whichever occurs first. In Part D of the study, radiographic scans will also be assessed by a blinded independent central review (BICR) committee. Confirmation of CR and PR per RECIST v1.1 by consecutive radiographic imaging (computed tomography [CT]/magnetic resonance imaging [MRI]; same modality to be used for a given subject throughout the study) assessment 4-8 weeks from the date of first documentation is required. In Parts A, B, and C, radiographic scans are/will be collected and held for possible future retrospective independent evaluation.

To account for tumor pseudoprogression or delayed response with anti-PD1/PD-L1 immunotherapies, subjects may continue to receive IP beyond RECIST v1.1 defined progression at the discretion of the investigator and be assessed at a subsequent tumor assessment time point (≥ 4 weeks after the date of initial documentation of disease progression) to confirm PD according to iRECIST. Subjects must be consented to receive the IP beyond the initial progression and will discontinue IP once the progression is confirmed by iRECIST.

Safety assessments for all study patients (Parts A, B, C, and D) during each treatment cycle include complete or abbreviated physical examinations, routine safety laboratory testing (hematology, clinical chemistry, coagulation), thyroid hormone testing, vital sign evaluations, and electrocardiograms (ECGs).

All subjects will undergo end of treatment (EoT) visit 30 days post last treatment with IP. Subjects will be followed every 3 months until death, withdrawal of consent, loss to follow-up, or study termination by the Sponsor, whichever occurs first. Long-term follow-up can be via clinic visit, phone call to the subject or referring physician, or other method deemed appropriate by the site and should assess survival, progression, subsequent anti-cancer therapy and response. Any subject who discontinues treatment for reasons other than disease progression will continue to have radiographic assessments per standard of care and no less than every 3 months for the first year, and then every 6 months until documented disease progression, initiation of a new anti-cancer treatment, or end of follow-up. Subjects in Parts A and B only who discontinued treatment due to disease progression per RECIST 1.1 and did not receive post-progression treatment could be asked to complete standard of care radiographic assessments every 3 months for up to 1 year and then every 6 months until initiation of a new anti-cancer treatment or completion of follow-up. Response assessment in follow-up will include at minimum the modality used to determine response.