THIO Sequenced With Cemiplimab in Advanced NSCLC

Study Overview
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Brief Summary
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THIO is a first-in-class small molecule telomere targeting agent, in development for the treatment of non-small cell lung cancer (NSCLC) in combination with cemiplimab (LIBTAYO®). THIO is preferentially incorporated into telomeres sequence in telomerase-positive cells leading to rapid telomere uncapping, genomic instability, and cell death. Cemiplimab is a programmed cell death protein 1 (PD-1) inhibitor recently approved as a first-line treatment for patients with locally advanced or metastatic NSCLC with 50% or more PD-L1 expression. It is hypothesized that THIO administration prior to cemiplimab would restore tumor responses to immunotherapy in subjects who either developed resistance or relapsed after receiving first line treatment with an immune check point inhibitor.

Detailed Description
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The current Phase 2, open-label, multicenter study, comprised of 3 parts, is designed to evaluate the safety and efficacy of THIO sequenced with cemiplimab in subjects with advanced NSCLC. This study could establish THIO followed by cemiplimab as a potential treatment regimen in a high unmet medical need setting. The study evaluates the safety and efficacy of different doses of THIO sequenced with fixed-dose of cemiplimab (collectively called investigational product [IP]) in subjects with advanced NSCLC who progressed or relapsed after receiving first line therapy which included ICI. This study will be a Phase 2, open-label, multicenter study comprised of 3 parts: Part A -Safety lead-in, modified 3+3 design Part B - Simon's 2-stage design, randomized, dose-finding, 3-arm (or 2 arm, based on Part A emerging data) Part C (optional) - high dose arm, 3+3 design followed by Simon's 2-stage design if cohort expansion occurs 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 and opening Part C (optional) of the study based on emerging data from prior study parts. In each study part, on Cycle 1, Day 1, eligible subjects will initiate treatment with THIO (doses will be as described for each study part below) as intravenous (IV) infusion on Days 1-3 of every 3 week cycle (Q3W) followed by a fixed-dose of cemiplimab (350 mg IV) on Day 5 Q3W. Subjects may continue dosing with THIO followed by cemiplimab Q3W until disease progression or occurrence of an unacceptable toxicity, withdrawal of consent, death, or one year on treatment. The initial radiographic imaging for baseline assessment will be conducted by the investigator within 28 days of the first dose of THIO (if not performed in the 4-6 weeks prior to screening) for tumor evaluation and measurements. The on-treatment radiographic assessments will be performed initially at 6 weeks intervals (ie. Cycle 3, Day 1 and Cycle 5, Day 1) and repeated thereafter every 9-12 weeks ± 7 days as clinically indicated. The radiographic scans will be assessed by the investigator according to RECIST v1.1 and/or immune RECIST (iRECIST) until disease progression, or until initiation of a new anticancer treatment (whichever occurs first). Confirmation of CR, PR, stable disease (SD),and PD by a consecutive radiographic imaging (computed tomography/magnetic resonance imaging; same modality to be used for a given subject throughout the study) assessment at least 4 weeks from the date of first documentation will be required. Radiographic scans will be collected and held for possible future retrospective independent evaluation. To account for tumor pseudoprogression or delayed response with anti-PD-1/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 later but not exceeding 6 to 8 weeks from the date of initial documentation of disease progression) to confirm disease progression according to iRECIST. Subjects must be consented to receive the IP beyond the initial progression and will discontinue IP once the progression is confirmed. All subjects will undergo end of treatment (EoT) visit 30 days post last treatment with IP. Subjects will have follow-up visits every 6 weeks for approximately 6 months and then at 9 months and 12 months after the last dose of IP or until they start a new anticancer therapy, whichever is earlier. In subjects who discontinued IP due to toxicity, radiographic imaging will be done every 3 months until disease progression or until the subject initiates another anti-cancer therapy. In each study part, for each subject, the study is expected to last as follows: Screening period: Up to 28 days Treatment period: Until disease progression assessed by the Investigator per RECIST v1.1 and/or iRECIST or occurrence of an unacceptable toxicity, withdrawal of consent, unacceptable toxicity, disease progression, death, or one year on treatment Short-term Follow- up: Up to 30 days after the last dose of THIO Long-term Follow-up: Up to a maximum of 12 months after the last dose of IP of the last subject or earlier if the study is terminated by the Sponsor The Safety Review Committee (SRC) will be comprised of Sponsor's Medical Monitor (or designee), safety physician, statistician and a subset of investigators. The SRC will meet regularly to review the safety information of each study part and make recommendation to the Sponsor. The Sponsor has carefully considered potential risks, uncertainties, and antitumor benefits that may be associated with THIO + cemiplimab for the treatment of advanced NSCLC. The potential risks have been taken into consideration in the design and safety monitoring of this study to mitigate any risk. The study safety measures comprise of specific inclusion/exclusion criteria for participation in the study. This study also includes the medical management of potential toxicities as well as guidance on investigational product (IP) dosing, interruption or discontinuation.

Official Title
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A Multicenter, Open-Label, Dose-Finding, Phase 2 Study Evaluating THIO Sequenced With Cemiplimab (LIBTAYO®) in Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: 6-Thio-2'-Deoxyguanosine
* Drug: Cemiplimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for participation in this study, subjects must meet all the following: At least 18 years of age at the time of signing the Informed Consent Form (ICF) prior to initiation of any study specific activities/procedures. Stage 3 or Stage 4 NSCLC who either progressed or relapsed after ICI, as defined by the Society for Immunotherapy of Cancer (SITC) immunotherapy resistance task force. Subjects with drug exposure >6 weeks but not meeting the criteria for either primary or secondary resistance, can also be included (e.g., have achieved initially a PR, then progressed before 6 months). Subjects who received neoadjuvant or adjuvant therapies with ICIs for the initial cancer diagnosis may also be eligible, following consultation with Sponsor's Medical Monitor (or designee). Prior treatment with PD-1/PD-L1 ICIs therapy alone or in combination with a platinum-based chemotherapy (i.e., platinum-based chemotherapy followed by ICI therapy) will be allowed. ICI treatment may have been part of 1st or 2nd line, but not both. Must have histologically or cytologically confirmed NSCLC. At least one measurable target lesion that meets the definition of RECIST v1.1. Willing to provide archived tumor tissue samples either formalin fixed paraffin embedded (FFPE) block OR at least 10 unstained slides. Life expectancy of greater than 12 weeks. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Demonstrate adequate organ function as defined below. All screening laboratories should be performed within 14 days of initiating IP: Bone marrow function: neutrophil count ≥ 1500/mm3, hemoglobin ≥ 9.0 g/dL, platelet count ≥ 100,000/mm3; Liver function: total bilirubin ≤ 1.5 x the upper limit of normal (ULN) based on the standard value of each institution, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN; Renal function: serum creatinine ≤ 1.5 x ULN based on the reference laboratory. Women of childbearing potential (WOCBP) must have negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to receiving the first administration of IP. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. WOCBP must agree to use a highly effective birth control and refrain from oocyte donation during the study (prior to the first dose with THIO, for the duration of the treatment with THIO plus 6 months after last dose of IP), if conception is possible during this interval. Male subjects and WOCBP partners of male subjects should use a combination of a male condom from first dose of THIO (Cycle 1, Day 1), for the duration of the treatment with THIO plus 6 months after last dose of IP, unless permanently sterile by bilateral orchidectomy. Male subjects should also refrain from sperm donation during this time. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Exclusion Criteria: Have not recovered from adverse events (must be Grade ≤1) due to agents administered more than 4 weeks earlier. Untreated or symptomatic central nervous system (CNS) metastases. Note: subjects with treated asymptomatic brain metastasis are eligible. Active gastrointestinal bleeding as evidenced by either hematemesis or melena. History of another concurrent malignancy other than the present condition (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off all therapy for that disease for a minimum of 3 years. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, adrenal replacement doses 10 mg daily prednisone equivalents, and systemic corticosteroids to manage adverse events (AEs) are permitted in the absence of active autoimmune disease. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy within 2 weeks of screening. Positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active hepatitis B or hepatitis C. Positive for COVID-19 using polymerase chain reaction (PCR) test; subjects with positive PCR test will be eligible after 2 consecutive negative results are obtained, minimum 1 week apart. Significant cardiovascular impairment (history of New York Heart Association Functional Classification System Class III or IV) or a history of myocardial infarction or unstable angina within the past 6 months prior to IP initiation. Ongoing immune-related/stimulated adverse events (irAEs) from other agents or required permanent discontinuation of prior ICIs due to immune-related AEs (irAEs). Subjects with resolved irAE may be allowed to enroll following consultation with Sponsor's Medical Monitor (or designee). Active autoimmune diseases or history of autoimmune diseases that may relapse, with the following exceptions: Controlled type 1 diabetes; Hypothyroidism (provided it is managed with hormone replacement therapy only); Controlled celiac disease; Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia); Any other disease that is not expected to recur in the absence of external triggering factors. Pregnancy or lactating. A serious nonmalignant disease (eg, psychiatric, substance abuse, uncontrolled intercurrent illness, etc.) that could compromise protocol objectives in the opinion of the investigator and/or the Sponsor. Any other condition that, in the opinion of the investigator, would prohibit the subject from participating in the study. Prior chemotherapy, targeted therapy, and immunotherapy within the 28 days prior to Screening. Undergone major surgery within 4 weeks prior to Cycle 1, Day 1. Received blood, red blood cell or platelet transfusion within 2 weeks before the first dose of IP. Any vaccines (live, attenuated, inactivated or research vaccines) within 30 days prior to the first dose of IP. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. Prior allogeneic hematopoietic stem cell transplant or solid organ transplant. Actively participating in another clinical study. 20. Currently enrolled in a clinical study involving another IP or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. 21. Participated, within the last 30 days, in a clinical study involving an IP (other than the IP used in this study), unless a minimum of 30 days or 5 half-lives (whichever is longer) have passed before enrollment in the present clinical study. 22. History of allergy to excipients of THIO or cemiplimab.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part A will utilize a modified 3+3 design whereby up to 2 safety lead-in cohorts of 6 subjects each, will be sequentially assigned to receive THIO and cemiplimab.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>Safety lead-in, modified 3+3 design. Part A: Cohort 1: THIO total 360 mg per cycle (120 mg on Days 1-3 Q3W) plus 350 mg cemiplimab on Day 5; Cohort 2 (pending emerging data from Cohort 1): THIO total 180 mg per cycle (60 mg on Days 1-3 Q3W) plus 350 mg cemiplimab on Day 5 | Drug: 6-Thio-2'-Deoxyguanosine<br>* small molecule telomere targeting agent<br>* Other names: THIO;Drug: Cemiplimab<br>* programmed cell death protein 1 (PD-1) inhibitor<br>* Other names: LIBTAYO®;|
| Experimental: Part B<br>Cohort 1: THIO total 60 mg per cycle (20 mg on D1-3 Q3W) plus 350 mg cemiplimab on Day 5; Cohort 2: THIO total 180 mg per cycle (60 mg on D1-3 Q3W) plus 350 mg cemiplimab on Day 5; Cohort 3 (pending emerging data from Part A): THIO total 360 mg per cycle (120 mg on Days 1-3 Q3W) plus 350 mg cemiplimab on Day 5 | Drug: 6-Thio-2'-Deoxyguanosine<br>* small molecule telomere targeting agent<br>* Other names: THIO;Drug: Cemiplimab<br>* programmed cell death protein 1 (PD-1) inhibitor<br>* Other names: LIBTAYO®;|
| Experimental: Optional Part C<br>THIO total 540 mg per cycle (180 mg on D1-3 Q3W) plus 350 mg cemiplimab on Day 5 | Drug: 6-Thio-2'-Deoxyguanosine<br>* small molecule telomere targeting agent<br>* Other names: THIO;Drug: Cemiplimab<br>* programmed cell death protein 1 (PD-1) inhibitor<br>* Other names: LIBTAYO®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the incidence of dose limiting toxicities (DLTs) [Safety and Tolerability] of THIO administered in sequence with cemiplimab in subjects with advanced NSCLC | Incidence of dose limiting toxicities (DLTs; applicable for Part A and Part C) overall, by severity, by relationship to THIO, and those that led to discontinuation of THIO and/or withdrawal from study. | Up to 1 year | 
| To determine the incidence of treatment-emergent adverse events (TEAEs) [Safety and Tolerability] of THIO administered in sequence with cemiplimab in subjects with advanced NSCLC | Incidence of treatment-emergent adverse events (TEAEs) overall, by severity, by relationship to THIO, and those that led to discontinuation of THIO and/or withdrawal from study. | Up to 1 year | 
| To determine the incidence of serious adverse events (SAEs) [Safety and Tolerability] of THIO administered in sequence with cemiplimab in subjects with advanced NSCLC | Incidence of serious adverse events (SAEs) overall, by severity, by relationship to THIO, and those that led to discontinuation of THIO and/or withdrawal from study. | Up to 1 year | 
| To assess the efficacy of THIO administered in sequence with cemiplimab in subjects with advanced NSCLC by observing the Overall Response Rate (ORR) in telomerase-positive subjucts. | Overall Response Rate (ORR) defined as the proportion of subjects with best overall confirmed response of either a complete response (CR) or partial response (PR) as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. | Up to 1 year | 
| To assess the efficacy of THIO administered in sequence with cemiplimab in subjects with advanced NSCLC by observing the Disease Control Rate (DCR) in telomerase-positive subjects. | Disease Control Rate (DCR) defined as a complete response (CR), partial response (PR), or stable disease (SD) as assessed by the investigator based on RECIST v1.1 criteria. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Additional efficacy measurement by observing Duration of Response (DoR) in subjects. | Duration of Response (DoR) in telomerase-positive subjects assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. | Up to 1 year | 
| Efficacy measured by observing Progression-Free Survival (PFS) in subjects. | Progression-Free Survival (PFS) in telomerase-positive subjects assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. | Up to 1 year | 
| Measure efficacy by observing Overall Survival (OS) in subjects. | Overall Survival (OS) in telomerase-positive subjects assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. | Up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SQUAMOUS CELL CARCINOMA, ADENOCARCINOMA, LARGE CELL CARCINOMA, Carcinoma, Non Small Cell Lung, Carcinomas, Non-Small-Cell Lung, Lung Carcinoma, Non-Small-Cell, Lung Carcinomas, Non-Small-Cell, Non-Small-Cell Lung Carcinomas, Non-Small-Cell Lung Carcinoma, Carcinoma, Non-Small Cell Lung, Non-Small Cell Lung Carcinoma, Non-Small Cell Lung Cancer, Nonsmall Cell Lung Cancer