Phase 2 Study of Sequential THIO and Cemiplimab in Advanced Non-Small Cell Lung Cancer
- Trial ID
- 2023-504595-26-00
- Protocol
- THIO-101
- Sponsor
- Maia Biotechnology Inc.
Trial statistics
Objectives
The primary objectives of this multicenter, open-label, dose-finding, Phase 2 study are to evaluate the **safety** and **tolerability** of THIO administered in sequence with **cemiplimab** in subjects with advanced or metastatic **Non-Small Cell Lung Cancer (NSCLC)**. Additionally, the study aims to assess the efficacy of this sequential administration. In Part C, the objective is to obtain clinical evidence of the efficacy and safety of the sequential combination of THIO 180 mg per cycle plus cemiplimab compared to single-agent THIO 180 mg per cycle as a third-line treatment. Part D focuses on establishing the efficacy of THIO 180 mg per cycle sequenced with cemiplimab as a third-line treatment. These objectives are clinically relevant as they aim to explore potential therapeutic strategies for patients with advanced NSCLC, a condition with limited treatment options and significant morbidity and mortality.
The secondary objectives involve additional efficacy evaluations across Parts A, B, C, and D, providing further insights into the therapeutic potential of the treatment regimen.
Participants
The clinical trial involves a total of **70 participants** diagnosed with **Non-Small Cell Lung Cancer** (NSCLC). The study population includes both male and female subjects, aged 18 years and older, who have advanced or metastatic NSCLC. Participants were selected based on specific inclusion criteria, such as having stage 3 or 4 NSCLC that has progressed or relapsed after prior treatment. The trial includes individuals who have demonstrated secondary resistance to prior immune checkpoint inhibitors. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population is characterized by a diverse range of individuals, including those considered vulnerable. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study does not provide specific information on the general health status beyond the requirements for adequate organ function and measurable disease. Key inclusion criteria include the ability to provide informed consent and compliance with study protocols, while exclusion criteria are not detailed in the provided data.
Plans and Procedures
The clinical trial is a multicenter, open-label, dose-finding, Phase 2 study designed to evaluate the sequential administration of **THIO** and **cemiplimab** in subjects with advanced **non-small cell lung cancer** (NSCLC). The primary objectives are to determine the safety, tolerability, and efficacy of the treatment regimen. The trial is structured into multiple parts, each with specific endpoints, including the incidence of dose-limiting toxicities (DLTs) and overall response rate (ORR) as assessed by RECIST v1.1 criteria. The study is expected to run from May 2022 to November 2025, with participant involvement lasting up to 24 months.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, disease stage, and prior treatment history. The screening process will include assessments of organ function and performance status. Following successful screening, participants will enter the treatment phase, receiving THIO and cemiplimab via intravenous infusion. Regular follow-up visits will be scheduled to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, with final assessments conducted to evaluate long-term outcomes.
Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the occurrence of severe adverse events, disease progression, or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to support the evaluation of the investigational treatment's impact on NSCLC. The study's methodology and procedures adhere to established clinical research standards, ensuring the integrity and reliability of the findings.
Treatment
The clinical trial involves the administration of **LIBTAYO** (cemiplimab), a **concentrate for solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for intravenous infusion. The active substance, cemiplimab, is a protein-based therapeutic agent. The dosage for LIBTAYO is set at 350 mg per administration, with a maximum daily dose of 350 mg. The treatment is administered via intravenous infusion, and the maximum treatment period is 24 weeks. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.
In addition to LIBTAYO, the study also evaluates the use of **THIO**, a synthetically modified small molecule nucleoside. THIO is provided in a **vial for intravenous use** and is also administered via intravenous infusion. The active substance in THIO is a chemical compound identified as 2-amino-9-((2R,4R,5R)-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-1,4,5,9-tetrahydro-6H-purine-6-thione. The dosage for THIO is 180 mg per cycle, with a maximum total dose of 540 mg over the treatment period. The maximum treatment period for THIO is also 24 weeks. As with LIBTAYO, participant compliance with the dosing schedule for THIO will be closely monitored to ensure protocol adherence.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)**, defined as the proportion of subjects achieving either a Complete Response (CR) or Partial Response (PR), as evaluated by the investigator based on RECIST v1.1 criteria. This assessment will be conducted for Part C and Part D of the study. Additionally, the incidence of Dose-Limiting Toxicities (DLTs) will be evaluated in Part A, and the incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) will be assessed in Parts A and B.
Secondary endpoints include the Duration of Response (DoR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS). These will be assessed by the investigator based on RECIST v1.1 criteria for Parts A, B, and C, and by Blinded Independent Central Review (BICR) for Part D. The schedule for measuring these efficacy parameters will align with the trial's protocol, ensuring systematic data collection and analysis throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 4 histologically or cytologically confirmed NSCLC which has progressed or relapsed after treatment in the advanced setting ○ Stage 4 subjects: Part A and Part B: must have progressed or relapsed after first line treatment. Part C and Part D: must have progressed, discontinued due to toxicity, or relapsed after receiving (only) two prior lines of treatment for NSCLC in the advanced setting. ○ Stage 3 subjects – must have already failed, or be ineligible for, local, curative-intent therapy including surgery, and/or chemoradiation. Stage 3 subjects with documented relapse/progression after consolidation therapy with durvalumab following definitive chemoradiotherapy are eligible.
- Subjects must have secondary resistance to the prior ICI, as defined by the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Task Force (IRTF) (Kluger 2020) Note: Subjects with drug exposure > 6 weeks who achieved a PR or CR then progressed before 6 months, would still be eligible.
- Part A and Part B: Only one prior treatment for NSCLC in the advanced setting, which must have included one anti-PD-1/PD-L1 agent with documented radiographic disease progression on or after treatment. ○ Prior treatment may have been with anti-PD-1/PD-L1 agent either alone or in combination with a non-anti-PD-1/PD-L1 treatment (e.g., chemotherapy) ○ Prior platinum-based chemotherapy is not required for eligibility. ○ Subjects receiving more than one ICI in the advanced setting (e.g., anti-PD-1/PD-L1 and anti-CTLA-4 compounds) will not be eligible. Part C and Part D: Only two prior treatments for NSCLC in the advanced setting, which must have included an anti-PD-1/PD-L1 agent, a platinum-based chemotherapy, and docetaxel, regardless of order or combination, with documented radiographic disease progression, intolerable toxicity, or relapse after treatment. ○ Combination of immune therapy is allowed (e.g., anti-PD-1/PD-L1 and anti-CTLA-4 compounds; anti-PD-1/PD-L1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT)-based immunotherapy).
- No prior targeted therapy for driver mutations.
- At least one measurable target lesion that meets the definition of RECIST v1.1.
- Part A and Part B: An archival tissue sample (formalin fixed paraffin-embedded [FFPE] tissue block or unstained slides) is required if tissue is available at baseline. Sample does not need to be received by central lab prior to Cycle 1, Day 1 (C1D1). Subjects without archival tissue available at baseline may be eligible with Medical Monitor approval. Part C and Part D: Blood sample collection at baseline is not required. Archival tissue is optional for Parts C and D. Sites will only collect archival tissue at the sponsor’s request.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
- Demonstrate adequate organ function as defined below. All screening laboratories should be performed up to 14 days before 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), up to ≤ 3 × ULN due to Gilbert’s syndrome ○ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN. For subjects with liver metastases present at baseline, ALT and/or AST ≤ 3 × ULN is permitted. Renal function: ○ Creatinine clearance ≥ 60 mL/min calculated by the Cockcroft-Gault formula using actual body weight (see Table 15) or 24-hour urine collection. For Asian countries, a creatinine clearance of ≥ 50 mL/min calculated by the Cockcroft-Gault formula using actual body weight (see Table 15) or 24-hour urine collection is acceptable.
- 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. Refer to Appendix 4, Section 10.4 for details and definitions of WOCBP, postmenopausal females and contraception guidance.
- 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 the methods specified in Section 10.4 for the women along with 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 prior anti-cancer treatment.
- 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.
- 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. a) QTcF > 480 msec at screening (based on average of triplicate ECGs at baseline). i. If the QTc is prolonged in a subject with a pacemaker or bundle branch block, the subject may be enrolled in the study if confirmed by the Medical Monitor.
- Ongoing immune-related/stimulated adverse events (irAEs) from other agents or required permanent discontinuation of prior ICIs due to 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 (e.g., 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 (e.g., 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.
- Part C and Part D: more than two prior systemic treatments for advanced disease.
- Prior chemotherapy and/or non-biologic targeted therapy within 4 weeks, or biologic targeted therapy, immunotherapy, and/or radiation therapy within 6 weeks prior to Cycle 1 Day 1. Subjects who receive targeted radiation therapy for localized palliative care may be eligible to start treatment < 6 weeks with Medical Monitor agreement.
- Part A and Part B: Prior treatment with cemiplimab. Note: Part C and Part D: prior cemiplimab is permitted.
- For subjects who have received prior treatment with an ICI: primary resistance to prior ICI therapy, as defined by the SITC IRTF (Kluger 2020) Note: Subjects with drug exposure > 6 weeks who achieved a partial or complete response then progressed before six months, would still be eligible.
- 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 live, attenuated, inactivated or research vaccines within 30 days prior to the first dose of IP. Refer to Section 6.9.1 for prohibited vaccines. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed.
- Prior allogeneic hematopoietic stem cell transplant or solid organ transplant.
- 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.
- History of allergy to excipients of THIO or cemiplimab.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 04 May 2022 | 23 |
 Hungary | Recruiting | 04 May 2022 | 70 |
 Poland | Recruiting | 04 May 2022 | 100 |
 Romania | Recruiting | 04 May 2022 | 29 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
LIBTAYO 350 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 350 | 24 | PRD7478447 |
THIO | Test | VIAL FOR INTRAVENOUS USE | INTRAVENIOUS INFUSION | 180 | 24 | PRD9867889 |