Phase 1/2 Open-Label Study of CTL-002 and Nivolumab in Advanced Relapsed/Refractory Solid Tumors

Trial ID: 2024-512575-12-00
Protocol: CTL-002-001
Sponsor: CatalYm GmbH

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Diseases & Conditions

Neoplasm

Objectives

The primary objective of this clinical trial is to explore the preliminary **anti-tumor activity** of CTL-002 when administered in combination with an anti-PD-1 checkpoint inhibitor in subjects with advanced-stage, relapsed/refractory solid tumors that are in a non-curable state. This is clinically relevant as it aims to address the therapeutic needs of patients who have exhausted existing treatment options or are not eligible for them anymore, particularly those with specific types of cancer such as bladder cancer, hepatocellular cancer, non-small cell lung cancer, cutaneous squamous cell carcinoma, melanoma, and colorectal cancer, depending on the country-specific cohort. Additionally, the trial seeks to confirm the safety and tolerability of CTL-002 administered as an intravenous infusion in combination with an anti-PD-1 checkpoint inhibitor.

Secondary objectives include:

To confirm and further explore the pharmacokinetics/pharmacodynamics of CTL-002 when given in combination with an anti-PD-1 checkpoint inhibitor.
To confirm the recommended Phase 2 dose (RP2D) of CTL-002.

Participants

The clinical trial involves a total of **30 participants** diagnosed with **advanced-stage, relapsed/refractory solid tumors**. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on their diagnosis of non-curable solid tumors, with specific conditions such as bladder cancer, hepatocellular cancer, non-small cell lung cancer, cutaneous squamous-cell carcinoma, melanoma, and colorectal cancer, depending on the country-specific criteria. The trial does not include a vulnerable population. Participants are required to have a life expectancy of more than three months and adequate organ function. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific medical requirements, including the use of highly effective contraception methods if applicable. The trial aims to explore the preliminary anti-tumor activity of CTL-002 in combination with an anti-PD-1 checkpoint inhibitor, confirming the safety and tolerability of the treatment. The sponsor has not provided additional information regarding lifestyle factors or other demographic details.

Plans and Procedures

The clinical trial is designed as a **Phase 1/2**, first-in-human, two-part, open-label study to evaluate the safety, tolerability, and preliminary anti-tumor activity of **CTL-002** administered intravenously, both as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor, in subjects with advanced-stage, relapsed/refractory solid tumors. The trial is not categorized as low intervention and is conducted under the authorization of relevant regulatory bodies. The trial commenced on February 4, 2021, with an estimated completion date of June 30, 2025. Recruitment began on November 25, 2020, and is expected to conclude by April 26, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as life expectancy, organ function, and previous treatment history. The trial includes multiple follow-up visits to monitor safety and efficacy, with assessments including clinical laboratory data, vital signs, and imaging studies to evaluate tumor response according to RECIST V1.1 criteria. The end-of-study visit will occur after the final treatment cycle, where comprehensive evaluations will be conducted to assess the overall outcomes of the intervention.

The expected duration of participant involvement varies depending on individual response and tolerance to the treatment, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. Participants are required to comply with study procedures, including the use of highly effective contraception methods during the study and for a specified period after the last dose of CTL-002. The trial aims to confirm the safety and tolerability of CTL-002, with primary endpoints focusing on clinical efficacy and safety assessments, while secondary endpoints include pharmacokinetic parameters and biomarker evaluations.

Treatment

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **LIBTAYO** (cemiplimab) is provided as a 350 mg concentrate for solution for infusion. It is administered intravenously. The pharmaceutical form is a concentrate for solution for infusion, and it is produced by Regeneron Ireland D.A.C. The active substance, cemiplimab, is a protein of other origin, and the product is authorized in the EU under the marketing authorization number EU/1/19/1376/001.

**OPDIVO** (nivolumab) is another experimental medication used in the trial. It is available as a 10 mg/mL concentrate for solution for infusion and is administered intravenously. The pharmaceutical form is a solution for infusion, and it is manufactured by Bristol-Myers Squibb Pharma EEIG. Nivolumab, the active substance, is also a protein of other origin. The product is authorized in the EU with multiple marketing authorization numbers, including EU/1/15/1014/001, EU/1/15/1014/002, EU/1/15/1014/003, and EU/1/15/1014/004.

**CTL-002** is an investigational drug provided as a solution for infusion. It is administered intravenously and is produced by Catalym GmbH. The active substance, CTL-002, is a protein of other origin. This product is currently in the trial phase and does not have a marketing authorization status. The sponsor product code for CTL-002 is CTL-002.

All medications are administered intravenously, and the trial aims to explore the preliminary anti-tumor activity of CTL-002 in combination with an anti-PD-1 checkpoint inhibitor in subjects with advanced-stage, relapsed/refractory solid tumors. The trial also seeks to confirm the safety and tolerability of CTL-002 when administered as an IV infusion in combination with an anti-PD-1 checkpoint inhibitor. Participant compliance and dosing schedules are monitored throughout the trial to ensure adherence to the protocol.

Efficacy

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the evaluation of clinical efficacy according to RECIST V1.1 criteria for **CTL-002** in combination with an anti-PD-1 checkpoint inhibitor. This will involve assessing the proportion of subjects with tumor shrinkage, confirmed partial response (PR) and/or complete response (CR), and overall response rate (ORR). Additionally, the time to response (TTR) will be measured, defined as the interval between the date of first **CTL-002** administration and the first documented evidence of a PR or CR.

Secondary endpoints will focus on pharmacokinetic (PK) parameters of **CTL-002**, such as maximum concentration (Cmax), area under the curve (AUC), and half-life (t1/2). The trial will also evaluate treatment-emergent cytokine and chemokine profiles in peripheral blood, treatment-induced anti-drug antibodies (ADA), and serum levels of GDF-15, correlating these with pharmacodynamics and clinical response.

Data collection will include clinical laboratory data, vital signs, electrocardiograms (ECGs), physical examinations (including neurological assessments), and Eastern Cooperative Oncology Group (ECOG) performance status. The schedule for these assessments will be aligned with the trial protocol, ensuring systematic and consistent data collection throughout the study duration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Provide signed and dated informed consent. For Part A only: signed pre-screening consent for participants that undergo pre-screening procedures or collection of historical data prior to informed consent procedure.
Male or female aged ≥ 18 years.
Participants with histologically or cytologically confirmed/documented diagnosis of advancedstage, relapsed/refractory solid tumors in non-curable state as per current clinical knowledge (specific for Germany: who have exhausted all available approved standard treatments or are not eligible for them anymore)
For Part A (Phase 1), participants must have received during their prior treatment at least one antiPD-1/PD-L1 treatment (alone or in combination) and progressed on or relapsed after completion of the anti-PD-1/PD-L1 treatment (with a minimum of 12 weeks of anti-PD1/PD-L1 exposure). (1) For Part B (Phase 2a), participants must either have bladder cancer, hepatocellular cancer, nonsmall cell lung cancer or melanoma (for melanoma, only cutaneous and mucosal forms, not uveal/ocular) (approved anti-PD-1/PD-L1 indications) that relapsed on or were primary refractory to prior anti-PD-1/PD-L1 therapy with an approved anti-PD-1/PD-L1 compound (with a minimum of 12 weeks of anti-PD-1/PD-L1 exposure) (specific for Germany: and have exhausted all available approved standard treatments or are not eligible for them anymore). (2) colorectal cancer (MSS/mismatch-repair competent) and have not received any prior anti-PD1/PD-L1 therapy (Not applicable in Germany) (3) biomarker cohort with mixed solid tumors (”basket” cohort;) that relapsed on or were primary refractory to prior anti-PD1/PD-L1 therapy with an approved anti-PD-1/PD-L1 compound and that have exhausted available approved therapies for their disease or do not qualify for them anymore (specific for Germany: and have exhausted all available approved standard treatments or are not eligible for them anymore). Note: All Participants in cohorts (1) and (3) must have received an approved anti-PD-1/PD-L1 compound with a minimum of 12 weeks of anti-PD1/PD L1 exposure. Non-approved, experimental anti-PD-1/PD-L1 treatments are not permissive for enrolment (does not apply for cohort (2))
Ability to understand the purpose of the trial, provide signed and dated informed consent prior to performing any protocol-related procedures (including Screening evaluations), and able to comply with the trial procedures and any locally required authorization.
For Part A, ideally ~50% of participants enrolled per dose level should have increased GDF-15 serum levels (based on pre-screening result or historic serum GDF-15 data [up to 2 months prior to the start of treatment with CTL-002 where available]).
All participants must have biopsy-accessible tumor lesions and be willing to undergo tumor biopsy: triple-sequential biopsies (Part A) or dual-sequential biopsies (Part A backfill); in Part B, baseline biopsy (new or archived if obtained within 120 days prior to treatment start) from all participants. In the melanoma and the biomarker cohort with mixed solid tumors (“basket” cohort), an additional on-treatment biopsy is mandatory. All biopsies are mandatory unless not seen as safe and feasible by the treating physician or another specific reason that precludes a biopsy sample being taken and which should be discussed with the Medical Monitor prior to Screening or if applying to the sequential biopsy, prior to that biopsy. All other trial eligibility criteria must be met before the baseline biopsy sample is obtained. Important note for the biomarker [“basket”] cohort: in case biopsy cannot be taken for medical reasons and no archived biopsy <120 days is available, participant cannot be included, as biopsy is mandatory in this cohort for biomarker-correlation reasons). Note: Aspiration cytology is not acceptable as biopsy technique
For Part B, presence of radiologically measurable disease at baseline – with at least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate, repeated measurements as per RECIST V1.1/iRECIST is required. This shall not be the lesion that is going to be biopsied
ECOG performance status 0-1.
Life expectancy > 3 months as assessed by the Investigator.
Adequate organ function: a. Bone marrow function: hemoglobin ≥ 9.0 g/dL (equal to 5.59 mmol/L); platelet count ≥ 100 × 10^9 /L; leukocyte count ≥ 2.5 × 10^9 /L. b. Hepatic function: AST and ALT ≤ 2 × upper limit of normal (ULN) (3 × ULN in the case of liver metastases); bilirubin ≤ 1.5 × ULN (2 × ULN in case of liver metastases/participants with Gilbert’s disease). c. Renal function: serum creatinine < 1.5 × ULN and/or creatinine clearance ≥ 50 ml/min. d. Coagulation: no evidence for clinically relevant hypo- or hypercoagulability or presence of thrombosis/thrombotic event as per D-Dimer, antithrombin III (ATIII), prothrombin time (PT)/international normalized ratio (INR), and activated partial thromboplastin time (aPTT) analysis and treating physician’s assessment. Note: D-Dimer elevation by itself does not preclude inclusion if no clinical evidence of thrombosis is present.
All toxicities related to prior radiotherapy, chemotherapy, and any type of immunotherapy or other anti-cancer therapy, or surgical procedure must have recovered to Grade ≤ 1 based on NCICTCAE v5.0, except alopecia (any grade), and Grade 2 peripheral sensory neuropathy, and AEs that are clinically not considered as significant in this context and/or are stable on supportive therapy.
If participant has type II diabetes and receives metformin, metformin has to be replaced with other antidiabetic(s) prior to start of trial treatment (at minimum 7 days prior to trial baseline GDF-15 measurement at C1D1 prior trial IMP administration) and for the whole trial treatment duration
Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to CTL-002 treatment. If a pregnancy test is not performed within 7 days of dosing with CTL-002, a repeat test must be performed prior to Day 1 dosing. Women of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression.
All participants, male and female, who are not surgically sterilized or postmenopausal as defined above, and participants’ partners of childbearing potential must agree to use “highly effective methods of contraception” during the trial and for at least 5 months (5 times the predicted half-life of CTL-002 in humans) after the last dose of CTL-002. “Highly effective methods of contraception” are combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence. The double-barrier method (synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream or gel), periodic abstinence (such as calendar, symptothermal, or post-ovulation), withdrawal (coitus interruptus), lactational amenorrhea method and spermicide only are NOT acceptable as “highly effective methods of contraception.”

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Exclusion Criteria

Pregnant or breastfeeding.
Has received any tumor-directed therapy within 21 days before start of trial treatment.
Treatment with any investigational agent within 21 days before start of trial treatment.
Radiotherapy within 14 days before the start of the trial treatment; however, participants may receive palliative radiotherapy upon discussion and approval from the Medical Monitor if needed on non-target lesions
Any acute or chronic major tissue injury that may require maintained GDF-15 function for tissue protection as per Investigator assessment (diagnosed with liver, kidney, myocardial infarction, or other major organ failure, all within < 6 months prior to Screening).
Pre-existing arrhythmia (unless considered clinically not relevant), uncontrolled angina pectoris, diagnosed with heart failure New York Heart Association (NYHA) Grade IV, any myocardial infarction/coronary event as well as any central nervous system (CNS)-ischemic event and any thromboembolic event at any time < 6 months prior to Screening or presence of uncontrolled heart failure NYHA Grade III or higher
Left ventricular ejection fraction (LVEF) < 50% as measured by an echocardiogram (ECHO) or multigated acquisition (MUGA) scan if ECHO cannot be performed at site for any reason.
QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval > 450 ms for men or > 470 ms for women
Any active autoimmune disease that requires systemic immunosuppressive treatments, for which (re-)activation may present a medical threat to the participant as per Investigator’s assessment.
Any history of non-infectious pneumonitis < 6 months prior to Screening
Any active inflammatory bowel disease such as Crohn’s disease or ulcerative colitis which are generally excluded or active autoimmune thyroiditis present < 6 months prior to Screening.
Type I diabetes.
History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (< 6 months prior to Screening).
Any history of motor neuron disorder or disease that affects motor neuron function.
Ongoing immune-related AEs (irAEs) and/or AEs ≥ Grade 2 not resolved from previous therapies except vitiligo, stable peripheral sensory neuropathy up to Grade 2, hair loss, and stable endocrinopathies with substitutive hormone therapy.
Active allergy requiring systemic treatment (with the exception of histamine H1 receptor blocker treatment) or active infections requiring systemic anti-infectious therapy.
History of or clinical evidence of CNS primary tumors or metastases including leptomeningeal metastases, unless they have been previously treated, demonstrated no progression at least for 3 months before Screening, are asymptomatic and have had no requirement for steroids or enzyme inducing anticonvulsants in the last 14 days before Screening – participants with suspected brain metastases at Screening should undergo a CT/MRI of the brain prior to trial entry.
Systemic steroids at a daily dose of > 10 mg of prednisolone, > 2 mg of dexamethasone or equivalent, except non-systemic (inhaled, topical, nasal), for the last 28 days and ongoing.
Participants with rapidly progressing disease (as per Investigator assessment), which may predispose to inability to tolerate treatment and/or trial procedure.
Major surgery within last 4 weeks prior to Screening.
Known/expected hypersensitivity against CTL-002 and/or anti-PD-1/PD-L1 agents or their ingredients or previously had a severe hypersensitivity (≥ Grade 3) reaction to treatment with monoclonal antibodies (including pembrolizumab, nivolumab, cemiplimab etc.) and/or any of their excipients
Evidence for active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), tuberculosis (TB), or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as per adequate testing performed
Dementia or altered mental status that would prohibit informed consent.
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory abnormality giving reasonable suspicion of a disease or condition that in the opinion of the Investigator would contraindicate the use of an investigational medicinal product.
Receipt of any organ transplantation, including hematopoietic cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
Paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment (systemic steroids or immunosuppressive agents) or a clinical symptomatology suggesting worsening of PNS.
Vaccine administration within 4 weeks of IMP administration (exception: coronavirus disease 2019 [COVID-19] vaccination). Vaccination with live vaccines while on trial is prohibited. Administration of inactivated vaccines like inactivated influenza vaccines or RNA vaccines is allowed, including COVID-19.
Known active drug or alcohol abuse.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Germany	Not Recruiting	25 Nov 2020	18
Spain	Not Recruiting	25 Nov 2020	151

Sites & Investigators

Research sites

Hospital Vall d’Hebron Hestia Duran I Reynals Hospital Clinic De Barcelona Goethe University Frankfurt

Investigators

Maria Elisa R. M.Guzman A.Ernest N. A.Elena G. C.

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
VisugromabCTL-002	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	—	—	PRD8524649
OPDIVO 10 mg/mL concentrate for solution for infusion.	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	—	—	PRD2941375
OPDIVO 10 mg/mL concentrate for solution for infusion.	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	—	—	PRD2941372
OPDIVO 10 mg/mL concentrate for solution for infusion.	Test	CONCENTRATE FOR SOLUTION FOR INFUSION.	INTRAVENOUS	—	—	PRD9332410
OPDIVO 10 mg/mL concentrate for solution for infusion.	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	—	—	PRD6183485
LIBTAYO 350 mg concentrate for solution for infusion.	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	—	—	PRD7478447