First-in-Human Study of the GDF-15 Neutralizing Antibody Visugromab (CTL-002) in Patients With Advanced Cancer (GDFATHER)

Study Overview
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Brief Summary
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The Phase 1 part (Part A) is a dose escalation study of IV visugromab (CTL-002, a monoclonal antibody neutralizing GDF-15) as monotherapy and in combination with an approved checkpoint inhibitor (CPI) in patients with advanced solid tumors. Enrolment into the Ph 1 part is completed. The Phase 2 parts (Part B) are cohort expansions with visugromab (CTL-002) in combination with a defined CPI at a fixed dose into seven different solid tumor indications.

Official Title
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A Phase 1/2, FIH, Two-part, Open-label Clinical Trial of Intravenous (IV) Administration of CTL-002 Given as Monotherapy and/or in Combination With an Anti-PD-1 Checkpoint Inhibitor in Subjects With Advanced-stage, Relapsed/Refractory Solid Tumors (The GDFATHER-Trial: GDF-15 Antibody-mediaTed Human Effector Cell Relocation).

Conditions
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Solid Tumor, Adult

Intervention / Treatment
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* Biological: visugromab (CTL-002)


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Signed and dated informed consent, and able to comply with the study procedures and any locally required authorization. Male or female aged ≥ 18 years. Relapsed/refractory patients with histologically or cytologically confirmed diagnosis of advanced-stage or recurrent cancer (Germany-specific: and have exhausted all standard of care treatments or are not eligible for such treatments) Progressed on/relapsed after at least one prior anti-PD-1/PD-L1 treatment (Part A) Biopsy-accessible tumor lesions and willing to undergo triple sequential tumor biopsy (Part A) and dual biopsy (Part B, only for selected cohorts). At least 1 radiologically measurable lesion per RECIST V1.1/imRECIST (Part B). Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Life expectancy > 3 months as assessed by the Investigator. Adequate organ function (bone marrow, hepatic, renal function and coagulation). Main Exclusion Criteria: Pregnant or breastfeeding. Any tumor-directed therapy within 21 days before study treatment. Treatment with investigational agent within 21 days before study treatment. Radiotherapy within 14 days before study treatment. Pre-existing arrhythmia, uncontrolled angina pectoris, uncontrolled heart failure (NYHA) Grade IV, any myocardial infarction/coronary event, CNS-ischemic event and any thromboembolic event at any time < 6 months prior to Screening or presence of any uncontrolled heart failure NYHA Grade III or higher. Left ventricular ejection fraction (LVEF) < 50% measured by echocardiogram or MUGA. QTcF > 450 ms for men or > 470 ms for women. Any active autoimmune requiring systemic immunosuppressive treatments. . 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 autoimmunthyroiditis present < 6 months prior to Screening. History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (< 6 months prior to Screening). 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).

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: Parallel Assignment
Interventional Model Description: Patients will be assigned to a dose level of CTL-002 (Part A) or an expansion cohort (Part B) at the time of their enrollment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 (Part A; dose escalation): CTL-002 Monotherapy + Checkpoint Inhibitor Combination<br>Up to 5 dose levels with visugromab (CTL-002) administered as IV monotherapy and in combination with a CPI | Biological: visugromab (CTL-002)<br>* monoclonal antibody<br>|
| Experimental: Phase 2 (Part B; expansion): visugromab (CTL-002) + Checkpoint Inhibitor Combination<br>At defined dose level(s) with visugromab (CTL-002) | Biological: visugromab (CTL-002)<br>* monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (Parts A & B) | Incidence of treatment emergent adverse events in monotherapy and/or combination therapy | min. 2 months | 
| Determination of DLT and MTD (Part A) | Assessment of toxicities in monotherapy and/or combination therapy per dose level | 28 days | 
| Evaluation of clinical efficacy according RECIST (Part B) | RECIST is measured every 6-8 weeks treatment | min. 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax following the first dose of CTL-002 (Part A & B) | PK parameter from serum CTL-002 levels | 1 day | 
| AUC following the first dose of CTL-002 (Part A & B) | PK parameter from serum CTL-002 levels | 14 days | 
| Half-life of CTL-002 (Part A & B) | PK parameter from serum CTL-002 levels | min. 6 weeks | 
| Evaluation of treatment-emergent cytokine/chemokine concentrations (Part A & B) | Measurement of concentration in peripheral blood | min. 6 weeks | 
| Evaluation of clinical efficacy according RECIST (Part A) | RECIST is measured every 6-8 weeks during treatment | min. 6 weeks | 
| Evaluation of appetite (Part A) | Assessment of appetite via quality of life questionnaire | min. 6 weeks | 
| Assessment of Body-Mass-Index (BMI) (kg/m2) (Part A) | Calculation of BMI in kg/m2 by combining measurement of body weight in kg and body height in cm | min. 6 weeks | 
| Assessment of lumbar vertebra skeletal muscle index (L3SMI) (cm2/m2) (Part A) | Combining measurement of L3 vertebra skeletal muscle mass via computed tomography (CT) in cm2 and patient height (squared) in m2 | min. 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CTL-002, GDF-15, visugromab