VISUGROMAB for Advanced-stage relapsed/refractory solid tumors

Inclusion criteria

• {"criterion_text":"- 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."}
• {"criterion_text":"- Life expectancy > 3 months as assessed by the Investigator."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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.”"}
• {"criterion_text":"- Male or female aged ≥ 18 years."}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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))"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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])."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- ECOG performance status 0-1."}

Exclusion criteria

• {"criterion_text":"- Pregnant or breastfeeding."}
• {"criterion_text":"- Has received any tumor-directed therapy within 21 days before start of trial treatment."}
• {"criterion_text":"- Treatment with any investigational agent within 21 days before start of trial treatment."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval > 450 ms for men or > 470 ms for women"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Any history of non-infectious pneumonitis < 6 months prior to Screening"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Type I diabetes."}
• {"criterion_text":"- History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (< 6 months prior to Screening)."}
• {"criterion_text":"- Any history of motor neuron disorder or disease that affects motor neuron function."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Active allergy requiring systemic treatment (with the exception of histamine H1 receptor blocker treatment) or active infections requiring systemic anti-infectious therapy."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Participants with rapidly progressing disease (as per Investigator assessment), which may predispose to inability to tolerate treatment and/or trial procedure."}
• {"criterion_text":"- Major surgery within last 4 weeks prior to Screening."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Dementia or altered mental status that would prohibit informed consent."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment (systemic steroids or immunosuppressive agents) or a clinical symptomatology suggesting worsening of PNS."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Known active drug or alcohol abuse."}

Primary endpoints

• {"endpoint_text":"- Evaluation of the clinical efficacy according to RECIST V1.1 of CTL-002 in combination with an anti-PD-1 checkpoint inhibitor by assessment of: o The proportion of participants with tumor shrinkage (defined as reduction in sum of diameters of target lesions ≥ -5%), a confirmed PR and/or CR, and ORR. o The interval between the date of first CTL-002 administration and first documented evidence of a PR or CR (TTR). See protocol","definition_or_measurement_approach":"Efficacy assessed per RECIST v1.1 / iRECIST: proportion with tumor shrinkage (reduction in sum of diameters of target lesions ≥ -5%), confirmed partial response (PR) and/or complete response (CR), overall response rate (ORR); time to response (TTR) measured from first CTL-002 administration to first documented PR or CR."}
• {"endpoint_text":"- Evaluation of the number of participants with AEs, including SAEs, clinical laboratory data, vital signs, ECGs, physical examination (including neurological assessment), and ECOG performance status.","definition_or_measurement_approach":"Safety assessed by counting treatment-emergent adverse events (AEs), serious adverse events (SAEs), review of clinical laboratory data, vital signs, ECGs, physical exams (including neurological), and ECOG PS."}

Secondary endpoints

• {"endpoint_text":"- Evaluation of PK parameters of CTL-002 (e.g., Cmax, AUC, and t1/2).","definition_or_measurement_approach":"Pharmacokinetic parameters including Cmax, AUC, and half-life (t1/2) measured from plasma/serum CTL-002 concentrations."}
• {"endpoint_text":"- Evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood.","definition_or_measurement_approach":"Assessment of cytokine/chemokine changes in peripheral blood following treatment (assays as per protocol)."}
• {"endpoint_text":"- Evaluation of treatment-induced ADA.","definition_or_measurement_approach":"Measurement of anti-drug antibodies (ADA) induced by treatment using validated immunogenicity assays."}
• {"endpoint_text":"- Evaluation of GDF-15 serum levels and their correlation with pharmacodynamics and clinical response.","definition_or_measurement_approach":"Quantification of GDF-15 serum levels and correlation analyses with PD markers and clinical response outcomes."}
• {"endpoint_text":"- To assess muscle mass (e.g., L3 skeletal muscle index [L3SMI]).","definition_or_measurement_approach":"Assessment of muscle mass metrics such as L3 skeletal muscle index using imaging measurements."}

Germany

Earliest CTIS Part Ii Submission Date

11-07-2024

Latest Decision Or Authorization Date

12-07-2024

Processing Time Days

1

Number Of Sites

3

Number Of Participants

18

Spain

Earliest CTIS Part Ii Submission Date

25-06-2024

Latest Decision Or Authorization Date

03-07-2024

Processing Time Days

8

Number Of Sites

7

Number Of Participants

151

Primary sponsor

Full Name

CatalYm GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Contract research organisations

Name

Lonza AG

Responsibilities

Manufacturing of Drug Product - GMP, Primary Packaging of Drug Product

Name

Medidata Solutions Inc.

Responsibilities

Electronic data capture / data services (code:7)

Name

Primevigilance Limited

Responsibilities

Pharmacovigilance (code:8)

Name

Precision For Medicine Inc.

Responsibilities

Kitting; laboratory/biomarker services (code:4)

Name

Biotel Research LLC

Responsibilities

Clinical services (code:13)

Name

Clinigen Clinical Supplies Management GmbH

Responsibilities

Drug supply, QP services

Name

Discovery Life Sciences Biomarker Services GmbH

Responsibilities

Biomarker services (code:4)

Third parties

• {"country":"Switzerland","full_name":"Lonza AG","duties_or_roles":"Manufacturing of Drug Product - GMP, Primary Packaging of Drug Product","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"CeGaT GmbH","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"code:7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"code:8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Precision For Medicine Inc.","duties_or_roles":"Kitting; code:4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Biotel Research LLC","duties_or_roles":"code:13","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Synexa Life Sciences GmbH","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Eurofins Adme Bioanalyses","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Clinigen Clinical Supplies Management GmbH","duties_or_roles":"Drug supply, QP services","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"BioLizard","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Discovery Life Sciences Biomarker Services GmbH","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Precision For Medicine (UK) Limited","duties_or_roles":"codes:1,10,11,12,2,6","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Alderley Analytical Limited","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Precision for Medicine GmbH","duties_or_roles":"Storage of samples; code:15","organisation_type":"Laboratory/Research/Testing facility"}