A Phase I/II, 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)
Study Identifier:
CTL-002-001
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
Recruitment Complete
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Study Summary
To evaluate CTL 002 in cancer.
To Determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination.
Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect).
Biomarker and response assessments will be reported.
To assess the prediction accuracy of response for two potential biomarkers in a total of 25 cancer patients treated with the GDF-15-targeting antibody visugromab in combination with the anti-PD1 antibody nivolumab in patients that are relapsed/refractory to prior anti-PD1/PD-L1 treatment.
To explore the preliminary anti-tumor activity of CTL-002 administered in combination with an anti-PD-1 checkpoint inhibitor in in subjects with advanced-stage relapsed/refractory solid tumors in non-curable state as per current clinical knowledge that have either (1) bladder cancer, hepatocellular cancer, non-small 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 or (2) colorectal cancer (micro-satellite stable [MSS]/mismatch-repair competent) and have not received any prior anti-PD-1/PD-L1 therapy, or (3) mixed solid tumors (“basket” cohort) with tumors that are demonstrated to be PD-L1+ (Tumor Proportion Score [TPS] > 1) at baseline and are relapsed on or were primary refractory to prior anti-PD-1/PD-L1 therapy.
To evaluate Visugromab in combination with an anti-PD1 antibody in patients with advanced solid tumors that are relapsed/refractory to prior anti-PD1/-PD-L1 treatment.
To investigate the treatment of advanced stage cancer patients that are relapsed/refractory to prior anti-PD-1/-PD-L1 treatment with the GDF-15 neutralizing antibody, visugromab, in combination with the anti-PD-1 checkpoint inhibitor nivulomab.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
I/II
Sex
Female & Male
Age
18+ years
Study Drug
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Study Status
Indicates the current recruitment status or the expanded access status
Recruitment Complete
Requirements information
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).
- Screening:
- 1.Provide signed and dated informed consent. For Part A only: signed pre-screening consent for patients that undergo pre-screening procedures or collection of historical data prior to informed consent procedure.
- 2. Male or female aged ≥ 18 years.
- 3.Subjects with histologically or cytologically confirmed/documented diagnosis of advanced-stage, relapsed/refractory solid tumors in non-curable state as per current clinical knowledge who have exhausted all standard of care according to current guidelines or are considered by the Investigator as not eligible for such treatments.
- 4. For Part A (Phase 1), subjects must have received during their prior treatment at least one anti-PD-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). For Part B (Phase 2a), subjects must either have (1) bladder cancer, hepatocellular cancer, non-small 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 a minimum of 12 weeks of anti-PD1/PD-L1 exposure), or (2) colorectal cancer (MSS/mismatch-repair competent) and have not received any prior anti-PD-1/PD-L1 therapy. (Note: The latter is not applicable for Germany), or (3) PD-L1+ (TPS > 1 as per local testing) tumors (biopsy not older than 120 days prior to treatment start) and anti-PD-1/PD-L1 relapsed/refractory disease. In this cohort all solid tumor entities can be enrolled (mixed solid tumor ”basket” cohort; biomarker-selected).
- 5.Ability to understand the purpose of the study, provide signed and dated informed consent prior to performing any protocol-related procedures (including Screening evaluations), and able to comply with the study procedures and any locally required authorization.
- 6. For Part A, ideally ~50% of subjects 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)].
- 7.All subjects 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 subjects and sequential biopsies in individual cohorts (i.e., melanoma) at set time points. All biopsies are mandatory unless not seen as safe 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 study eligibility criteria must be met before the baseline biopsy sample is obtained.
- 8. 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/imRECIST is required. This shall not be the lesion that is going to be biopsied (melanoma and head & neck cancer).
- 9. ECOG performance status 0-1.
- 10. Life expectancy > 3 months as assessed by the Investigator.
- 11. Adequate organ function.
- 12. All toxicities related to prior radiotherapy, chemotherapy, any type of immunotherapy or other anti-cancer therapy, or surgical procedure must have recovered to Grade ≤ 1 based on NCI-CTCAE v5.0, except alopecia (any grade), Grade 2 peripheral sensory neuropathy, and AEs that are clinically not considered as significant in this context and/or are stable on supportive therapy.
- 13. If subject has type II diabetes and receives metformin, metformin has to be replaced with other antidiabetic(s) prior to start of study treatment (at minimum 7 days prior to study baseline GDF-15 measurement) and for the whole study treatment duration.
- 14. 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.
- 15. 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.
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).
- 4. Any history of motor neuron disorder or disease that affects motor neuron function.
- 15. 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.
- 16. Active allergy requiring systemic treatment (with the exception of histamine H1 receptor blocker treatment) or active infections requiring systemic anti-infectious therapy.
- 17. 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 - subjects with suspected brain metastases at Screening should undergo a CT/MRI of the brain prior to study entry.
- 18. 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.
- 19. Subjects with rapidly progressing disease (as per Investigator assessment), which may predispose to inability to tolerate treatment and/or study procedure.
- 20. Major surgery within last 4 weeks prior to Screening.
- 21. 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.
- 22. 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.
- 23. Dementia or altered mental status that would prohibit informed consent.
- 24. 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 drug.
- 25. 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).
- 26. Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment (systemic steroids or immunosuppressive agents) or has a clinical symptomatology suggesting worsening of PNS
- 27. Vaccine administration within 4 weeks of investigational drug administration (exception: coronavirus disease 2019 (COVID-19) vaccination). Vaccination with live vaccines while on trial is prohibited......
- For full list of inclusion criteria please refer tot he Protocol
- 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).
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Maria de Miguel
Status
Recruitment Complete
Condition(s) Treated at Site
Bladder
Breast Cancers
Bowel (Colorectal)
Non-Small Cell Lung Cancer
Melanoma
Liver
Head & Neck
Solid Tumor
Mesothelioma
Cervical cancer