| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advance-stage, relapsed/refractory solid tumors in non-curable state, that relapsed post or were refractory to a prior anti-PD-1/PD-L1 therapy. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced-stage, relapsed/refractory solid tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Part B: 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 CA, hepatocellular CA, 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 an approved anti-PD-1/PD-L1 compound and have exhausted all available approved standard treatments or are not eligible for them anymore, or (2) CRC (micro-satellite stable [MSS]/mismatch-repair competent) and have not received any prior anti-PD-1/PD-L1 therapy, or (3) biomarker cohort with mixed solid tumors that relapsed or were primary, anti-PD-1/PD-L1 therapy
Note: The colorectal cancer cohort is not applicable for Germany. |
|
| E.2.2 | Secondary objectives of the trial |
PART A:
- To explore the pharmacokinetics (PK) of CTL-002 administered as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor.
- To explore the pharmacodynamics of CTL-002 administered as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor.
- To determine the recommended dose(s) for the expansion cohorts (Part B [expansion]) of CTL-002 administered as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor.
- To explore the preliminary anti-tumor activity of CTL-002 administered in combination with an anti-PD-1 checkpoint inhibitor.
- To explore the effect of CTL-002 on prevention of anorexia and muscle wasting (cachexia).
PART B:
- To confirm and further explore the PK/pharmacodynamics of CTL-002 given in combination with an anti-PD-1 checkpoint inhibitor.
- To confirm the recommended Phase 2 dose (RP2D) of CTL-002.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Screening:
1.Provide signed and dated informed consent. For Part A only: signed pre-screening consent for patients that undergo pre-screening procedures
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 available approved standard treatments or are not eligible for them anymore.
4. For Part A (Ph 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 (Ph 2a), subjects must either have (1) bladder CA, hepatocellular CA, 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 an approved anti-PD-1/PD-L1 compound (with a minimum of 12 weeks of anti-PD-1/PD-L1 exposure), and have exhausted all available approved standard treatments or are not eligible for them anymore (2) CRC (MSS/mismatch-repair competent) and have not received any prior anti-PD-1/PD-L1 therapy. (Note: Not applicable in Germany), or (3) biomarker cohort with mixed solid tumors (”basket” cohort;) that relapsed or were primary refractory to prior anti PD-1/PD-L1 therapy with an approved anti-PD-1/PD-L1 compound and have exhausted all available approved standard treatments or are not eligible for them anymore. Note: All Subjects 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 into this group.
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)
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. 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 study eligibility criteria must be met before the baseline biopsy sample is obtained. (Important note for the biomarker cohort: in case biopsy cannot be taken for medical reasons and no archived biopsy <120 days is available, subject cannot be included.
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 CT or 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.
9. ECOG 0-1.
10. Life expectancy > 3 months
11. Adequate organ function. Note: D-Dimer elevation by itself does not preclude inclusion if no clinical evidence of thrombosis is present.
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.
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.
For full list of IC please refer to the Protocol |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or breastfeeding.
2. Has received any tumor-directed therapy within 21 days before start of study treatment.
3. Treatment with any investigational agent within 21 days before start of study treatment.
4. Radiotherapy within 14 days before the start of the study treatment; however, subjects may receive palliative radiotherapy upon discussion and approval from the Medical Monitor if needed on non-target lesions.
5. 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).
6. 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
7. 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
8. QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval > 450 ms for men or > 470 ms for women.
9. Any active autoimmune disease that requires systemic immunosuppressive treatments, for which (re-)activation may present a medical threat to the subject as per Investigator’s assessment
10. Any history of non-infectious pneumonitis < 6 months prior to Screening.
11. 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.
12. Type I diabetes.
13. History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (< 6 months prior to Screening).
14. 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. Paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment (systemic steroids or immunosuppressive agents) or 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 exclusion criteria please refer to the Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PART A:
- Evaluation of the number of subjects with adverse events (AEs), including serious adverse events (SAEs), clinical laboratory data, vital signs, electrocardiograms (ECGs), physical examination (including neurological assessment) and Eastern Cooperative Oncology Group (ECOG) performance status.
- Determination of dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in Part A of the study using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.
PART B:
- 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 subjects with tumor shrinkage, a confirmed partial response (PR) and/or complete response (CR), and overall response rate (ORR).
o The interval between the date of first CTL-002 administration and first documented evidence of a PR or CR (time to response [TTR]).
o The interval between the date of first documented evidence of PR or CR, until first documented evidence of disease progression or death, due to any cause (duration of response [DOR]).
o The interval between the date of first CTL-002 administration and the earliest date of disease progression or death (progression free survival [PFS]).
o The interval between the date of first CTL-002 administration and date of death due to any cause (overall survival [OS]).
- Evaluation of the number of subjects with AEs, including SAEs, clinical laboratory data, vital signs, ECGs, physical examination (including neurological assessment), and ECOG performance status. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to Schedule of Assessments |
|
| E.5.2 | Secondary end point(s) |
PART A:
- Evaluation of PK parameters of CTL-002 (e.g., maximum concentration [Cmax], area under the curve [AUC], and half-life [t1/2]).
- Evaluation of treatment-emergent cytokine profiles in peripheral blood.
- Evaluation of treatment-induced anti-drug antibodies (ADA).
- Evaluation of the clinical efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 of CTL-002 as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor by assessment of:
o The proportion of subjects with tumor shrinkage, a confirmed partial response (PR) and/or complete response (CR), and overall response rate (ORR).
o The interval between the date of first CTL-002 administration and first documented evidence of a PR or CR (Time to Response [TTR]).
o The interval between the date of first documented evidence of PR or CR, until first documented evidence of disease progression or death, due to any cause (Duration of Response [DOR]).
o The interval between the date of first CTL-002 administration and the earliest date of disease progression or death (Progression Free Survival [PFS]).
o The interval between the date of first CTL-002 administration and date of death due to any cause (Overall Survival [OS]).
- To assess appetite, body mass index (BMI), and muscle mass (e.g., L3 skeletal muscle index [L3SMI]).
PART B:
Secondary Endpoints:
- Evaluation of PK parameters of CTL-002 (e.g., Cmax, AUC and t1/2).
- Evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood.
- Evaluation of treatment-induced ADA.
- Evaluation of GDF-15 baseline serum levels and their correlation with pharmacodynamics and clinical response.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to Schedule of Assessments |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| United Kingdom |
| United States |
| Germany |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the core study is defined as the time point when the last
subject has completed the last Safety Follow-up Visit (End of Core
Study Visit) 30 days from the last dose.
The end of study is defined as the time point when the last subject has
completed the last Efficacy and Survival follow-up. This is 12 months
after end of the core study for Part A and 24 months after end of the
core study for Part B. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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