| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Advanced Solid Tumor Malignancy | |
| E.1.1.1 | Medical condition in easily understood language | | Advanced Solid Tumor Malignancy | |
| 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 | 10065147 | | E.1.2 | Term | Malignant solid tumor | | E.1.2 | System Organ Class | 100000004864 | |
| 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 | 1. To assess the safety and to identify the MTD of Allocetra-OTS as monotherapy when repeatedly administered via IV or IP infusion in patients with advanced solid tumor malignancy (applicable to Stage 1).
2. To assess the safety and to identify the MTD of Allocetra-OTS administered via IV or IP infusion in combination with nivolumab in patients with advanced solid tumor malignancy (applicable to Stage 2). | |
| E.2.2 | Secondary objectives of the trial | 1. To assess preliminary efficacy parameters following IV or IP administration of Allocetra-OTS as monotherapy in patients with advanced solid tumor malignancy (applicable to Stage 1).
2. To assess preliminary efficacy parameters following IV or IP administration of Allocetra-OTS in combination with nivolumab in patients with advanced solid tumor malignancy (applicable to Stage 2) | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Patients must have histologically or cytologically confirmed locally advanced, unresectable or metastatic solid tumors, that have relapsed or have been refractory to available approved therapies specific to their cancer type, based upon standard clinical practice guidelines, with agents that are approved and available to them in their country. Patients who are either not eligible for or have specifically declined additional standard of care systemic therapy may also be enrolled. Patients with peritoneal carcinomatosis with no or minimal extraperitoneal disease (as per Investigator discretion) can be eligible for treatment with IP Allocetra-OTS if an appropriate IP catheter (e.g. PleurX) or port is in place or can be placed.
2. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1), assessed within 28 days prior to study treatment.
3. Age ≥18 years old at the time of signing the ICF.
4. Patients who have had major surgery must be fully recovered and a recovery period of ≥4 weeks has elapsed prior to enrolling in the study.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
6. Adequate renal function, defined as a serum creatinine ≤1.5×upper limit of normal (ULN), or measured creatinine clearance ≥50 mL/min/1.73m2 (or estimated creatinine clearance ≥50 mL/min [Cockcroft-Gault]).
7. Adequate hepatic function, defined as aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤3×ULN and total bilirubin <1.5×ULN, in the absence of cancer within the liver or a known diagnosis of Gilbert’s syndrome. Bilirubin ≤5 mg/dL will be permitted in patients with Gilbert’s syndrome, if direct bilirubin is ≤1.0 mg/dL. AST and ALT ≤5×ULN and total bilirubin ≤3×ULN will be permitted in the setting of primary or metastatic liver tumors.
8. Adequate bone marrow function, defined as absolute neutrophil count (ANC) ≥1,200/mm3 (≥1.2×10 6/L), platelet count ≥75,000/mm3 (≥75×10 6
/L) without transfusions for at least one week, and hemoglobin ≥8 g/dL without transfusions for at least one week.
9. International normalized ratio (INR) or activated partial thromboplastin time (aPTT) <1.5×ULN unless the patient is receiving anticoagulant therapy. Patients on anticoagulant therapy should have a prothrombin time (PT) or PTT within therapeutic range for the specific intended use and no history of severe hemorrhage.
10. Contraceptive use by women or men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies:
a. Female patients must have a negative serum pregnancy test at screening.
b. Female patients: women of childbearing potential must use a highly effective form of contraception from the screening visit until at least 4 weeks after the final dose of Allocetra-OTS and at least five months after the final dose of nivolumab.
c. Male patients: men must be sterile (biologically or surgically) or use a highly effective method of contraception from the screening visit until at least 4 weeks after the final dose of Allocetra-OTS and at least seven months after the final dose of nivolumab.
11. Ability of the patient to understand, and willingness to provide informed consent as described in this study protocol, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
12. To the discretion of the investigator, ability to comply with all study procedures, availability for the duration of the study, ability and willingness to return for follow-up visits (for example, life expectancy of more than 3 months).
Additional Inclusion Criteria for Stage 2 Only
1. Patients with malignant indications approved for immune checkpoint inhibitors (ICI) and available to them must have relapsed following, or have been refractory to at least one immune checkpoint inhibitor (eg, nivolumab, pembrolizumab, or atezolizumab). | |
| E.4 | Principal exclusion criteria | 1. Primary central nervous system (CNS) malignancy or CNS involvement, unless asymptomatic, previously treated, and stable clinically and radiographically without steroids during the last three months.
2. Squamous cell carcinoma of the skin or melanoma. Metastatic uveal melanoma is allowed.
3. Receipt of any biological therapy (immunotherapy and monoclonal antibodies), hormonal therapy, or chemotherapy within four weeks prior to initiation of study treatment (or five half-lives, whichever is shorter). Receipt of any radiation (except palliative radiation) within two weeks prior to study treatment.
4. Participation in other concurrent interventional clinical trials or have been treated with any investigational agent within 30 days prior to starting study treatment, unless approved by the Sponsor.
5. Lack of recovery of prior AEs to Grade 1 or resolution, according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE v5.0), except alopecia (any grade) or Grade 2 neuropathy due to therapy administered prior to the initiation of study drug dosing.
6. Clinically significant, active infection requiring systemic antibacterial, antifungal or antiviral therapy with 7 days of study enrollment.
7. Patients with a history of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or acute hepatitis A infection will be
excluded from trial participation given the unknown impact of ongoing infection with these agents on the immune regulatory function of AllocetraOTS
administered alone or in combination with nivolumab in patients with cancer. Patients with a history of hepatitis C therapy will be allowed if patients have been treated with approved antiviral therapy, and no residual virus is detectable currently (and at least 12 weeks since completion of antiviral therapy).
8. Concomitant conditions (autoimmune or inflammatory diseases) requiring systemic immunosuppression or chronic (daily or almost daily for ≥ 1 month prior) use of steroids at a dose equivalent to more than 10 mg prednisone.
9. Patient received any live vaccines within 30 days prior to enrollment.
10. Clinically significant cardiovascular disease, including stroke or myocardial infarction within six months prior to first infusion of Allocetra-OTS; or the
presence of unstable angina, severe myocardial insufficiency, severe arrhythmias or congestive heart failure of New York Heart Association Class III or higher.
11. Clinically significant pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis or severely
impaired pulmonary function. History of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection with residual clinically significant residual pulmonary compromise in the judgement of the Investigator.
12. Known hypersensitivity to any component of study treatment or excipients.
13. Known history of transfusion reactions, hemolytic anemia, or repetitive allergic reaction to cellular therapies.
14. Uncontrolled intercurrent illness or any medical, psychiatric, social or substance abuse condition, that in the opinion of the Investigator may be of greater safety risk or would limit compliance with study requirements or interpretation of the results.
15. Women who are pregnant or breastfeeding.
16. Patients who have previously received Allocetra-OTS.
17. Any known additional malignancy (with exception of non-melanoma skin cancer, in-situ breast cancer or a malignancy diagnosed ≥3 years ago and with no evidence of requiring active treatment).
18. History of liver cirrhosis with Child-Pugh classification of B or C or signs of portal hypertension, portal vein thrombosis. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | 1. Stage 1: Characterize the safety of Allocetra-OTS from the first infusion of Allocetra-OTS up to Day 21, based on the DLTs and MTD (or MAD if no MTD is defined) of Allocetra-OTS as monotherapy.
2. Stage 2: Characterize the safety of Allocetra-OTS from the first infusion of Allocetra-OTS up to Day 35, based on the DLTs and MTD (or MAD if no MTD is defined) of Allocetra-OTS in combination with nivolumab. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | 1. Overall Response Rate (ORR)/Best Overall Response Rate (BORR) (percentage of patients who achieve best response of complete response [CR] or partial response [PR]).
2. Clinical benefit rate (CBR) (percentage of patients who achieve best response of CR, PR or stable disease [SD] ≥6 months). (Stage 1 and 2)
3. Duration of response (DoR), defined as the time from first documented evidence of CR or PR until disease progression or death.
4. Time to response (TTR), defined as the time from first infusion of AllocetraOTS to the first documented CR or PR.
5. Kaplan-Meier estimated median progression-free survival (PFS), defined as the time from the first infusion of Allocetra-OTS to disease progression or death due to any cause, whichever occurs first.
6. Kaplan-Meier estimated median overall survival (OS) defined as the time from the first infusion of Allocetra-OTS to death due to any cause.
Note: All secondary endpoints are applicable to both Stage 1 and Stage 2 of the study, unless otherwise specified | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description | | IV and IP cohorts are in parallel | |
| 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 | 8 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 | |
| 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 | | LPLV | | última visita del último paciente | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
