CEB-01 in Pediatrics With Locally Resectable Abdominal Tumors

CEB-01-RLP01-CT trial is first-in-pediatrics, open label, exploratory, externally controlled clinical trial to evaluate safety, efficacy and pharmacokinetics of 7-ethyl-10-hydroxy-camptothecin (SN-38) formulated as a biocompatible polymeric nanofiber membrane (CEB-01) for treatment, in addition to standard of care, of pediatric patients from birth to less than 18 years of age with de novo or recurrent, locally resectable, abdominal tumors in comparison to standard of care.

The trial population will consist of 80 participants who fulfill all the inclusion and exclusion criteria, allocated in three cohorts:

Cohort 1: 20 participants with abdominal STS, open label treatment arm consisting of CEB-01 plus the standard of care (which may include surgery, with or without radiotherapy and/or chemotherapy). The outcomes will be compared to a well-matched population of about 10 participants from the same participating sites, including historical controls or contemporary controls.

Cohort 2: 20 participants with high-risk NB, open label treatment arm consisting of CEB-01 plus the standard of care (which may include surgery, with or without radiotherapy and/or chemotherapy). The outcomes will be compared to a well-matched population of about 10 participants from the same participating sites, including historical controls or contemporary controls.

Cohort 3: 20 participants with rare abdominal tumors including WT, GCT, eMRT, SS, DSRCT and FL-HCC, open label uncontrolled treatment arm to obtain additional safety and efficacy data.

For measurement of primary safety and efficacy endpoints, follow-up will consist of short-term evaluation at 365 ± 30 days and long-term evaluation at 1095 ± 30 days post-surgery as it is considered sufficient for the assessment of the therapeutic effect of CEB-01 regarding local recurrence.

For pharmacokinetic assessment, blood samples will be collected at baseline and at 9 different time points until 56 ± 4 days post-surgery.

For each participant the trial duration will be composed of a screening period for up to 28 days, one day for surgery and 1095 ± 30 days of follow-up.

A Data Safety Monitoring Board (DSMB) will review data in an unblinded fashion; details are given in the DSMB charter. The scheduled review will be performed by the DSMB once 10 treated participants have completed 6 months of follow-up. The DSMB can be convened at the request of the sponsor should safety signals be detected

• Standard surgery (Procedure): The location and size of the tumor determine the type of surgery.
• CEB-01 (Drug): It is novel formulation for local release of chemotherapy. It consists of a biocompatible and biodegradable nanofiber membrane made of poly(lactic-co-glycolic acid) (PLGA), which is loaded with the anti-tumor drug SN-38 and implanted in the surgical bed after tumor removal.

Primary outcomes

• Frequency of Adverse Events (AEs) (Safety) [Through study completion, average 3 years]: Adverse Events (AE), serious and non-serious, with their frequency, severity, and relatedness to study drug and coded according to the most updated version of the Common Terminology Criteria for Adverse Events (CTCAE).

Secondary outcomes

• Progression-free survival (PFS) [Through study completion, average 3 years]: Defined as the time from surgery to objective tumor progression or death from any cause.
• Overall survival (OS). [Through study completion, average 3 years]: Defined as time from surgery to death from any cause.
• Local recurrence-free survival (LRFS) [Through study completion, average 3 years]: Defined as the time from surgery until the progression of the disease in the area of implanted CEB-01.
• New lesions either distant or metastatic by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1) [Through study completion, average 3 years]: Number of new lesions either distant or metastatic by RECIST 1.1. (Response Evaluation Criteria in Solid Tumors, version 1.1)
• Area under the concentration-time curve (AUC0-inf) of SN-38 ( 7-ethyl-10-hydroxy Camptothecin) [During 60 days]: Represents the total SN-38 (f 7-ethyl-10-hydroxy Camptothecin) exposure in the peripheral blood across time
• Maximum concentration (Cmax) of SN-38. [During 60 days]: The highest concentration of SN-38 in the peripheral blood samples taken at sequential timepoints
• Time of maximum plasma concentration (Tmax) of SN38. [During 60 days]: Time from the surgery to the moment with the highest concentration of SN-38 in the peripheral blood samples taken at sequential timepoints
• Terminal half-life (t1/2) of SN-38 [During 60 days]: The time required for the plasma concentration of SN-38 to fall by 50% from the Cmax
• Score of Quality of Life [Through study completion, average 3 years]: Quality of Life Questionnaire (QoL) using KIDSCREEN-27

Sex: All, ages: any to 18 Years

Inclusion Criteria:

To be eligible to participate in this trial, an individual must meet all the following criteria:

1. ≤ 18 years.
2. Participants must have a diagnosis of:

   1. De novo or recurrent abdominal soft-tissue sarcoma.
   2. De novo or recurrent high-risk neuroblastoma according to Children's Oncology Group (COG) risk classification, regardless of response to frontline therapy, diagnosed either by a former histologic verification of neuroblastoma and/or former demonstration of tumor cells in the bone marrow with increased urinary catecholamines at the time of study enrolment. Participants who were initially considered low or intermediate risk but were then reclassified as high risk are also eligible.
   3. Other tumors: recurrent Wilms tumor, de novo or recurrent Germ cell tumour, de novo or recurrent extracranial malignant rhabdoid tumor, de novo or recurrent synovial sarcoma, de novo or recurrent fibrolamellar hepatocellular carcinoma, and de novo or recurrent desmoplastic small round cell tumor.
3. A histology assessment is required for enrolment of de novo cases, except for patients with high-risk neuroblastoma for which a radioiodine-labelled meta-iodobenzyl-guanidine (MIBG) test is positive and excess of production od catecholamines is confirmed. A new histology assessment is not required for enrolment of the recurrent cases, it will be obtained from the resected tumor to assess whether the histology is identical to the original tumor.
4. Participants previously treated with irinotecan will be eligible if they have not had documented progressive disease during treatment.
5. Participants might have more than one surgically removable lesion.
6. Adequate liver, renal, hematological, and cardiac function as defined by biochemical and hematological parameters as follows: hemoglobin (Hb) >9.0 g/dL (with preoperative transfusion), platelets >80.000/mm3 with intraoperative transfusion, absolute neutrophil count ≥ 1.500/mm3 or below this threshold if there is clinical indication that the patient is on hematological recovery, albumin >3.0 g/dl, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 times the upper limit of normality \[ULN\], bilirubin <2 times the ULN, creatinine <1.0 mg/dl or creatinine clearance > 60 ml/min.
7. Participants must have fully recovered from the acute toxic clinically relevant effects (Grade 3 or above) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this trial.
8. Lansky or Karnofsky functional performance status score ≥ 50 at screening.
9. Female participants of childbearing potential must have a negative urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test at time of screening.
10. Female and male participants of childbearing potential must be willing to use adequate contraception throughout the study and for 6 months after surgery.
11. Life expectancy greater than 6 months.
12. The participant's legally authorized guardian must acknowledge in writing that consent to become a study subject has been obtained prior to any protocol screening procedures.

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this trial:

1. Metastatic lesions, that in the investigator's opinion will not jeopardize the assessment of efficacy and safety.
2. Other malignancies within past 2 years except for in-situ cancers or basal/squamous cell skin cancer. Subjects with other malignancies are eligible if they are disease-free for at least 24 months or have a clinically stable concurrent malignancy not requiring tumor-directed treatment.
3. Active bacterial, viral or fungal infection.
4. Known history of active human immunodeficiency virus (HIV) infection, hepatitis B, hepatitis C or chronic liver disease. Testing is not required in the absence of clinical findings or suspicion.
5. Impossibility of ensuring adequate follow-up.
6. Participants who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
7. Contraindication to computed tomography (CT) scan.
8. Major surgery within 14 days prior to the implant of study drug or still in recovery after experiencing surgical complications; neither tumor biopsy nor central line insertion are considered a major surgery.
9. Other relevant concomitant illnesses.
10. Participants´status post-allogeneic stem cell transplant are not eligible.
11. Participants with disease of any major organ system that would compromise their ability to withstand therapy.
12. Patients with tumor size requiring CEB-01 implant that exceeds the maximum implantable surface area based on Body Surface Area (BSA) correction.
13. Patients with known hypersensitivity to SN-38 or any of the CEB-01 excipients.
14. Pregnancy or lactation. Pregnant women are excluded from this study; if the patient is a lactating mother, breastfeeding should be discontinued.

• Marta Pilar Martin Gimenez, M.D.; Ph.D., Principal investigator, Hospital Sant Joan de Deu