A trial to determine the dose, and evaluate the safety and pharmacokinetics of lutetium Lu 177 edotreotide in children with somatostatin receptor-positive (SSTR+) tumors

Phase 1

Not yet recruiting

Conditions: Pediatric patients two years of age and above with somatostatin receptor positive (SSTR-positive) solid tumors or lymphoma, recurrent/refractory to at least one prior line of therapy

Interventions: Drug: Lutetium Lu 177-Edotreotide
Other: Amino Acid Solution

Registration Number: 2024-512831-66-00

Lead Sponsor: ITM Solucin GmbH

Brief Summary: Determine the appropriate pediatric dosage based on the safety profile and the pharmacokinetics of lutetium Lu 177 edotreotide targeted radiopharmaceutical therapy (RPT).

Detailed Description: Determine the dose, pharmacokinetics and safety of Lutetium Lu 177 Edotreotide as monotherapy or following sequential standard of care in pediatric participants with recurrent, progressive or refractory NET, CNS, lymphoma and other solid tumors that express SSTRs by immunohistochemistry and demonstrate uptake by somatostatin receptor imaging. Lutetium Lu 177 Edotreotide will be given intravenously once every 8 weeks for a total of up to 6 doses over an average of 48 weeks in participants aged 2-18 years.

Recruitment & Eligibility

Status: Authorised, recruitment pending

Sex: Not specified

Target Recruitment: 12

Inclusion Criteria

Confirmed diagnosis of SSTR-positive tumors including, but not limited to the following: a. Neuroendocrine tumors (NETs): i. GEP-NET ii. Pulmonary NET iii. Thymus NET iv. Breast NET v. Parathyroid NET vi. Gonadal and cervical NET vii. NET of unknown primary viii. Neuroblastoma ix. Paraganglioma x. Pheochromocytoma xi. Medullary thyroid carcinoma xii. Pituitary adenoma b. CNS Tumors: i. Meningioma ii. Medulloblastoma and other embryonal tumors iii. High grade gliomas and ependymomas iv. Low grade gliomas (gangliogliomas, dysembryoplastic neuroepithelial tumor) c. Lymphoma: i. Hodgkin lymphoma ii. Non-Hodgkin lymphoma (diffuse large B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma). d. Rhabdomyosarcoma e. Peripheral primitive neuroectodermal tumors pPNETS (Ewing family of sarcomas) f. Gastrointestinal stromal tumor (GIST)

In case of prior therapy or in case of sequential treatment with SoC, the protocol defined washout periods apply before starting the targeted RPT

If the child has previously received anthracyclines or external beam radiotherapy to the chest: An ejection fraction of ≥55% within an echocardiogram performed within four weeks prior to enrollment

Written informed consent from parent(s) or legal guardian(s) and written assent from participant in accordance with local regulations, prior to registration or any trial-related screening procedures

Age ≥ 24 months and < 18 years at the time of enrollment into this trial (enrollment will be opened by age groups sequentially; see trial design for more details)

Tumor which is relapsed or is refractory to at least one line of prior systemic antineoplastic therapy (depending on the tumor type one line of therapy may involve multimodality treatment). In cases where the participant has experienced only one relapse, the Investigator should assess whether enrolling the patient in the clinical trial or pursuing an existing second-line treatment would be the most appropriate course of action. Investigators should carefully evaluate the potential risks and benefits of the investigational treatment compared to the available standard therapies, ensuring that the chosen approach aligns with the patient’s best interests and overall treatment goals

Tumor progression according to Investigator judgment

SSTR expression confirmed by immunohistochemistry of a tumor histology sample (biopsy or surgical sample). An existing histology report showing SSTR positivity by IHC is acceptable. A SSTR IHC positive results is mandatory before moving forward with the rest of the screening assessments in particular the SSTR SPECT/CT or PET/CT imaging. No further screening evaluation should take place in case of a negative IHC result and patient should be considered not eligible for this trial; this is to limit exposure to unnecessary SSTR SPECT/T or PET/CT ionizing radiations.

Radioactivity uptake within the primary tumor or metastatic tumor sites measured by locally available 111In-based, 99mTc-based, or 68Ga -based SSTR SPECT/CT or PET/CT imaging, which is higher than the liver uptake, and performed within two months prior to enrollment. (Planar images only are not accepted). If not already available, this SSTR imaging can only take place after a positive result is observed by IHC (see inclusion criterium 5 above).

CT or MRI of the primary tumor and metastatic sites within two months prior to enrollment. All the CT/MRI target lesions and lesions considered dominant must also be SSTR-positive, based on Investigator judgement

Karnofsky ≥ 50% (for participants > 16 years of age), Lansky ≥ 50% (for participants ≤ 16 years of age) at the time of screening

Participants must have recovered from the acute treatment related toxicities (defined as ≤ grade 1 if not defined in eligibility criteria, excluding alopecia, stable treated electrolyte abnormalities on replacement and stable treated hypothyroidism) of all prior chemotherapy, immunotherapy, radiotherapy, or any other treatment modality prior to entering this trial

Exclusion Criteria

Known hypersensitivity to Lutetium Lu 177 edotreotide or any of its components (DOTA/edotreotide, lutetium-177, etc.), or excipients

Previous treatment with metaiodobenzylguanidine (MIBG) if the predicted overall absorbed dose is expected to exceed 2 Gy to the bone marrow or 23 Gy to the kidney. If a participant received a lower cumulative dose of these critical organs, he/she may participate for a number of cycles (at least 2) until this dose is reached

Previous treatment with external beam radiation therapy (EBRT), if the predicted overall absorbed dose is expected to exceed more than 2 Gy to the bone marrow or 23 Gy to the kidney. If a participant received a lower cumulative dose of these critical organs, he/she may participate for a number of cycles (at least 2) until this dose is reached

Previous treatment with oncologic immune vaccine or CAR-T cell therapy

Bulky disease in the CNS defined as: a. Any signs of intracranial hypertension, e.g., papilledema b. Tumor with evidence of clinically significant mass effect in the brain or spine, e.g., uncal herniation or midline shift c. Tumor with diameter of > 5 cm in one dimension on T2/FLAIR d. Patients with metastatic or multi-focal disease, in case that the sites of disease meet above criteria for bulky CNS disease

Presence of severe renal, hepatic, electrolyte, cardiovascular, or hematological dysfunction, potentially interfering with the safety of the trial treatments, defined as follows and assessed within seven days prior to commencing trial treatment: a. Renal: i. eGFR < 60 mL/minute/1.73 m2 assessed by a recognized method, such as cystatin C performed within four weeks prior to enrollment ii. Renal tract obstruction. b. Hepatic: i. Hyperbilirubinemia > Grade 1 (NCI-CTCAE version 5.0) ii. Hypoalbuminemia > Grade 1 (NCI-CTCAE version 5.0), unless prothrombin time is within normal range. iii. Elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > Grade 1, or > Grade 2 in the presence of liver metastasis and elevation of gamma glutamyl transferase (GGT)/ alkaline phosphatase (ALP) > Grade 2 (NCI-CTCAE version 5.0). iv. Known ascites c. Cardiovascular: i. Heart failure (New York Heart Association (NYHA) classification III and IV) ii. Uncontrolled hypertension iii. Hyperkalemia > 6.0 mmol/L which is not corrected iv. QTc interval >450 ms for males and >460 ms for females aged 12 to 18 years, or QTc interval >450 ms for any participant under 12 years of age d. Hematopoietic: i. Platelets ≤ 75 x 10^9 /L ii. Absolute neutrophil count (ANC) < 0.75 x 10^9 cells/L iii. Hemoglobin (Hb) concentration < 9.0 g/dL e. Any other ongoing Grade 2-4 toxicity from previous standard traditional or investigational therapies (NCI-CTCAE version 5.0)

Any psychological, familial, sociological or geographical condition that may hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient or legal guardian before registration in the trial

Pregnancy or lactation

Female participants of childbearing potential or male participants with female partners of childbearing potential, unless: a. willing to practice full and true sexual abstinence b. surgically/permanently sterile (bilateral tubal occlusion, hysterectomy, or vasectomy) c. willing to practice highly effective contraception in combination with a barrier method of contraception (e.g., condom). Contraception methods that are considered highly effective are: oral or non-oral (injected or implanted) non-estrogen progesterone-based hormonal method; oral, intravaginal, or transdermal combined estrogen and progesterone-based hormonal methods; and/or intrauterine device (IUD), and/or intrauterine hormone-releasing system (IUS). Sexual abstinence or the contraception methods described above must be followed up to seven months (the end of relevant systemic exposure incl. potential genotoxic metabolites [i.e. five terminal half-lives] plus six months) for female participants and up to four months (until the end of relevant systemic exposure in the exposed male [i.e., five terminal half-lives] plus 90 days) for male participants with female partners of childbearing potential, after the last treatment. d. they are female participants whose male partners have medically successful vasectomy (provided the partner is the sole sexual partner of the female participant of childbearing potential)

Participants who have received a live-attenuated vaccine up to four weeks prior to enrollment. Live attenuated vaccines should not be administered during the trial treatment and over the next three months after the last treatment dose

Other known malignancies, unless in complete remission for at least two years

Serious non-malignant disease (e.g., psychiatric, infectious, autoimmune or metabolic), that may interfere with the objectives of the trial or with the safety or compliance of the participant, as judged by the Investigator

Previous history of acute leukemia unless in remission for at least two years

Extensive bone/bone marrow involvement as per Investigator’s judgement unless peripheral blood stem cells (PBSC) are available at a minimum of 2.5 x 10^6 CD34+ cells/kg (optimally 4 x 10^6 CD34+ cells/kg) for each participant prior to registering

Patients who have received previous systemic targeted RPT, including Lutetium Lu 177 edotreotide, Yttrium Y 90 edotreotide, Lutetium Lu 177 oxodotreotide, high-dose Indium In 111 pentetreotide or other targeted RPT agents targeting somatostatin receptors

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Three sequential age cohorts	Amino Acid Solution	Arms are based upon age at enrollment. The opening of the 2nd and 3rd cohort will depend on the recruitment of at least four participants with dosimetry and safety data for cycle 1, in the previous cohort. 1. ≥ 12 to \< 18 years old 2. ≥ 6 years to \< 12 years old 3. ≥ 2 to \< 6 years old
Three sequential age cohorts	Lutetium Lu 177-Edotreotide	Arms are based upon age at enrollment. The opening of the 2nd and 3rd cohort will depend on the recruitment of at least four participants with dosimetry and safety data for cycle 1, in the previous cohort. 1. ≥ 12 to \< 18 years old 2. ≥ 6 years to \< 12 years old 3. ≥ 2 to \< 6 years old

Primary Outcome Measures

Name	Time	Method
Determine the recommended dose defined as the highest lutetium Lu 177 edotreotide dose which will comply with all the following criteria: 1. The median kidney absorbed dose of lutetium Lu 177 edotreotide is below 23 Gy for full treatment. 2. The median bone marrow absorbed dose is below 2 Gy for full treatment 3. Acceptable dose limiting toxicity (DLT) profile (based on adverse event reporting) as evaluated by the data monitoring committee (DMC)		Determine the recommended dose defined as the highest lutetium Lu 177 edotreotide dose which will comply with all the following criteria: 1. The median kidney absorbed dose of lutetium Lu 177 edotreotide is below 23 Gy for full treatment. 2. The median bone marrow absorbed dose is below 2 Gy for full treatment 3. Acceptable dose limiting toxicity (DLT) profile (based on adverse event reporting) as evaluated by the data monitoring committee (DMC)

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR): proportion of targeted RPT-treated participants with a complete response (CR) or partial response (PR), evaluated by the Investigator, under consideration of available guidelines for monitoring response in the different tumors involved (please see protocol for further details)		Objective Response Rate (ORR): proportion of targeted RPT-treated participants with a complete response (CR) or partial response (PR), evaluated by the Investigator, under consideration of available guidelines for monitoring response in the different tumors involved (please see protocol for further details)
Rate of AEs: occurrence of AEs, severity, seriousness (including SAEs), adverse reactions of special interest, SUSARs, AEs of special interest (AESIs), outcome, treatment/trial procedure-relatedness, action taken (including any treatment, and including any change in administration of the trial drug/auxiliary medication),dose-modifying toxicity (DMT), DLT. Pre and post administration: vital signs, physical examination, ECG, safety laboratory parameters (please see protocol for further details)		Rate of AEs: occurrence of AEs, severity, seriousness (including SAEs), adverse reactions of special interest, SUSARs, AEs of special interest (AESIs), outcome, treatment/trial procedure-relatedness, action taken (including any treatment, and including any change in administration of the trial drug/auxiliary medication),dose-modifying toxicity (DMT), DLT. Pre and post administration: vital signs, physical examination, ECG, safety laboratory parameters (please see protocol for further details)
Overall Survival (OS) PFS and Duration of Response (DoR) According to Investigator’s criteria, based on anatomical/functional imaging (MRI and/or CT and/or PET/CT and/or SPECT/CT): every nine ± 3 weeks (depending on histology or tumor type) from enrollment until adequately documented disease progression or for up to two years according to the current guidelines appropriate for the applicable tumor types		Overall Survival (OS) PFS and Duration of Response (DoR) According to Investigator’s criteria, based on anatomical/functional imaging (MRI and/or CT and/or PET/CT and/or SPECT/CT): every nine ± 3 weeks (depending on histology or tumor type) from enrollment until adequately documented disease progression or for up to two years according to the current guidelines appropriate for the applicable tumor types
The following assessments, done in cycles 1 and 2;in addition, and a reduced number of measurements of the below mentioned assessments per method done in cycle 4, the timepoints of these measurements will be based on cycle 1 data: 1. Full 3D of one or two bed-position (depending on the size of the participants) SPECT/low dose CT imaging. 2. Whole body planar imaging (fast acquisition using a gamma camera). 3. Blood radioactivity concentration measurements. Please see protocol for further details		The following assessments, done in cycles 1 and 2;in addition, and a reduced number of measurements of the below mentioned assessments per method done in cycle 4, the timepoints of these measurements will be based on cycle 1 data: 1. Full 3D of one or two bed-position (depending on the size of the participants) SPECT/low dose CT imaging. 2. Whole body planar imaging (fast acquisition using a gamma camera). 3. Blood radioactivity concentration measurements. Please see protocol for further details

Trial Locations

Locations (3): Fondazione IRCCS Istituto Nazionale Dei Tumori
🇮🇹
Milan, Italy
Hospital Universitari Vall D Hebron
🇪🇸
Barcelona, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸
Madrid, Spain
Fondazione IRCCS Istituto Nazionale Dei Tumori
🇮🇹Milan, Italy
Marta Podda
Site contact
+390223903254
Marta.podda@istitutotumori.mi.it