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3-Iodobenzylguanidine

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Eligible patients received a diagnostic imaging dose of Ultratrace™ Iobenguane I 131 (1-5 mCi) within 7 days of study enrollment, followed by three dosimetry scans over 3-6 days. If the imaging dose demonstrated normal biodistribution and tumor uptake, then the patient received a therapeutic dose within 7-28 days of the diagnostic imaging dose, followed by a single imaging scan on Day 7 post therapy. As per protocol, therapeutic dosing was to begin at 12.0 mCi/kg and escalate to 15.0, 18.0, and 21.0 mCi/kg until the MTD was established or the 21.0 mCi/kg dose level was reached. Actual doses administered ranged from 8.8 to 18.6 mCi/kg. Based on actual doses administered, patients were grouped into 3 mean dose groups: 11.2, 15.5, and 18.2 mCi/kg.

The dosimetry dose was administered over a period of 1-3 minutes by injection; the therapeutic dose was diluted in up to 25 mL normal saline and infused intravenously over 30 to 60 minutes.

0.1 mCi/kg \[3.7 MBq/kg\] (minimum dose 1mCi \[37MBq\] but not to exceed 5 mCi \[185 MBq\]) of UltratraceTM Iobenguane I 131 given 7 -28 days before therapeutic dose administration on day 0. Thyroid protection will be administered per institutional protocol for I-131-MIBG however, thyroid blocking must be started prior to the Ultratrace imaging dose. Anterior and posterior whole body images will be taken to assess organ distribution, tumor uptake and dosimetry calculations.

UltratraceTM Iobenguane I 131 Imaging

Therapeutic dose will be given on Day 0 if dosimetry scans showed that the prescribed or adjusted dose will not exceed \> 23 Gy to the kidneys, \> 30 Gy to the liver, or \> 15 Gy to the lungs. and tumor uptake confirmed with UltratraceTM imaging dose. Only one treatment course of therapeutic UltratraceTM will be given in this study.

UltratraceTM Iobenguane I 131 Therapy

Katherine K. Matthay, MD

RATIONALE: Radioactive drugs, such as iodine I 131 metaiodobenzylguanidine (MIBG), may carry radiation directly to tumor cells and not harm normal cells. A bone marrow or peripheral stem cell transplant using stem cells from the patient may be able to replace blood-forming cells that were destroyed by I 131 MIBG.

PURPOSE: This phase II trial is studying the side effects and best dose of iodine I 131 MIBG followed by a stem cell transplant in treating young patients with relapsed or refractory high-risk neuroblastoma.

OBJECTIVES:

Primary

* To establish the maximum tolerated dose of iodine I 131 metaiodobenzylguanidine (\^131I-MIBG) in patients with relapsed/refractory high-risk neuroblastoma.

Secondary

* To describe toxicity following treatment with \^131I-MIBG in patients with relapsed/refractory high-risk neuroblastoma.
* To estimate radiation absorbed doses to measurable lesions and to a standard set of normal organs following a 0.1 mCi/kg \[3.7 MBq/kg\] (minimum dose of 1.0 mCi \[37 MBq\] but not to exceed 5.0 mCi \[185 MBq\]) intravenous administration of \^131I-MIBG in patients with relapsed/refractory high-risk neuroblastoma.
* To describe, within the confines of a phase IIa trial, objective tumor response following treatment with \^131I-MIBG in patients with relapsed/refractory high-risk neuroblastoma.
* To explore dose-response following treatment with \^131I-MIBG in patients with relapsed/refractory high-risk neuroblastoma.
* To explore quality of life assessment following treatment with \^131I-MIBG in patients with relapsed/refractory high-risk neuroblastoma.

OUTLINE:

* Dosimetry: Patients receive a dosimetric dose of iodine I 131 metaiodobenzylguanidine (\^131I-MIBG) IV over 1-3 minutes. Patients then undergo 2 or 3 MIBG scans within 5 days of the dosimetry dose to assess biodistribution and tumor uptake. Patients with normal tumor uptake and biodistribution proceed to treatment.
* Treatment: Within 1-4 weeks of the dosimetric dose, patients with normal tumor uptake and biodistribution receive a therapeutic dose of \^131I-MIBG IV over 1 hour on day 0 and undergo MIBG scan on day 7. Patients then proceed to autologous stem cell infusion.
* Autologous stem cell infusion: Patients receive an infusion of autologous stem cells from peripheral blood or bone marrow on day 14. Patients with an ANC of \< 500/µl at any point after autologous stem cell infusion receive filgrastim (G-CSF) IV or subcutaneously once daily until ANC is \> 2,000/µl.

Patients complete a quality of life questionnaire at baseline and then at day 60.

After completion of study treatment, patients are followed at day 60 and periodically thereafter.

N2007-01: Ultratrace™ Iobenguane I 131 in Patients With Relapsed/Refractory High-Risk Neuroblastoma

A Phase 2a Study of Ultratrace™ Iobenguane I 131 in Patients With Relapsed/Refractory High-Risk Neuroblastoma

The maximum tolerated dose (MTD) was defined as the dose immediately below the level at which dose escalation would be stopped due to dose limiting toxicities (DLTs). Once the MTD was reached, an additional 3 patients were to be treated at that dose level, for a total of 6 patients at that planned dose level. DLTs were defined as any of the events that are possibly, probably or definitely attributable to UltratraceTM iobenguane I 131. The MTD was supposed to be the highest dose tested at which fewer than 1/3 of pts experience a DLT when 6 patients have been treated at the MTD but the dosimetry results indicated that the maximal dosage allowed to normal organs would be exceeded if the highest planned dose (21.0 mCi/kg) was administered, so the highest dose administered in the study was 18.6 mCi/kg .

Dose limiting toxicities include treatment emergent adverse events (TEAEs) that were possibly, probably, or definitely related to Ultratrace™ Iobenguane I 131.

The dosimetric endpoint was to estimate radiation absorbed doses to measurable lesions and to a standard set of normal organs following an imaging dose of 0.1 mCi/kg Ultratrace™ Iobenguane I 131. Biodistribution was assessed by determination of total body residence (TBR) time and by visual examination of whole body camera images. 3 timepoints were used, the 1st image was taken within 1hr after the imaging dose, the 2nd image was taken at \~24hr after imaging dose, the 3rd image was taken 2-5d after imaging dose. Whole body radiation absorbed dose estimates \& kidney, liver, and lung were calculated using the Medical Internal Radiation Dose (MIRD) schema.TBR time is derived from time integration of curve-fitted injected activity across all 3 timepoints when the isotope is emitting radiation.Three points are sampled to estimate a singular value for each organ and tissue according to the commonly used methods of the Society of Nuclear Medicine and Molecular Imaging Committee on MIRD.

The International Neuroblastoma Response Criteria (INRC) were utilized as a basis for the overall response criteria, which incorporated responses in MIBG positive lesions,bone marrow disease, and CT/MRI lesions that met NANT-modified RECIST criteria. Efficacy success was defined as the proportion of pts who were successful overall \[i.e., achieving a Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR)\] determined by independent reviewers. CR = Disappearance of all target lesions, homovanillic acid/ vanillylmandelic acid (HVA/VMA) normal (NL); VGPR = \> 90% decr of disease for CT/MRI target lesions, all pre-existing bone lesions with CR by MIBG; MIBG scan can be SD/CR in soft tissue lesions. CR in bone marrow, no new tumor sites, and NL HVA/VMA.; PR = At least 30% decr in disease measurement for CT/MRI target lesions. Bone marrow with CR, MIBG with either PR/CR in bone lesions, MIBG may be SD /CR in soft tissue lesions, and HVA/VMA may still be elevated.

Measurable disease was defined for a conventional CT scan by the presence of at least one lesion that could be accurately measured in at least one dimension with the longest diameter at least 20 mm by Independent Review. Efficacy success was defined as a patient achieving a Complete Response (CR)=disappearance of all target and non-target CT/MRI lesions; or, Very Good Partial Response (VGPR)=greater than 90% decrease of the disease measurement for CT/MRI lesions, taking as reference the disease measurement done to confirm measurement disease at study entry. Non-target CT/MRI lesions stable to smaller in size; or, Partial Response (PR)=at least 30% decrease in the disease measurement for CT/MRI lesions, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size.

Patients (aged 5-18) and parents (of patients aged 2-18) were asked to complete the 23-item Pediatric Quality of Life InventoryTM (PedsQLTM). PedsQLTM consists of 4 scales (physical, emotional, social, school functioning) which are then averaged into an overall summary score (scale: 0-100 with 0 representing the worst possible Quality of Life overall summary score and 100 representing the best possible Quality of Life overall summary score). The mean difference between the post treatment overall summary score and the baseline overall summary score is reported.

Molecular Insight Pharmaceuticals, Inc.

Serious adverse events (SAEs) that were ongoing at study completion (Day 60 ±10 days) were followed for 60 days or until resolution, whichever occurred first.

Eligible patients received a diagnostic imaging dose of Ultratrace™ Iobenguane I 131 (1-5 mCi) within 7 days of study enrollment, followed by three dosimetry scans over 3-6 days. If the imaging dose demonstrated normal biodistribution and tumor uptake, then the patient received a therapeutic dose within 7-28 days of the diagnostic imaging dose, followed by a single imaging scan on Day 7 post therapy. Mean therapeutic dosing groups were 11.2 mCi/kg, 15.5 nCi/kg and 18.2 mCi/kg. The dosimetry dose was administered over a period of 1-3 minutes by injection; the therapeutic dose was diluted in up to 25 mL normal saline and infused intravenously over 30 to 60 minutes.

Ultratrace™ Iobenguane I 131

Eligible patients received a diagnostic imaging dose of Ultratrace™ Iobenguane I 131 (1-5 mCi) within 7 days of study enrollment, followed by three dosimetry scans over 3-6 days. If the imaging dose demonstrated normal biodistribution and tumor uptake, then the patient received a therapeutic dose within 7-28 days of the diagnostic imaging dose, followed by a single imaging scan on Day 7 post therapy. Therapeutic dosing began at 12.0 mCi/kg and escalated to 15.0, 18.0, and 21.0 mCi/kg until the MTD was established or the 21.0 mCi/kg dose level was reached. The dosimetry dose was administered over a period of 1-3 minutes by injection; the therapeutic dose was diluted in up to 25 mL normal saline and infused intravenously over 30 to 60 minutes.

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

NANT Operations Center

Following therapeutic dosing at the 12.0, 15.0, and 18.0 mCi/kg cohorts, 4 patients who were to receive the 21.0 mCi/kg therapeutic dose were required to have their planned dose reduced below the dose that was calculated based on the patient's dosimetry results, in order to meet the protocol guidelines for maximal dosage allowed to normal organs described above. Because of the differences between the planned and actual therapeutic doses that were administered to several patients, patients were grouped and the study data were presented and analyzed by actual doses rather than by the planned dose cohorts of 12.0, 15.0, 18.0, and 21.0 mCi/kg. Based on the actual doses administered, patients were grouped into 3 dose groups of 6, 3, and 6 patients, according to the mean doses of the groups, which were 11.2, 15.5, and 18.2 mCi/kg, respectively.

A total of 15 patients underwent dosimetry (received a single imaging dose of Ultratrace™ Iobenguane I 131 injection) and all 15 patients later received a single therapeutic dose of Ultratrace™ Iobenguane I 131.

Maximum Tolerated Dose

11.2 mCi/kg Ultratrace™ Iobenguane I 131 represents the mean dose administered to this group of subjects.

11.2 mCi Group

15.5 mCi/kg Ultratrace™ Iobenguane I 131 represents the mean dose administered to this group of subjects.

15.5 mCi Group

18.2 mCi/kg Ultratrace™ Iobenguane I 131 represents the mean dose administered to this group of subjects.

18.2 mCi Group

Dose Limiting Toxicities

Kidney

Liver

Lungs

A total of 15 patients underwent dosimetry (received a single imaging dose of Ultratrace™ Iobenguane I 131 injection).

Dosimetric Estimation of Radiation Absorbed Doses to Measurable Lesions

The proportion of patients who were considered successful defined as a patient achieving a Complete Response, Very Good Partial Response or Partial Response as determined by the Independent Reviewers.

The evaluable population (which excludes non-evaluable responses) contains one patient less than the full ITT population.

Overall Objective Tumor Response Post Therapeutic Treatment

Over Tumor Response

Tumor Response in CT/MRI Lesions Post Therapeutic Treatment

Based on the actual doses administered, patients were grouped into 3 dose groups of 6, 3, and 6 patients, according to the mean doses of the groups, which were 11.2, 15.5, and 18.2 mCi/kg, respectively.

Self reported PedsQL™ scores were obtained for 9 patients in the ITT population (n=15) at baseline (prior to the start of the Ultratrace™ Iobenguane I 131 imaging studies) and at the end of therapy (60 ±10 days post treatment).

Quality of Life

Eligible patients received a diagnostic imaging dose of Ultratrace™ Iobenguane I 131 within 7 days (d) of enrollment, followed by 3 dosimetry scans over 3-6 days. For the imaging dose, 0.1 mCi/kg (3.7 MBq/kg), at a min dose of 1 mCi (37 MBq) but not to exceed 5 mCi (185 MBq) of Ultratrace™ Iobenguane I 131 was administered 7-28 d prior to the therapeutic dose on Day 0. If the imaging dose demonstrated NL biodistribution/tumor uptake, pts received a therapeutic dose within 7-28 d of the imaging dose followed by a single imaging scan on Day 7 post therapy.

Therapeutic dosing was to begin at 12.0 mCi/kg and escalate to 15.0, 18.0, and 21.0 mCi/kg until the MTD was established or the 21.0 mCi/kg dose level was reached. Based on actual doses administered, pts were grouped into 3 mean dose groups: 11.2, 15.5, and 18.2 mCi/kg.

The dosimetry dose was administered over 1-3 mins by injection; the therapeutic dose was diluted in up to 25 mL normal saline and infused over 30 to 60 mins.

Spots Global Cancer Trial Database for ultratracetm iobenguane i 131 imaging