A Study Evaluating Ultratrace Iobenguane I131 in Patients With Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma

Study Overview
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Brief Summary
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This clinical trial is designed to evaluate the effectiveness and collect additional safety information on AZEDRA® (iobenguane I 131) for the treatment of metastatic or relapsed/refractory (to other treatment) or unresectable pheochromocytoma or paraganglioma. The purpose of this trial is to test the use of AZEDRA® as a treatment for pheochromocytoma and paraganglioma, a rare disease. This Phase II study will help determine primarily if using the drug reduces the amount of blood pressure medication being taken as a result of the cancer and secondarily to determine such things as the effectiveness of the study drug in treating the cancer, additional safety measures, and to assess if the drug helps the quality of life and use of pain medication. All subjects will receive an imaging dose with scans followed by two therapeutic doses given approximately 3 months apart.

Detailed Description
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AZEDRA® (Iobenguane I 131) is a very high-specific-activity iobenguane I 131, produced using proprietary Ultratrace® platform. Based on the well-characterized cellular active transport mechanism, the high specific activity of allows for effective cellular uptake of radioactivity and hence greater tumor uptake. During this study the subjects will receive two (2) Therapy Doses that are given approximately three (3) months apart. Prior to administration of the first Therapy Dose, subjects will be given an Imaging Dose of AZEDRA® and will undergo iobenguane I 131 scans to evaluate tumor uptake and to measure normal organ distribution and allow for the calculation of radiation dose to normal organs. Screening procedures for eligibility will need to be done before imaging or therapeutic doses of AZEDRA® are administered. Hospitalization is required for approximately one (1) week after each of the two (2) Therapeutic Doses. Frequent follow up is necessary for the first year and some of the follow up visits may be done by a visiting health care professional in the subjects' homes. Subjects will be followed in the treatment study for one (1) year and for an additional four (4) years in long-term follow up.

Official Title
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A Phase II Study Evaluating the Efficacy and Safety of Ultratrace Iobenguane I 131 in Patients With Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma

Conditions
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Pheochromocytoma, Paraganglioma

Intervention / Treatment
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* Radiation: Ultratrace® Iobenguane I131


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be at least 12 years of age Have a documented (medical record) diagnosis of either pheochromocytoma or paraganglioma Be ineligible for curative surgery for pheochromocytoma Have failed a prior therapy for pheochromocytoma/paraganglioma or are not candidates for chemotherapy or other curative therapies Be on stable antihypertensive medication for pheochromocytoma-related hypertension for at least 30 days Have at least one tumor site by CT or MR or iobenguane I 131 scan Have an expected survival of at least 6 months Subjects must agree to use an acceptable form of birth control (abstinence, IUD, oral contraception, barrier and spermicide or hormonal implant) during this study and for 6 months following Therapeutic Doses of Ultratrace Iobenguane I 131. Male subjects must agree not to father a child during the period beginning immediately after administration of the first Therapeutic Dose of Ultratrace Iobenguane I 131 during the study and ending six months after administration of the last Therapeutic Dose of Ultratrace Iobenguane I 131. Exclusion Criteria: Subjects will be excluded if any of the following conditions are observed: <50% of FDG (if data are available) positive lesions are MIBG avid Pregnant or nursing females Active CNS lesions by CT/MR scanning within 3 months of study entry New York Heart Association class IV heart failure, symptomatic congestive heart failure [New York Heart Association class IV with another medical disorder], unstable angina pectoris, cardiac arrhythmia Received any previous systemic radiotherapy resulting in marrow toxicity within 3 months of study entry or have active malignancy (other than pheochromocytoma/paraganglioma) requiring additional treatment during the active phase or follow up period of the Ultratrace® iobenguane I 131 trial. Administered prior whole-body radiation therapy Received external beam radiotherapy to > 25% of bone marrow Administered prior chemotherapy within 30 days or have active malignancy (other than pheochromocytoma/ paraganglioma) requiring additional treatment during the active phase or follow up period of the Ultratrace iobenguane I 131 trial. Karnofsky Performance Status is < 60 Platelets < 80,000/μL Absolute neutrophil count (ANC) < 1,200/μL, Total bilirubin > 1.5 times the upper limit of normal, AST/SGOT or ALT/SGPT > 2.5 times the upper limit of normal Diagnosed with AIDS or HIV-positive Active chronic alcohol abuse, chronic liver disease or hepatitis Renal dysfunction/impairment Known allergy to iobenguane that has required medical intervention Received a therapeutic investigational compound and/or medical device/prior chemotherapy within 30 days before admission into this study Receiving a medication which inhibits tumor uptake of iobenguane I 131 Any medical condition or other circumstances (i.e., uncontrolled current illness including but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with the study requirements. Any other condition, that in the opinion of the investigator, may compromise the safety or compliance of the subject or would preclude the subject from successful completion of the study

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ultratrace® Iobenguane I 131 Treatment<br> | Radiation: Ultratrace® Iobenguane I131<br>* Each subject will be administered 3 mCi to 6 mCi Ultratrace® Iobenguane I 131, referred to as the Imaging Dose, to confirm that subject meets radiological entry criteria and to establish dosimetry. All subjects meeting entry criteria will then receive the investigational product referred to as the Therapeutic Dose (500 mCi or 8 mCi/kg if the subject weighs 62.5 kg or less) of Ultratrace Iobenguane I 131, followed by imaging at 7 days post infusion or upon discharge from isolation. The Therapeutic Doses will be adjusted equally if warranted by results of the dosimetry evaluation. At least 3 months later, subjects will receive the second Therapeutic Dose.<br>* Other names: MIBG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Experienced a 50% or Greater Reduction (Including Discontinuation) of All Antihypertensive Medication(s) Lasting for at Least Six Months. |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Confirmed Overall Tumor Response of Complete Response (CR) or Partial Response (PR) by RECIST 1.0. | Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 was assessed by two independent central reviewers and one adjudicator, and overall response (PR or CR) was confirmed by follow-up imaging at the subsequent timepoint. Complete response was defined as confirmed disappearance of all target lesions and Partial Response was defined as confirmed decreased of >= 30% in baseline sum of the longest diameter of target lesions. | 12 months | 
| Changes From Baseline in Overall Quality of Life (QoL) - Best Response Within 12 Months After First Therapeutic Dose of AZEDRA®. | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 v.3 was used to evaluate QoL. This questionnaire was comprised of 30 questions, two of which pertain to a patient's Global Health Status and QoL. The two questions used a 7-point Likert scale of 1 (very poor) to 7 (excellent), in which the scores were averaged and linearly transformed to a 0-100 scale with higher scores indicating better health status and QoL. The questionnaire was administered at baseline and through 12 months after the first therapeutic dose of AZEDRA®. The results of QoL and changes from baseline were summarized by visit and the best response within 12 months after first therapeutic dose of AZEDRA® was reported. The outcome represents the mean change from baseline in overall QoL based on the best response reported within 12 months after first therapeutic dose of AZEDRA®. | 12 Months | 
| Overall Survival | Duration of overall survival was calculated from the date of first therapeutic dose of AZEDRA® to death, or at the last date the patient was known to be alive. Results are presented per December 2017 data-cut. Survival was censored at the end of the 5-year long-term follow-up period, thus the upper limit of the confidence interval reported below for two therapeutic doses is actually >60 months. | Up to 5 Years (60 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiotherapy, MIBG, Azedra, neuroendocrine tumors, Iobenguane I 131, progenics