Paraganglioma, Pheochromocytoma
Conditions
Keywords
MIBG, iobenguane, iodine, I 131, radiotherapy, radiopharmaceutical, dosimetry, neuroendocrine tumor, Ultratrace, no carrier added, metaiodobenzyl-guanidine
Brief summary
The purpose of this study is to determine whether iobenguane I 131 is safe and effective in patients with malignant pheochromocytoma or paraganglioma.
Detailed description
This was originally designed as a phase 1/2 study. The phase 1 patients received a small dose of study drug to see if the tumors absorb the drug. If the patient's tumors absorbed the drug, then the patient received one therapeutic dose. In the phase 1 portion, the study employed a 3 + 3 dose escalation design. Enrollment in the phase 1 portion was to be completed once researches believed that they found the highest dose that they could give patients without causing unacceptable toxicity. This dose is called the maximum tolerated dose (MTD). Following discussions with the Food and Drug Administration (FDA) that occurred during the dose escalation stage of the study, the protocol was amended to conclude the trial upon the identification of the MTD. The Phase 2 safety/ efficacy stage of the study was conducted with modifications of the primary endpoint as Protocol MIP IB12B, with Special Protocol Assessment Agreement with the FDA in March 2009.
Interventions
DRUGUltratrace Iobenguane (MIBG) I 131
Phase I: Dose escalation protocol Phase II: Treatment schedule at therapeutic dose
Sponsors
Molecular Insight Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of either adrenal pheochromocytoma or extra-adrenal paraganglioma by histological confirmation OR plasma-free metanephrines and 24-hour urine test for catecholamines/ metanephrines * Disease is metastatic or has recurred following surgery * At least one measurable lesion seen by computed tomography (CT) or magnetic resonance (MR) scan performed within 4 weeks prior to the first dose of study drug * At least one known tumor site is also seen on Ultratrace iobenguane I 131 scan * Provide written informed consent and are willing to comply with protocol requirements * Are at least 18 years of age * If female, then not of childbearing potential as documented by history (e.g., tubal ligation or hysterectomy) or is post menopausal with a minimum 1 year without menses * If female of childbearing potential, has a negative serum b-HCG pregnancy test within 48 hours prior to receiving iobenguane I 131 * Females who agree not to become pregnant and males who agree not to father a child during the 1 year period following the therapeutic dose of Ultratrace iobenguane I 131. Both females and males must use an acceptable method of birth control during the first year following the therapeutic dose of Ultratrace iobenguane I 131.
Exclusion criteria
* Females who are nursing * Active CNS lesions by CT/MR scanning within 3 months of study entry * New York Heart Association class III-IV heart failure * Received any previous systemic radiotherapy within 6 months of study entry * Administered prior whole-body radiation therapy * Received external beam radiotherapy to greater than 25 percent of bone marrow * Administered prior chemotherapy within 30 days of study entry * Karnofsky performance status is less than 60 * Platelets are less than 100,000/uL * Absolute neutrophil count (ANC) is less than 1,500/uL * Serum creatinine is greater than 1.5 mg/dL * Total bilirubin is greater than 1.5 times the upper limit of normal * AST/SGOT or ALT/SGPT is greater than 2.5 times the upper limit of normal * Has received a therapeutic investigational compound and/or medical device within 30 days before admission into this study * Has any medical condition or other circumstances which would significantly decrease the chances of obtaining reliable data, achieving study objectives, or completing the study and/or post dose follow-up examinations * Is determined by the Investigator that the patient is clinically unsuitable for the study. * Has received a medication which inhibits uptake of iobenguane I 131: * phenothiazines or decongestants within 2 weeks prior to enrollment; or, * a tricyclic antidepressant within 6 weeks prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MTD of Ultratrace Iobenguane I 131 | 6 weeks post therapy dose | Although no primary efficacy endpoint was defined for this study, the MTD of Ultratrace iobenguane I 131 in patients with malignant pheochromocytoma/paraganglioma (a safety rather than an efficacy parameter) is the primary objective. |
Countries
United States
Participant flow
Recruitment details
24 patients with confirmed pheochromocytoma/paraganglioma were recruited for participation in the trial at 3 US sites. 21 patients received Ultratrace Iobenguane I 131 while 3 patients failed to meet all inclusion/exclusion criteria and were therefore not dosed.
Pre-assignment details
Planned Doses: 6, 7, 8 & 9 mCi/kg. Dose reductions in 7, 8 & 9 mCi/kg cohorts were made so total activity administered to pts would not greatly exceed allowed total activity of 525, 600, & 675 mCi for these groups, respectively. Thus, pts were subsequently analyzed in 2 groups of ≤500 mCi and \>500mCi, consisting of 7 & 14 patients, respectively.
Participants by arm
| Arm | Count |
|---|---|
| =< 500 mCi Ultratrace Iobenguane I 131 7 subjects received a mean dose less than or equal to 500 mCi of Ultratrace Iobenguane I 131 | 7 |
| >500 mCi 14 subjects received a mean dose of greater than 500 mCi of Ultratrace Iobenguane I 131 | 14 |
| Total | 21 |
Baseline characteristics
| Characteristic | >500 mCi | =< 500 mCi Ultratrace Iobenguane I 131 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 6 Participants | 18 Participants |
| Age, Continuous | 52.4 years STANDARD_DEVIATION 11.41 | 46.4 years STANDARD_DEVIATION 15.99 | 50.4 years STANDARD_DEVIATION 13.02 |
| Region of Enrollment United States | 14 participants | 7 participants | 21 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 11 Participants | 5 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 21 |
| serious Total, serious adverse events | 15 / 21 |
Outcome results
Primary
MTD of Ultratrace Iobenguane I 131
Although no primary efficacy endpoint was defined for this study, the MTD of Ultratrace iobenguane I 131 in patients with malignant pheochromocytoma/paraganglioma (a safety rather than an efficacy parameter) is the primary objective.
Time frame: 6 weeks post therapy dose
Population: 24 patients with confirmed pheochromocytoma/paraganglioma were recruited for participation in this trial. Of the 24 consenting patients, 21 patients were administered Ultratrace iobenguane I 131. Three patients did not meet all the inclusion and exclusion criteria, and were not allowed into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ultratrace Iobenguane I 131 | MTD of Ultratrace Iobenguane I 131 | 8 mCi/kg |