Radionuclide Therapies for Neuroendocrine Tumors

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: David Bushnell

Must not be taking: Somatostatin analogues

Disqualifiers: Pregnancy, Congestive heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 16

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of two radioactive drugs, 131I-MIBG (Iobenguane I-131 or Metaiodobenzylguanidine) and 90Y-DOTATOC, to determine the safest doses for treating midgut neuroendocrine tumors. It targets individuals with these specific tumors that have not responded to other treatments and cannot be surgically removed. Eligible participants must have at least one tumor larger than 1.5 cm visible on a scan and have had these tumors for some time. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this novel combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications known to affect MIBG uptake and long-acting somatostatin analogues at least 14 days before starting the study. If your doctor thinks stopping somatostatin analogue therapy for 24 hours is risky for you, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both 131I-MIBG and 90Y-DOTATOC treatments have been studied for safety in humans, though not in combination.

For 131I-MIBG, studies have found it generally safe and well-tolerated for treating certain neuroendocrine tumors. A combined analysis of safety data indicated that high-specific-activity 131I-MIBG was safe for patients with similar cancer types, with no major safety concerns reported.

Similarly, 90Y-DOTATOC has been shown to be safe for people with neuroendocrine tumors. Research supports its use as a targeted therapy and notes its effectiveness without causing serious side effects.

This trial is in an early phase, focusing primarily on finding the safest way to combine these two treatments. Early-phase trials typically aim to determine the safest dose, so some safety data is still being collected. However, past studies on each drug separately suggest they are well-tolerated on their own. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for neuroendocrine tumors because they utilize radioactive isotopes, 131I-MIBG and 90Y-DOTATOC, which are designed to target and destroy cancer cells with precision. Unlike traditional chemotherapy, these radionuclide therapies are specific, delivering radiation directly to the tumor cells while sparing much of the surrounding healthy tissue. This targeted approach not only promises to enhance effectiveness but also reduces the potential side effects commonly associated with broader cancer treatments. By focusing radiation on specific areas, these treatments could potentially improve outcomes and quality of life for patients with neuroendocrine tumors.

What evidence suggests that this trial's treatments could be effective for neuroendocrine tumors?

Research has shown that 131I-MIBG effectively treats certain neuroendocrine tumors. Studies have found it can reduce tumor size and help manage symptoms in patients with advanced cases. Evidence suggests that 90Y-DOTATOC is a well-tolerated treatment that effectively targets and shrinks these tumors. The overall response to this treatment has been promising, with many patients experiencing significant improvements. This trial will explore various treatment arms to assess the combined effectiveness of 131I-MIBG and 90Y-DOTATOC in fighting midgut neuroendocrine tumors. ^{1 3 5 6 7}

Who Is on the Research Team?

David Bushnell, MD

Principal Investigator

University of Iowa

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with midgut neuroendocrine tumors that can't be surgically removed and have worsened despite treatment. They must have certain levels of blood cells, liver function, kidney function, and a tumor visible on scans. Pregnant or breastfeeding women, those at fall risk, with heart failure or other serious health issues are excluded.

Inclusion Criteria

ALT (SGPT) ≤ 2.5 x institutional ULN

To participate, you need to meet at least one of the following requirements:

absolute neutrophil count ≥ 2000 cells/mm3

Exclusion Criteria

I have had radiation that affected my kidneys, but it was limited.

I have not taken long-acting somatostatin analogues in the last 14 days.

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

3 visits (in-person)

Imaging and Dosimetry

Participants undergo imaging to verify tumor types and dosimetry to estimate radiation dose

1 week

3 visits (in-person)

Treatment Cycle 1

Participants receive a customized dose of 90Y-DOTATOC and 131I-MIBG over two days

2 days

2 visits (1 outpatient, 1 inpatient)

Treatment Cycle 2

Participants may receive a second cycle of treatment 12 weeks after the first cycle

2 days

2 visits (1 outpatient, 1 inpatient)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Regular visits every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• 131I-MIBG
• 90Y-DOTA-3-Tyr-Octreotide

Trial Overview The study tests combining two radioactive drugs (131I-MIBG and 90Y-DOTATOC) to find the safest doses for treating midgut neuroendocrine tumors. These therapies target tumor cells with radiation from within the body.

How Is the Trial Designed?

Group I: Cohort 3.2 (bone marrow alternative) Experimental Treatment 2 Interventions

This treatment arm is opened if the kidney radiation exposure was not tolerated in cohort 2. 131I-MIBG and 90Y-DOTATOC are administered once per cycle, for up to 2 cycles 12 weeks apart. Radiation exposure to the bone marrow is limited to 150 centiGray (cGy) Radiation exposure to the kidneys is limited to 2300 centiGray (cGy) No further dose evaluations are done after this cohort is completed.

Group II: Cohort 3.1 (renal alternative) Experimental Treatment 2 Interventions

This treatment arm is opened if the kidney radiation exposure was not tolerated in cohort 3. 131I-MIBG and 90Y-DOTATOC are administered once per cycle, for up to 2 cycles 12 weeks apart. Radiation exposure to the bone marrow is limited to 250 centiGray (cGy) Radiation exposure to the kidneys is limited to 1900 centiGray (cGy) No further dose evaluations are done after this cohort is completed.

Group III: Cohort 3 Experimental Treatment 2 Interventions

This treatment arm is opened if Cohort 2 is successful. 131I-MIBG and 90Y-DOTATOC are administered once per cycle, for up to 2 cycles 12 weeks apart. Radiation exposure to the bone marrow is limited to 250 centiGray (cGy) Radiation exposure to the kidneys is limited to 2300 centiGray (cGy)

Group IV: Cohort 2.2 (bone marrow alternative) Experimental Treatment 2 Interventions

This treatment arm is opened if the kidney radiation exposure was not tolerated in cohort 2. 131I-MIBG and 90Y-DOTATOC are administered once per cycle, for up to 2 cycles 12 weeks apart. Radiation exposure to the bone marrow is limited to 100 centiGray (cGy) Radiation exposure to the kidneys is limited to 2300 centiGray (cGy) No further dose evaluations are done after this cohort is completed.

Group V: Cohort 2.1 (renal alternative) Experimental Treatment 2 Interventions

This treatment arm is opened if the kidney radiation exposure was not tolerated in cohort 2. 131I-MIBG and 90Y-DOTATOC are administered once per cycle, for up to 2 cycles 12 weeks apart. Radiation exposure to the bone marrow is limited to 200 centiGray (cGy) Radiation exposure to the kidneys is limited to 1500 centiGray (cGy) No further dose evaluations are done after this cohort is completed.

Group VI: Cohort 2 Experimental Treatment 2 Interventions

This treatment arm is opened if Cohort 1 is successful. 131I-MIBG and 90Y-DOTATOC are administered once per cycle, for up to 2 cycles 12 weeks apart. Radiation exposure to the bone marrow is limited to 200 centiGray (cGy) Radiation exposure to the kidneys is limited to 2300 centiGray (cGy)

Group VII: Cohort 1 Experimental Treatment 2 Interventions

This is the initial treatment arm. 131I-MIBG and 90Y-DOTATOC are administered once per cycle, for up to 2 cycles 12 weeks apart. Radiation exposure to the bone marrow is limited to 150 centiGray (cGy) Radiation exposure to the kidneys is limited to 1900 centiGray (cGy)

Group VIII: Cohort -1 (alternative cohort) Experimental Treatment 2 Interventions

This treatment arm is opened if Cohort 1 is not tolerated. 131I-MIBG and 90Y-DOTATOC are administered once per cycle, for up to 2 cycles 12 weeks apart. Radiation exposure to the bone marrow is limited to 100 centiGray (cGy) Radiation exposure to the kidneys is limited to 1500 centiGray (cGy) No further dose evaluations are done after this cohort is completed.

131I-MIBG is already approved in United States, European Union for the following indications:

Approved in United States as Azedra for:

• Pheochromocytoma
• Neuroblastoma

Approved in European Union as Iobenguane I-131 for:

• Neuroblastoma
• Pheochromocytoma
• Paraganglioma

Who Is Running the Clinical Trial?

David Bushnell

Lead Sponsor

Trials

4

Recruited

50+

Holden Comprehensive Cancer Center

Collaborator

Trials

27

Recruited

710+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6066492/

Current Consensus on I-131 MIBG Therapy - PMC I-131 MIBG therapy is one of the considerable effective treatments in patients with advanced NB, PC, and PG.

2. jnm.snmjournals.org jnm.snmjournals.org/content/62/5/685

Effects of Repeated 131I-Meta-Iodobenzylguanidine ... The aim of this study was to evaluate the effects of repeated 131 I-MIBG therapy on tumor size and tumor metabolic response in patients with metastatic NETs.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6495236/

Efficacy and Safety of High-Specific-Activity 131I-MIBG ... Conclusion: HSA 131I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients. Keywords: high-specific- ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0969805108001054

Optimizing MIBG therapy of neuroendocrine tumors We observed supra-additive tumor cell kill and inhibition of tumor growth following combined topotecan and [131I]MIBG treatment. The improved efficacy is ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT00874614

NCT00874614 | A Study Evaluating Ultratrace Iobenguane ... This clinical trial is designed to evaluate the effectiveness and collect additional safety information on AZEDRA® (iobenguane I 131) for the treatment of ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.4_suppl.388

Pooled safety analysis of high-specific-activity I-131 MIBG ... A pooled analysis was conducted to assess the safety profile of high-specific-activity I-131 metaiodobenzylguanidine (HSA I-131 MIBG [AZEDRA]) ...

7. asco.org asco.org/abstracts-presentations/ABSTRACT240937

Pooled safety analysis of high-specific-activity I-131 MIBG ... Conclusions: HSA I-131 MIBG was safe and well-tolerated among subjects with iobenguane scan positive cancers. No trends were discerned between baseline ...