NeuroblastomaPhase 1NCT01313936
High-Dose 131I-MIBG Therapy Combined With Vincristine and Five Days of Irinotecan for Resistant/Relapsed Neuroblastoma
A Phase 1 study testing Metaiodobenzylguanidine (MIBG) in people with Neuroblastoma, run by University of California, San Francisco at 1 site in United States.
Trial summary
This is a pilot study to determine whether doses of 15 mCi/kg and 18 mCi/kg of 131I-MIBG are tolerable when given with irinotecan/vincristine on a one week schedule to children and young adults with high-risk refractory/relapsed neuroblastoma. Read more about this study
- Who is it for?
- Ages 1 year to 30 years
- Conditions the study is for
- Neuroblastoma
- What is being tested?
- Metaiodobenzylguanidine (MIBG)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2011to May 2014
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 30 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Age: Patients must be >1 year and < 30 years of age when registered on study.
- Diagnosis: Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines.
- Disease status: Patients must have high-risk neuroblastoma with at least ONE of the following:
- Recurrent/progressive disease at any time. Biopsy not required, even if partial response to intervening therapy except in patients with only one site of MIBG-avid disease that has been radiated within the preceding two months. Such patients require biopsy confirmation of residual active disease, with positive bone marrow biopsy being adequate confirmation of residual active disease.
- Refractory disease (i.e. less than a partial response to frontline therapy, including a minimum of 4 cycles of induction chemotherapy). No biopsy is required for eligibility for this study.
- Persistent disease after at least a partial response to frontline therapy (i.e. patient has had at least a partial response to frontline therapy but still has residual disease by MIBG scan, CT/MRI, or bone marrow). Patients in this category are REQUIRED to have a biopsy (bone marrow biopsy included) of at least one residual site demonstrating viable neuroblastoma.
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- 131I-MIBG Uptake: Patients must have evidence of MIBG uptake into tumor at ≥ one site within 4 weeks prior to entry on study and subsequent to any intervening therapy.
- Hematopoietic stem cells: Patients must have an adequate unpurged peripheral blood hematopoietic stem cell product, with a minimum of 2 X 106 CD34+ cells/kg available. Having a back-up of 2.0 x 106 viable CD34+ cells/kg unpurged PBSC is recommended but not required. The use of purged stem cells or autologous bone marrow as donor source is not allowed. The use of PBSC from an identical twin is allowed.
- Performance and life expectancy: Must have a life expectancy of at least 6 weeks and a Lansky or Karnofsky score of at least 60.
- Prior therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
- Myelosuppressive chemotherapy and/or biologics: Patients are not required to complete re-induction chemotherapy prior to study entry following relapse. Last dose of any myelosuppressive or biologic therapy was given at least 2 weeks before the start date for irinotecan on this protocol.
- Radiation: Patients must not have received radiation for a minimum of two weeks prior to study entry. Patients who received radiation to the only site of MIBG-avid disease within two months of study entry require biopsy confirmation of residual active disease, with positive bone marrow biopsy being adequate confirmation of residual active disease. A minimum of 3 months is required following prior large field radiation therapy (i.e. craniospinal therapy, total lung, > 50% marrow space). Patients are excluded if they have received whole abdominal radiation or TBI (total body irradiation).
- Stem Cell Transplant (SCT): Patients are eligible three months after autologous stem cell transplant. Patients status post-allogeneic stem cell transplant are excluded. Must meet adequate bone marrow function definition (see organ function requirements, below) post-myeloablative therapy.
- Prior 131I-MIBG therapy: Patients may have received prior MIBG therapy, though cumulative lifetime dose should not exceed 18 mCi/kg prior to study entry. Patients must not have received MIBG in combination with irinotecan. For patients previously treated with MIBG, at least 6 months must have elapsed since last MIBG therapy.
- Growth factor(s): All cytokines or hematopoietic growth factors must be discontinued a minimum of 7 days prior to the start date for irinotecan on this protocol.
- Prior irinotecan and vincristine therapy: are allowed, subject to recovery of adequate bone marrow function as specified in the protocol.
- Concomitant Therapy Restrictions: Patients must not be receiving any other anti-cancer agents or radiotherapy at the time of study entry or while on study. Enzyme-inducing anticonvulsants (phenobarbital, phenytoin, carbamazepine) must not be used as these may interfere with irinotecan metabolism. Non-enzyme inducing anticonvulsants (Keppra, etc.) can be used after discussion with study chair. The use of high dose dexamethasone and the use of aprepitant as antiemetics is not recommended due to effects on irinotecan metabolism.
- Hematologic function: a. ANC: > 750/uL (no hematopoietic growth factors within 7 days of the start date for irinotecan on this protocol) b. Platelet count: > 50,000/µl, transfusion independent (defined as no platelet transfusion for one week).
- These criteria must be met by all patients, regardless of bone marrow involvement with tumor.
- Renal function: a. Glomerular Filtration Rate (GFR) or 12-24hr Creatinine Clearance >= 60 ml/min/1.73 m², OR b. Age-adjusted serum creatinine < 1.5 x normal for age (see below):
- Age Maximum Serum Creatinine (mg/dL) < 5 years 0.8 > 5 and < 10 years 1.0 > 10 and < 15 years 1.2 > 15 years 1.5
- Liver function:a. Total bilirubin <= 1.5 x normal for age, and b. SGPT (ALT) and SGOT (AST) < 3 x upper limit of normal
- Cardiac function: Normal ejection fraction (>=55%) documented by either echocardiogram or radionuclide MUGA evaluation OR normal fractional shortening (>= 27%) documented by echocardiogram.
- Lung function: Normal lung function with no dyspnea at rest, exercise intolerance, pleural effusion or oxygen requirement.
- Reproductive function: All post-menarchal females must have a negative urine or serum beta-HCG. Males and females of reproductive age and childbearing potential must use effective contraception for the duration of their participation.
- Coexisting medical conditions: Patients with other ongoing serious medical issues must be approved by the study chair prior to registration.
Who cannot join
- Pregnant or lactating.
- Patients status post-ALLOGENEIC stem cell transplant are NOT eligible.
- Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
- Patients with disease of any major organ system that would compromise their ability to withstand therapy.
- Patients who are on hemodialysis.
- Patients with a documented allergy to 3rd generation cephalosporins.
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- Patients must not have active diarrhea (defined as > Grade 2 per CTCAE v4 [ Grade 2 = increase of 4-6 stools/day over baseline] ).
- Patients with an active or uncontrolled infection, including C. difficile, of > grade 3 per CTCAE v4. Patients on prolonged antifungal therapy are eligible if they are culture and biopsy negative in suspected radiographic lesions and meet other organ function criteria.
- Patients and/or families who are physically and psychologically unable to cooperate with the radiation safety isolation.
- Patients who have received prior total body or whole abdominal radiation.
- Patients who have received prior 131I-MIBG therapy in combination with irinotecan.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California, San Francisco
San Francisco, California, 94143
About this study
Official title: Pilot Study of High-Dose 131I-MIBG Therapy Combined With Vincristine and Five Days of Irinotecan for Resistant/Relapsed High-Risk Neuroblastoma
This is a pilot study to determine whether doses of 15 mCi/kg and 18 mCi/kg of 131I-MIBG are tolerable when given with irinotecan/vincristine on a one week schedule to children and young adults with high-risk refractory/relapsed neuroblastoma.
Read the detailed description
131I-metaiodobenzylguanidine (131I-MIBG) is an active therapy in patients with widely metastatic, treatment-resistant neuroblastoma, where response rates are 20-40% at doses (> 15mCi/kg) requiring stem cell rescue. Irinotecan is a topoisomerase I inhibitor with single-agent chemotherapeutic activity against neuroblastoma and other pediatric solid tumors in phase I and II clinical trials. With more protracted schedules (e.g. daily for 5 days/week x 2 weeks), the major dose-limiting toxicity is diarrhea. With shorter schedules, myelosuppression becomes dose-limiting. In adult solid tumors, irinotecan has been an effective radiosensitizer and is currently being evaluated by the Children's Oncology Group for this purpose in rhabdomyosarcoma protocols incorporating external beam radiotherapy.
Compared to single-agent 131I-MIBG, the combination of topotecan (a related camptothecin) and 131I-MIBG demonstrated superior pre-clinical activity in mouse xenograft models of neuroblastoma. This combination had no unexpected toxicities in a pilot clinical study. We have completed a clinical trial of vincristine, irinotecan, 131I-MIBG that utilized irinotecan on a protracted schedule (5 days per week x 2 weeks). The rationale for this schedule was to provide a greater degree of overlap between the radiation sensitizer (irinotecan) and the radiation exposure provided following 131I-MIBG infusion. This combination was shown to be tolerable at doses up to 18 mCi/kg 131I-MIBG. However, more patients experienced grade 2 and 3 diarrhea than would be customary with the dose and schedule of irinotecan used in that trial. It is therefore of interest to determine whether this combination of irinotecan, vincristine, and 131I-MIBG will be better tolerated using irinotecan at higher doses in a shorter schedule. The current standard schedule in Children's Oncology Group protocols for the combination of vincristine, irinotecan is now a higher dose in five, rather than 10 days. In the current pilot study, we will evaluate the tolerability and anti-tumor activity of this combination using irinotecan given once daily for 5 days only. Two 131I-MIBG dose levels will be evaluated. This study will provide the basis for a future randomized trial.
- Conditions
- Neuroblastoma
- Being tested
- Metaiodobenzylguanidine (MIBG)
- Keywords
- Neuroblastoma, MIBG, 131I-MIBG, Irinotecan, Vincristine, Resistant, Relapsed, Treatment, UCSF, Pediatric, Oncology
- Medical subject headings
- Neuroblastoma, Recurrence, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metaiodobenzylguanidine (MIBG)Drug
Also called 131I-MIBG
Chemotherapy will be given over 5 days for each course, with a single dose of 131I-MIBG on the second day of irinotecan. A total course will be defined as 42 days, or longer if hematopoietic recovery to eligibility criteria occurs after day 42.
| Study group | Role | What they receive |
|---|---|---|
| 15 mCi/kg of 131I-MIBG | Experimental | The first cohort for safety will be 3-6 patients treated with vincristine and irinotecan and 15 mCi/kg of 131I-MIBG. Receives: Drug: Metaiodobenzylguanidine (MIBG) |
| 18 mCi/kg of 131I-MIBG | Experimental | The second cohort will be 3-6 patients at the same doses of vincristine and irinotecan and 18 mCi/kg of 131I-MIBG. Receives: Drug: Metaiodobenzylguanidine (MIBG) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Dose-limiting Toxicity as a Measure of Tolerability
To determine whether doses of 15 mCi/kg and 18 mCi/kg of 131I-MIBG are tolerable when given with irinotecan/vincristine on a 5-day schedule to children and young adults with high-risk refractory/relapsed neuroblastoma.
Measured: 6 weeks
Secondary outcomes (3)
Therapeutic Response Rate
Therapeutic response rate to regimen according to the NANT modified-version of the International Neuroblastoma Response Criteria.
Measured: 6 weeks
Changes in Diarrhea
Rate of protocol associated diarrhea according to UGT1A1 genotype.
Measured: One year
Changes in Standardized Uptake Values on FDG-PET Scans
To describe changes in standardized uptake values (SUVs) obtained by 18FDG-PET scan at study entry and in response to one cycle of protocol therapy.
Measured: One year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Mar 2011 (estimated)
- Study startMar 2011
- Primary completionMay 2014
- Study completionMay 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Thrasher Research Fund
- Responsible party
- Principal investigator, Steven Dubois, University of California, San Francisco
- Investigators
- Steven DuBois, M.D., Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01313936
- Sponsor's protocol ID
- MIBG Irino
- Status last verified
- Jan 2019
- First submitted
- 10 Mar 2011
- Last updated
- 29 Apr 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study of High-Dose 131I-MIBG Therapy Combined With Vincristine and Five Days of Irinotecan for Resistant/Relapsed High-Risk Neuroblastoma
- ClinicalTrials.gov ID
- NCT01313936
- Acronym / sponsor ID
- MIBG Irino
- Conditions
- Neuroblastoma
- Keywords
- Neuroblastoma, MIBG, 131I-MIBG, Irinotecan, Vincristine, Resistant, Relapsed, Treatment
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 32 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- Thrasher Research Fund
- Study start
- Mar 2011
- Primary completion
- May 2014 (actual)
- Study completion
- May 2014 (actual)
- First posted
- 14 Mar 2011 (estimated)
- Results
- Posted 7 Aug 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a pilot study to determine whether doses of 15 mCi/kg and 18 mCi/kg of 131I-MIBG are tolerable when given with irinotecan/vincristine on a one week schedule to children and young adults with high-risk refractory/relapsed neuroblastoma.
Detailed description
131I-metaiodobenzylguanidine (131I-MIBG) is an active therapy in patients with widely metastatic, treatment-resistant neuroblastoma, where response rates are 20-40% at doses (> 15mCi/kg) requiring stem cell rescue. Irinotecan is a topoisomerase I inhibitor with single-agent chemotherapeutic activity against neuroblastoma and other pediatric solid tumors in phase I and II clinical trials. With more protracted schedules (e.g. daily for 5 days/week x 2 weeks), the major dose-limiting toxicity is diarrhea. With shorter schedules, myelosuppression becomes dose-limiting. In adult solid tumors, irinotecan has been an effective radiosensitizer and is currently being evaluated by the Children's Oncology Group for this purpose in rhabdomyosarcoma protocols incorporating external beam radiotherapy.
Compared to single-agent 131I-MIBG, the combination of topotecan (a related camptothecin) and 131I-MIBG demonstrated superior pre-clinical activity in mouse xenograft models of neuroblastoma. This combination had no unexpected toxicities in a pilot clinical study. We have completed a clinical trial of vincristine, irinotecan, 131I-MIBG that utilized irinotecan on a protracted schedule (5 days per week x 2 weeks). The rationale for this schedule was to provide a greater degree of overlap between the radiation sensitizer (irinotecan) and the radiation exposure provided following 131I-MIBG infusion. This combination was shown to be tolerable at doses up to 18 mCi/kg 131I-MIBG. However, more patients experienced grade 2 and 3 diarrhea than would be customary with the dose and schedule of irinotecan used in that trial. It is therefore of interest to determine whether this combination of irinotecan, vincristine, and 131I-MIBG will be better tolerated using irinotecan at higher doses in a shorter schedule. The current standard schedule in Children's Oncology Group protocols for the combination of vincristine, irinotecan is now a higher dose in five, rather than 10 days. In the current pilot study, we will evaluate the tolerability and anti-tumor activity of this combination using irinotecan given once daily for 5 days only. Two 131I-MIBG dose levels will be evaluated. This study will provide the basis for a future randomized trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 15 mCi/kg of 131I-MIBG | Experimental | Drug: Metaiodobenzylguanidine (MIBG)The first cohort for safety will be 3-6 patients treated with vincristine and irinotecan and 15 mCi/kg of 131I-MIBG. |
| 18 mCi/kg of 131I-MIBG | Experimental | Drug: Metaiodobenzylguanidine (MIBG)The second cohort will be 3-6 patients at the same doses of vincristine and irinotecan and 18 mCi/kg of 131I-MIBG. |
Who may qualify
- Ages
- 1 year to 30 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (26 listed)
- Age: Patients must be >1 year and < 30 years of age when registered on study.
- Diagnosis: Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines.
- Disease status: Patients must have high-risk neuroblastoma with at least ONE of the following:
- 131I-MIBG Uptake: Patients must have evidence of MIBG uptake into tumor at ≥ one site within 4 weeks prior to entry on study and subsequent to any intervening therapy.
- Hematopoietic stem cells: Patients must have an adequate unpurged peripheral blood hematopoietic stem cell product, with a minimum of 2 X 106 CD34+ cells/kg available. Having a back-up of 2.0 x 106 viable CD34+ cells/kg unpurged PBSC is recommended but not required. The use of purged stem cells or autologous bone marrow as donor source is not allowed. The use of PBSC from an identical twin is allowed.
Key exclusion criteria (11 listed)
- Pregnant or lactating.
- Patients status post-ALLOGENEIC stem cell transplant are NOT eligible.
- Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
- Patients with disease of any major organ system that would compromise their ability to withstand therapy.
- Patients who are on hemodialysis.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Metaiodobenzylguanidine (MIBG)Also: 131I-MIBGChemotherapy will be given over 5 days for each course, with a single dose of 131I-MIBG on the second day of irinotecan. A total course will be defined as 42 days, or longer if hematopoietic recovery to eligibility criteria occurs after day 42. | Drug | 15 mCi/kg of 131I-MIBG, 18 mCi/kg of 131I-MIBG |
Primary outcome
Number of Participants With Dose-limiting Toxicity as a Measure of Tolerability
Time frame: 6 weeks
To determine whether doses of 15 mCi/kg and 18 mCi/kg of 131I-MIBG are tolerable when given with irinotecan/vincristine on a 5-day schedule to children and young adults with high-risk refractory/relapsed neuroblastoma.
3 secondary outcomes
Therapeutic Response Rate
Time frame: 6 weeks
Changes in Diarrhea
Time frame: One year
Changes in Standardized Uptake Values on FDG-PET Scans
Time frame: One year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Apr 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Steven DuBois, M.D. principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Metaiodobenzylguanidine (MIBG) in people with Neuroblastoma, run by University of California, San Francisco at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 26 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Aug 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Dose-limiting Toxicity as a Measure of Tolerability (time frame: 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Apr 2019.