RAPID Study: A Pilot Study for the Rapid Infusion of Dinutuximab
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 30
- 试验地点
- 7
- 主要终点
- Determine feasibility of administering dinutuximab in Cycle 1
研究概览
简要总结
Dinutuximab is an immunotherapy that has greatly improved outcomes for children with high-risk neuroblastoma and is now a standard part of treatment for both newly diagnosed and relapsed disease. However, the medication is typically given through an intravenous (IV) infusion over 10-20 hours a day for four consecutive days, requiring prolonged hospital stays that place a significant burden on children, families, and healthcare resources.
Earlier studies of dinutuximab, as well as experience with a similar immunotherapy, suggest that these medications can be safely given over a much shorter period of time.
This study is evaluating whether children with high-risk neuroblastoma can safely receive dinutuximab over five hours or less. Early results have been encouraging. The first group of patients successfully received most treatments with dinutuximab in about two hours. Children experienced very low pain levels and required approximately 78% less opioid pain medication compared with the traditional longer infusion. Several patients were able to receive treatment as outpatients without requiring hospital admission, while hospitalizations that did occur were primarily related to chemotherapy or other non-medical reasons rather than the rapid infusion itself.
The study is now expanded to further evaluate the safety of rapid infusion across multiple treatment cycles at different centers in the United States. Researchers will also examine how the drug is processed by the body, whether the immune system develops antibodies against the treatment, and whether the faster infusion continues to reduce the need for opioid pain medication. In addition, children and their caregivers will complete questionnaires about symptoms and treatment experiences to better understand the impact of the faster dinutuximab infusion on quality of life and the overall treatment experience.
详细描述
Neuroblastoma is the most common extra-cranial solid tumor of childhood. While it comprises only 8% of all childhood cancer cases, neuroblastoma is responsible for 12% of cancer deaths in children under 15 years of age. Approximately 50% of neuroblastoma patients are classified as high-risk, and over half of these children succumb to their disease despite intensive multi-modal therapy. The prognosis is worse for patients whose disease is refractory to initial therapy or who experience a recurrence of their tumor, as the majority of these patients cannot be cured of their disease. However, rates of event free survival and overall survival have improved over the past decades with the introduction of dinutuximab.
Dinutuximab is a chimeric monoclonal antibody that targets disialoganglioside (GD2) receptors. It has become an integral modality in the treatment of high-risk neuroblastoma (HR NBL) in up-front therapy and in the setting of relapsed or refractory disease. Additionally, there are numerous ongoing trials that include dinutuximab as part of the backbone therapy or in combination with other agents to improve tumor response in HR NBL patients.
A limiting factor for the use of dinutuximab has been the management of infusion-related toxicities. GD2 is expressed on neurons, skin melanocytes, and peripheral pain fibers of human tissues, which is evident in the common manifestation of pain during infusions. Other most common adverse effects include hypotension, capillary leak syndrome, and infusion-related reactions. These toxicities typically last during the standardized infusion duration of 10-20 hours but typically do not correlate with plasma levels. Pain that occurs during the infusion typically resolves shortly after the infusion is completed, despite the fact that dinutuximab persists in the circulation, which suggests that pain may be related to infusion rate rather than drug exposure (AUC). Due to the lengthy infusion duration and high frequency of side effects, dinutuximab infusions currently require significant hospital resources including nursing care, opioid infusions, around the clock supportive care medications, and a hospital stay for a minimum of 4-5 days.
With the expectation of repeated cycles of dinutuximab for different protocols in HR NBL treatment and with the expansion of dinutuximab studies in other GD2 positive tumors, there is a need to improve the administration and management of dinutuximab for future practicality and patient durability. A different anti-GD2 antibody naxitamab with a similar side effect profile to dinutuximab has been FDA approved for administration in the outpatient setting. Therefore, there is potential for dinutuximab to be administered in the outpatient setting. Although some studies have attempted to modify the administration of dinutuximab dosing and infusion durations, none have focused on shortening infusion time in the pediatric setting.
Dinutuximab was shown to significantly improve survival in children with HR NBL when administered after dose-intensive combination chemotherapy and high-dose myeloablative therapy with autologous stem cell rescue, and when combined with immunomodulating agents sargramostim and aldesleukin (IL-2) in the randomized phase 3 clinical trial, ANBL 0032. This Children's Oncology Group (COG) trial found that the combination of dinutuximab with sargramostim and IL-2 enhanced antibody-dependent cell-mediated cytotoxicity when given with isotretinoin in post-consolidation therapy. The addition of immunotherapy to isotretinoin in the post-consolidation phase was found to be significantly superior to isotretinoin alone. This led to the FDA approval of dinutuximab in the post-consolidation setting of neuroblastoma therapy. More recently, when dinutuximab was combined with irinotecan, temozolomide and sargramostim in patients with relapsed/refractory neuroblastoma (ANBL 1221) improved response rates were seen and as a result, this regimen is now considered first line for patients with relapsed or refractory disease in North America.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: Patients ≥ 12 months of age at the time of enrollment are eligible for this study.
- •Diagnosis: Patients must have a diagnosis of relapsed , refractory (defined as achieving less than a partial response), or persistent high-risk neuroblastoma or ganglioneuroblastoma (nodular) [verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites at the time of diagnosis] and have been designated as having high-risk disease based on COG risk classification.
- •No minimal sites of disease are required for this study.
- •Prior Therapy (all time-frames below apply from time of enrollment):
- •Must have completed high-risk Induction therapy with at least 4 cycles of chemotherapy.
- •At least 14 days must have elapsed since completion of myelosuppressive therapy.
- •Patients must have received previous treatment with dinutuximab (with or without chemotherapy) within 2 months prior to enrollment without any dose-modifications
- •Anti-cancer agents not known to be myelosuppressive (e.g. not associated with substantially reduced platelet or ANC counts) are permitted while on study with PI approval and must be held during dinutuximab therapy and may be resumed after completion of final dinutuximab day in each cycle per physician discretion.
- •Monoclonal antibodies: ≥ 7days ( 3 half-lives) from infusion of last dose of antibody and all related toxicity must have resolved to Grade ≤
- •Immunoglobulins: IVIG should not be given within 2 weeks of starting dinutuximab treatment or 1 week after completing dinutuximab therapy.
- •Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment and must not require ongoing pharmacologic doses of systemic corticosteroids during protocol therapy.
- •Patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study are ineligible. (The only exception is for patients known to require 2mg/kg or less of hydrocortisone, or an equivalent dose of an alternative corticosteroid, as premedication for blood product administration in order to avoid allergic transfusion reactions). The use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency.
- •Radiation may be given up to 7days prior to enrollment if clinically indicated. Palliative radiation while on study is permitted except during dinutuximab infusion days.
- •Stem cell transplant must be ≥ 6months prior to enrollment. Patients who received autologous stem cell infusion to support non-myeloablative therapy (such as 131 I-MIBG) are eligible at any time as long as they meet the other criteria for eligibility.
- •131I-MIBG therapy: Patients are eligible ≥6 weeks after therapeutic 131I-MIBG provided that all other eligibility criteria are met.
- •Adequate Bone Marrow Function Defined As:
- •Peripheral absolute neutrophil count (ANC) ≥750/microL
- •Platelet count ≥50,000/mL (transfusion independent for prior 7 days). Exemptions may be granted for patient specific criteria (i.e. low platelet function due to history of extensive prior therapy or bone marrow disease)
- •Hematologic growth factor (ie GM-CSF, GCSF or bioequivalent) may given up to 14 days prior to enrollment Note: concurrent use of platelet directed growth factor is permitted
- •Adequate Renal Function Defined As:
- •Creatinine clearance or radioisotope GFR ≥70mL/min/1.73m2 or
- •Adequate serum creatinine based on age/gender
- •Note: Patients with history of transplant-associated thrombotic microangiopathy (TA-TMA) must have a creatinine clearance or radioisotope GFR at baseline to assess renal function and must meet the above criteria.
- •Adequate Liver Function Defined As:
- •Total bilirubin ≤1.5 x ULN for age AND
- •SGPT (ALT) ≤ 5.0 x ULN for age (≤ 225 U/L). For the purpose of this study, the ULN for SGPT is 45U/L.
- •Adequate Central Nervous System Function Defined As:
- •Patients with a history of CNS disease must have no clinical evidence of active progressive CNS disease at the time of study enrollment. Patients with history of CNS disease need to have at least stable tumor in the CNS for at least one month.
- •Patients with seizure disorders may be enrolled if seizures are well controlled on antiepileptic medication
- •CNS toxicity ≤ Grade 2
- •Adequate Cardiac Function Defined As:
- •Shortening fraction of ≥27% by ECHO, or
- •Ejection fraction of ≥50% by ECHO or gated radionuclide study.
- •Adequate Pulmonary Function Defined As: No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry >94% if there is a clinical indication for pulse oximetry. For patients who do not have respiratory symptoms, full pulmonary function tests are NOT required.
排除标准
- •Men and women of childbearing potential and their partners must agree to use adequate contraception while enrolled on this study.
- •Females of childbearing potential (≥ 10 years of age and /or post-menarchal) must have a negative pregnancy test to be eligible for this study, and they must agree to use 2 acceptable methods of contraception or abstain from heterosexual intercourse while participating in this study.
- •Pregnant women will be excluded from this study.
- •Female patients who are lactating must agree to stop breastfeeding or will otherwise be excluded from this study.
- •Patients with uncontrolled hypertension are not eligible; uncontrolled hypertension is defined as sustained hypertension not well-controlled on blood pressure medication(s).
- •If enrolling on Regimen A (temodar, irinotecan, dinutuximab arm only): patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, or carbamazepine for at least 7days prior to study enrollment. Patients receiving non-enzyme inducing anticonvulsants such as gabapentin, valproic acid, or levetiracetam will be eligible. Patients who have received drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment are not eligible. Patients must not have ≥ Grade 2 diarrhea
- •Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than neuroblastoma.
- •Patients must not have uncontrolled infection.
- •Patients with a history of Grade 4 allergic reactions to anti-GD2 antibodies or reactions that required permanent discontinuation of the anti-GD2 therapy are not eligible.
- •Patients who could not tolerate standard dose of dinutuximab infusion in 20 hour or less are not eligible.
- •Patients with a significant intercurrent illness or disease of any major organ system that would impair their ability to withstand protocol therapy are not eligible
研究组 & 干预措施
Rapid infusion of dinutuximab with chemotherapy
Patients will receive chemotherapy and dinutuximab via rapid infusion
干预措施: Dinutuximab with Chemotherapy (Drug)
结局指标
主要结局
Determine feasibility of administering dinutuximab in Cycle 1
时间窗: Day 1 of therapy until Day 21
The number of dinutuximab days tolerated in 4 hours or less in Cycle 1 will be measured
Determine average dinutuximab infusion time in Cycle 1
时间窗: Day 1 of therapy until Day 21
The infusion time of dinutuximab days administered on Days 1-4 will be measured and the average infusion time will be calculated for each dinutuximab day during Cycle 1.
Feasibility Cohort Primary Aim #1: To determine the feasibility of administering rapid dinutuximab infusion in 5 hours or less on dinutuximab infusion days 1-4 in cycle 1
时间窗: Day 1 of therapy until Day 21 (or 28)
Feasibility will be defined as receiving at least one day of dinutuximab infusion in 5 hours or less without unacceptable toxicity in cycle 1. The proportion of patients successfully receiving at least one day of dinutuximab infusion in 5 hours or less will be documented for each of the two treatment groups with the 95% confidence interval to quantify variability.
Feasibility Cohort Primary Aim #2: To determine the average dinutuximab infusion time on dinutuximab infusion days 1-4 in cycle 1
时间窗: Day 1 of therapy until Day 21 (or 28)
The average dinutuximab infusion time will be computed across the 4 dinutuximab infusion days in cycle 1, along with the standard error to describe the variability.
Feasibility Cohort + Safety Expansion Cohort Primary Aim #1: To determine the safety and tolerability of administering rapid dinutuximab infusion in 5 hours or less for all cycles
时间窗: Day 1-126 (or 168 depending on cycle length)
The frequency of unacceptable toxicities in patients, the frequency of patient coming off study due to toxicity or treatment-related deaths will be tabulated. In addition, The incidence of all treatment-related toxicities and grade 3 or higher toxicities in aggregate will be reported.
次要结局
- Determine feasibility of administering Dinutuximab in Cycle 2-6 in 4 hrs or less(Day 22 of study therapy until Day 126)
- Determine average dinutuximab infusion time in Cycles 2-6(Day 22 of study therapy until Day 126)
- Feasibility Cohort Secondary Aim #2: To determine the average dinutuximab infusion time on dinutuximab days 1-4 in subsequent cycles.(Day 22 (or 28) of study therapy until Day 121 or 168)
- Feasibility Cohort Secondary Aim #1: To determine the feasibility of administering rapid dinutuximab infusion in 5 hours or less on dinutuximab infusion days 1-4 in subsequent cycles.(Day 22 (or 28) of study therapy until Day 121 or 168 (depending on cycle length))
- Feasibility Cohort + Safety Expansion Cohort Secondary Aim #1: To determine the average dinutuximab infusion time on dinutuximab infusion days in all cycles.(Day 1-126 (or 168 depending on cycle length))
研究者
Sara-Jane Onyeama
Assistant Professor
Children's Hospital Los Angeles