Neuroblastoma
Conditions
Brief summary
Patients will then be randomized at study entry to one of three treatment arms. Patients on Arm A will receive a single treatment course with 131I-MIBG with vorinostat. Patients on Arm B will receive a single treatment course with 131I-MIBG and dinutuximab. Patients on Arm C will receive a single treatment course with 131I-MIBG with dinutuximab + vorinostat. After this course of treatment, we will check to see your response and then check to see how you are doing over time. All patients may choose to proceed to a second course of the same treatment if they and their physician feel healthy enough to do so. Approximately 118 patients will be receiving therapy on this trial.
Detailed description
The proposed study is a 3-arm randomized, pick-the-winner, phase 2 trial designed to identify the optimal combination 131I-MIBG treatment regimen for further study. The three treatment arms are 131I-MIBG + vorinostat; 131I-MIBG + dinutuximab; and 131I-MIBG + dinutuximab + vorinostat. Objective response rate following a single course of therapy will be the primary endpoint driving selection of the regimen to move forward into future studies.
Interventions
DRUGRadiation: 131I-MIBG
Patients will receive 131I-MIBG 18 mCi/kg (maximum dose 1200 mCi) on Day 1
DRUGDinutuximab
Dinutuximab 17.5 mg/m2/day is given intravenously on Days 8-11 and 29-32 of therapy
DRUGVorinostat
Vorinostat will be given on days 0-13 at a dose of 180 mg/m2/dose (maximum dose 400 mg).
Sponsors
United Therapeutics
Jubilant DraxImage Inc.
New Approaches to Neuroblastoma Therapy Consortium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
Age Patients must be ≥ 1 year and \< 30 years of age at the time of study registration. Diagnosis Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma nodular subtype either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines. Disease Risk Group Patients must have high risk neuroblastoma according to COG risk classification at the time of study registration. Patients who were initially considered low or intermediate risk, but then reclassified as high risk are also eligible. Response to Prior Therapy (using INRC definitions) Patients must have at least ONE of the following: * Recurrent/progressive disease after the diagnosis of high risk neuroblastoma at any time prior to enrollment - regardless of response to frontline therapy. (Note that this excludes patients initially considered low or intermediate risk that progressed to high risk disease but have not progressed after the diagnosis of high risk neuroblastoma). * If no prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma, * Refractory disease: A best overall response of no response/stable disease since diagnosis of high risk neuroblastoma AND after at least 4 courses of induction therapy. * Persistent disease: A best overall response of minor response since diagnosis of high risk neuroblastoma AND after at least 4 courses of induction therapy: i. If a patient with persistent disease has 3 or more MIBG avid sites (including all soft tissue and/or bone lesions) OR a Curie Score of ≥ 3, then no biopsy is required for eligibility. ii. If a patient with persistent disease has only 1 or 2 MIBG avid sites (including all soft tissue and/or bone lesions) then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site (bone marrow, bone, or soft tissue) present at the time of registration is required. Bone and/or soft tissue lesions may be biopsied at any time point prior to study registration, bone marrow must be done at the time of study registration. Sites of Disease: MIBG Uptake Patients must have evidence of MIBG uptake into tumor at ≥ 1 site (bone or soft tissue) within 21 days prior to study entry and subsequent to any intervening therapy. See
Exclusion criteria
. Autologous peripheral blood stem cells (PBSC) * The minimum dose for peripheral blood stem cells is 1.5 x 106 viable CD34+ cells/kg. Patients who do not meet this minimum requirement for available PBSCs are not eligible. * Only un-purged stem cells are allowed unless a center has separate FDA approval for infusion of purged stem cells. * For patients whose body weight exceeds ideal body weight (IBW) by more than 20%, adjusted body weight may be used for the calculation of PBSC dose.47 Performance level Patients must have a Lansky (≤ 16 years) or Karnofsky (\> 16 years) score of ≥ 50 Note: Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study registration. Organ Function Requirements Hematologic Function: Patients must meet the following hematologic criteria for enrollment regardless of bone marrow disease involvement: 1. ANC ≥750/uL (no short-acting hematopoietic growth factors ≤ 7 days of blood draw documenting eligibility and no long-acting hematopoietic growth factors ≤ 14 days of blood draw documenting eligibility); and 2. Platelet count ≥ 50,0000/µl, transfusion independent (no platelet transfusions or platelet growth factors ≤ 7 days of blood draw documenting eligibility). Renal Function a. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN for age Liver Function 1. Total bilirubin ≤ 1.5 x ULN for age; and, 2. SGPT (ALT) ≤ 135 U/L (≤ 3x ULN). Note that for ALT, the upper limit of normal for all sites is defined as 45 U/L. Central Nervous System (CNS) Function: 1. Patients with a history of intraparenchymal or leptomeningeal based CNS disease must have no clinical or radiological evidence of active CNS disease at the time of study enrollment. 2. Patients with skull based tumors with direct intracranial extension are eligible as long as there are no neurologic signs or symptoms related to the lesion. Cardiac Function 1. Normal ejection fraction (≥ 55%) documented by either echocardiogram or radionuclide MUGA evaluation OR normal fractional shortening (≥ 27%) documented by echocardiogram. 2. Corrected QT (QTcF) interval ≤ 480 msec. Pulmonary Function No evidence of dyspnea at rest, no exercise intolerance, or oxygen requirement. Reproductive Function a. All females of childbearing potential (female patients 10 and older without documented ovarian failure) must have a negative serum or urine beta-HCG ≤ 7 days prior to registration. b. Male and female subjects of reproductive age and childbearing potential must agree to use two acceptable methods of birth control (i.e., intra-uterine device, hormonal contraception, diaphragm with spermicide, condom with spermicide, or abstinence) or to abstain from heterosexual intercourse for the duration of their participation in the study, or for 3 months after last dose of protocol therapy, whichever is longer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Tumor Response After One Course of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest overall response rate after one course of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Tumor Response After Two Courses of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest overall response rate after two courses of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
| Objective Bone Marrow Tumor Response After One Course of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest bone marrow response rate after one course of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
| Objective Bone Marrow Tumor Response After Two Courses of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest bone marrow response rate after two courses of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
| Objective Soft Tissue Tumor Response After One Course of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest soft tissue response rate after one course of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
| Number of Participants With Grade 3 or Greater Non-hematologic Toxicities | All toxicities from enrollment through 30 days following end of protocol therapy, an average of 6 months | Compare toxicity profiles for grade 3 or greater toxicities associated with each of 131I-MIBG treatment regimens; 131I-MIBG with vorinostat; 131I-MIBG with dinutuximab; or 131I-MIBG with vorinostat and dinutuximab |
| Objective Bone Tumor Response After One Course of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest bone response rate after one course of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
| Objective Bone Tumor Response After Two Courses of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest bone response rate after two courses of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
| Objective MIBG Tumor Response After One Course of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest MIBG response rate after one course of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
| Objective MIBG Tumor Response After Two Courses of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest MIBG response rate after two courses of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
| Objective Soft Tissue Tumor Response After Two Courses of Therapy | 43-50 days from study day 1 | To identify the MIBG treatment regimen associated with the highest soft tissue response rate after two courses of treatment on the three arms. The response evaluation was based on central review (intent to treat analysis). Responders defined as meeting CR/MRD/PR criteria. Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940). RECST 1.1 criteria was used for measurable tumors with PR criteria \> 30% decrease in target tumor size. Curie score was used with PR criteria \> 50% decrease in Curie score. Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease. Overall Response (OR)=CR+PR. |
Countries
United States
Contacts
Primary ContactAraz Marachelian, MD
Outcome results
None listed