NANT 2021-02: A Randomized Phase 2 Study of 131I-MIBG With Vorinostat VS. 131I-MIBG With Dinutuximab vs. 131I-MIBG With Dinutuximab and Vorinostat for Relapsed or Refractory Neuroblastoma
Overview
- Phase
- Phase 2
- Intervention
- Vorinostat
- Conditions
- Not specified
- Sponsor
- New Approaches to Neuroblastoma Therapy Consortium
- Enrollment
- 118
- Locations
- 13
- Primary Endpoint
- Objective Tumor Response After One Course of Therapy
- Status
- Not yet recruiting
- Last Updated
- 5 months ago
Overview
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.
Investigators
Eligibility Criteria
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.
Exclusion Criteria
- •Pregnancy, breast feeding, or unwillingness to use effective contraception during the study will not be entered on this study due to risks of fetal and teratogenic adverse events.
- •Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring or radiation isolation requirements of the study.
- •Patients with disease of any major organ system that would compromise their ability to withstand therapy.
- •Patients must not have received prior allogeneic stem cell transplant.
- •Patients who have received prior solid organ transplantation.
- •Patients must not have received prior total body irradiation.
- •Patients who are on hemodialysis.
- •Patients with an active or uncontrolled infection. Patients on prolonged antifungal therapy are still eligible if they are culture negative, afebrile, and meet other organ function criteria.
- •Known history of active human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C. Testing is not required in the absence of clinical findings or suspicion.
- •Patients with a history of having to permanently discontinue anti-GD2 antibody therapy, GM-CSF, or vorinostat due to toxicity are not eligible.
Arms & Interventions
Arm A: 131I-MIBG + vorinostat
Patients assigned to Arm A will receive vorinostat orally once daily on Days 0 to 13 at a dose of 180 mg/m2/dose (maximum dose 400 mg). Patients will receive 131I-MIBG 18 mCi/kg (maximum dose 1200 mCi) on Day 1 and autologous stem cell infusion on Day 15 (plus 2 days or minus 1 day, hereafter abbreviated as +2/-1 days). There must be at least 24 hours between the last dose of vorinostat and stem cell infusion. Disease evaluation is to occur between days 50-60. The time interval between performing end of Course 1 disease evaluation and administration of Course 2 131I-MIBG is not to exceed 4 weeks.
Intervention: Vorinostat
Arm B: 131I-MIBG + dinutuximab
Patients assigned to Arm B will receive 18 mCi/kg (maximum dose 1200 mCi) 131I-MIBG on Day 1 and autologous stem cell infusion on Day 15 (+2/-1 days). Dinutuximab 17.5 mg/m2/day is given intravenously on Days 8-11 and 29-32 of therapy. Disease evaluation is to occur between Days 50-60. In case of treatment delays with dinutuximab during Course 1, the time interval between performing end of Course 1 disease evaluation and administration of Course 2 131I-MIBG is not to exceed 4 weeks.
Intervention: Dinutuximab
Arm C: 131I-MIBG + vorinostat + dinutuximab
Patients assigned to Arm C will receive vorinostat 180 mg/m2/dose (maximum dose 400 mg) on Days 0 to 13, 131I-MIBG 18 mCi/kg (maximum dose 1200 mCi) on Day 1. Dinutuximab 17.5 mg/m2/day is given intravenously on Days 8-11 and 29-32 of therapy. Disease evaluation is to occur between Days 50-60. In case of treatment delays with dinutuximab during Course 1, the time interval between performing end of Course 1 disease evaluation and administration of Course 2 131I-MIBG is not to exceed 4 weeks.
Intervention: Dinutuximab
Arm C: 131I-MIBG + vorinostat + dinutuximab
Patients assigned to Arm C will receive vorinostat 180 mg/m2/dose (maximum dose 400 mg) on Days 0 to 13, 131I-MIBG 18 mCi/kg (maximum dose 1200 mCi) on Day 1. Dinutuximab 17.5 mg/m2/day is given intravenously on Days 8-11 and 29-32 of therapy. Disease evaluation is to occur between Days 50-60. In case of treatment delays with dinutuximab during Course 1, the time interval between performing end of Course 1 disease evaluation and administration of Course 2 131I-MIBG is not to exceed 4 weeks.
Intervention: Vorinostat
Outcomes
Primary Outcomes
Objective Tumor Response After One Course of Therapy
Time Frame: 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 Outcomes
- 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)
- Objective Tumor Response After Two Courses of Therapy(43-50 days from study day 1)
- Objective Bone Marrow Tumor Response After One Course of Therapy(43-50 days from study day 1)
- Objective Bone Marrow Tumor Response After Two Courses of Therapy(43-50 days from study day 1)
- Objective Soft Tissue Tumor Response After One Course of Therapy(43-50 days from study day 1)
- Objective Soft Tissue Tumor Response After Two Courses of Therapy(43-50 days from study day 1)
- Objective Bone Tumor Response After One Course of Therapy(43-50 days from study day 1)
- Objective Bone Tumor Response After Two Courses of Therapy(43-50 days from study day 1)
- Objective MIBG Tumor Response After One Course of Therapy(43-50 days from study day 1)
- Objective MIBG Tumor Response After Two Courses of Therapy(43-50 days from study day 1)