NANT 2021-02: Randomized MIBG With Vorinostat/Dinutuximab/Vorinostat + Dinutuximab

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.

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:

• 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
• 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

• Total bilirubin ≤ 1.5 x ULN for age; and,
• 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:

• 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.
• 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

• Normal ejection fraction (≥ 55%) documented by either echocardiogram or radionuclide MUGA evaluation OR normal fractional shortening (≥ 27%) documented by echocardiogram.
• 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.

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.

Patients who have received prior MIBG in combination with anti-GD2 monoclonal antibody and/or histone deacetylase inhibitor

The maximum total allowable dose of 131I-MIBG that can be given per institutional guidelines must be at least 90% of the calculated or protocol maximum 131I-MIBG dose or the patient is not eligible.

Patients with a history of deep venous thrombosis that was not associated with the presence of a central venous catheter.

Patient declines participation in NANT 2004-05, the NANT Biology Study.

Patients with evidence of active MIBG non-avid disease; patients with previously treated and stable disease that is not MIBG avid are still eligible.

Patients whose best response post previous MIBG therapy was progressive disease.

Patients with a cumulative lifetime dose of 131I-MIBG greater than 20 mCi/kg.