Inclusion Criteria:
- - Histologic Diagnosis: Patients must have had histologic verification of
neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the
bone marrow with elevated urinary catecholamines [i.e. > 2 x upper limit of normal
(ULN)], at the time of initial diagnosis.
- - Relapsed or Refractory Disease Patients must have ONE of the following:
-
1) Any prior episode of recurrent high-risk disease following completion of
frontline high-risk therapy.
Patients may have received other lines of
therapy for treatment of recurrent disease prior to enrolling to this
trial.
- -
2) Prior progressive high-risk disease during frontline high-risk therapy.
Patients may have received other lines of therapy for treatment of
progressive disease prior to enrolling to this trial.
- -
3) Primary resistant/refractory disease (less than partial response by INRC)
detected after the conclusion of at least 4 cycles of aggressive multidrug
induction chemotherapy on or according to a high-risk neuroblastoma
protocol (examples include ANBL0532, ANBL09P1, ANBL12P1, ANBL1531,
ANBL2131) that was treated with additional therapy with the goal of
improving remission status prior to enrolling to this trial.
- - Documentation of Disease: Patients must have at least ONE of the following at the
time of enrollment:
-
1) Measurable tumor on MRI or CT scan.
Measurable is defined as ≥ 10 mm in at
least one dimension (or 15 mm in short axis for lymph node) on
spiral/helical CT or MRI that is MIBG avid or demonstrates increased FDG
uptake on PET scan.
- -
2) MIBG-avid lesion detected on MIBG scan with positive uptake at a minimum
of one site.
This site must represent disease recurrence or known
refractory disease at a site not previously radiated.
- -
3) In patients with known MIBG non-avid disease, FDG-avid lesion detected on
FDG- PET scan with positive uptake at a minimum of one site.
This site
must represent disease recurrence or known refractory disease at a site
not previously radiated.
- - Of note, patients with isolated bone marrow only disease are NOT eligible for
this trial.
- - Prior Therapy: Prior lines of anticancer therapy allowed as described in eligibility
section above by disease status.
Washout periods from prior therapy are as follows:
- - Myelosuppressive chemotherapy: Last dose given 14 days prior to enrollment.
- - Small molecule targeted therapies (anti-neoplastic agents including retinoids):
Last dose given 7 days prior to enrollment.
- - Monoclonal antibodies: Last given at least 7 days or 3 half-lives, whichever is
longer, prior to enrollment.
- - Radiation:
- Craniospinal irradiation: Last fraction received minimum of six weeks
prior to enrollment.
- - All other radiation: Last fraction received minimum of 14 days prior to
enrollment.
- - Hematopoietic stem cell transplant: Date of autologous stem cell infusion
following myeloablative chemotherapy must have been a minimum of 12 weeks prior
to enrollment.
Patients are not eligible post allogeneic stem cell transplant.
- - Cellular therapies (including CAR-T cells, NK cells, other related cellular
therapies): 21 days from the last cellular therapy infusion prior to enrollment
and recovery from all associated toxicities.
- - 131I-MIBG therapy: Last therapy received a minimum of 6 weeks prior to
enrollment.
- - Age: Patients 1 - 30 years of age at the time of enrollment are eligible for this
study.
- - Performance level: Patients must demonstrate adequate performance level as measured
by Karnofsky ≥ 70% for patients aged 16 years or older, OR Lansky ≥ 70% for patients
younger than 16 years.
Please see Appendix A for performance score measurement.
- - Participants must meet the following organ and marrow function as defined below:
- Adequate bone marrow function as defined as BOTH of the following:
- Peripheral absolute neutrophil count (ANC) ≥ 750/uL.
Must be more than 14 days
from last administration of long-acting myeloid stimulating factor (e.g.
pegfilgrastim) or 7 days from last administration of short- acting myeloid
stimulating factor (e.g. filgrastim or sargramostim)
- - Peripheral platelet count ≥ 75,000/uL.
Must be without support, defined as at
least 7 days from last platelet transfusion and/or platelet stimulating agent.
- - Adequate renal function as defined as EITHER of the following:
- Radioisotope GFR ≥ 70ml/min/1.73 m2.
- - Serum creatinine based on age/sex as follows:
- Age Maximum Serum Creatinine (mg/dL)
- 1 to < 2 years Male 0.6 Female 0.6.
- - 2 to < 6 years Male 0.8 Female 0.8.
- - 6 to < 12 years Male 1.0 Female 1.0.
- - 12 to < 13 years Male 1.2 Female 1.2.
- - 13 to < 16 years Male 1.5 Female 1.4.
---≥ 16 years Male 1.7 Female 1.4.
- - The threshold creatinine values in this Table were derived from the
Schwartz formula for estimating GFR.
- - Adequate liver function defined as ALL of the following:
- Total bilirubin ≤ 1.5 x ULN for age*
- ALT ≤ 3.0 x ULN for age (≤ 135 U/L).
For the purpose of this study, the ULN for
ALT is 45 U/L.
- - Albumin > 3 g/dL --*If patient has known Gilbert syndrome, direct bilirubin
should be used to measure liver function instead of total bilirubin.
Direct
bilirubin must be within normal limits for age for these patients.
- - Adequate cardiac function measured by echocardiogram as defined as EITHER of the
following:
- Shortening fraction of ≥ 27%
- Ejection fraction of ≥ 50%
- Adequate blood pressure as defined by BOTH of the following:
- Patients must have < Grade 2 hypertension AND.
- - Be on no more than one standing antihypertensive.
- - Adequate pulmonary function: Patients must have adequate pulmonary function, defined
as:
- No dyspnea at rest.
- - No exercise intolerance.
- - Room air O2 saturation >94%
- Not on chronic oxygen therapy.
- - Adequate pancreatic function, defined as lipase < 1.5 x ULN.
- - Able to comply with protocol requirements.
- - Adequate contraception: The effects of naxitamab on the developing human fetus are
unknown.
For this reason and because other therapeutic agents used in this trial are
known to be teratogenic, participants with potential to become pregnant or to
impregnate a partner must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation. Should a participant become pregnant or suspect they are
pregnant while they or their partner is participating in this study, they should
inform the treating physician immediately. Patients treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and 4 months after completion of protocol therapy.
- - Ability to understand and/or the willingness of their parent or legally authorized
representative to sign a written informed consent document.
Exclusion Criteria:
- - Chronic (more than 2 weeks duration) diarrhea > grade 1.
- - Prior receipt of naxitamab.
- - Untreated central nervous system (CNS) metastatic disease.
- - Pregnant or currently breast feeding: Pregnant participants are excluded from this
study because protocol therapy has the potential for teratogenic or abortifacient
effects.
Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the parent with protocol therapy,
participants planning to continue breastfeeding are excluded from the study.
- - Clinically significant arrhythmias, i.e. those that cause clinical symptoms or
require medications for control of symptoms.
- - Prior allergic reaction to irinotecan or temozolomide.
- - Discontinuation of prior irinotecan or temozolomide due to unacceptable toxicity.
- - Discontinuation of prior GD2 directed immunotherapy due to unacceptable toxicity
other than allergic reaction.
- - Serious intercurrent illness.
- - Active uncontrolled infection.
- - Existing major organ dysfunction CTCAE >Grade 2, except for hearing loss and
hematological status, kidney, and liver function as described in eligibility
criteria.
- - Concomitant Medication Restrictions:
- Patients may not be receiving immunosuppressive medications including
pharmacologic doses of glucocorticoids or immunomodulatory agents due to
concern for inhibition of antibody effect.
Local and inhaled steroid agents are
permitted.
- - Patients may not be receiving concurrent anti-cancer agents or radiotherapy.
- - Patients may not have received valproic acid within 14 days prior to
enrollment.
- - Patients may not have received strong CYP3A4 inducers, strong CYP3A4
inhibitors, or strong UGT1A1 inhibitors within 14 days prior to enrollment.
- - Because the lists of these agents are constantly changing, it is important
to regularly consult a frequently-updated medical reference.
As part of
the enrollment/informed consent procedures, the participant will be
counseled on the risk of interactions with other agents, and what to do if
new medications need to be prescribed or if the participant is considering
a new over-the-counter medicine or herbal product.
