Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06172296 |
| Other study ID # |
NCI-2023-08530 |
| Secondary ID |
NCI-2023-08530AN |
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
April 19, 2024 |
| Est. completion date |
December 31, 2029 |
Study information
| Verified date |
May 2024 |
| Source |
National Cancer Institute (NCI) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy
along with standard of care surgical resection of the primary tumor, radiation, stem cell
transplantation, and immunotherapy works for treating children with newly diagnosed high-risk
neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2,
which is found on the surface of neuroblastoma cells, but is not present on many healthy or
normal cells in the body. When dinutuximab binds to the neuroblastoma cells, it helps signal
the immune system to kill the tumor cells. This helps the cells of the immune system kill the
cancer cells, this is a type of immunotherapy. When chemotherapy and immunotherapy are given
together, during the same treatment cycle, it is called chemoimmunotherapy. This clinical
trial randomly assigns patients to receive either standard chemotherapy and surgery or
chemoimmunotherapy (chemotherapy plus dinutuximab) and surgery during Induction therapy.
Chemotherapy drugs administered during Induction include, cyclophosphamide, topotecan,
cisplatin, etoposide, vincristine, and doxorubicin. These drugs work in different ways to
stop the growth of cancer cells, either by killing the cells, by stopping them from dividing
or by stopping them from spreading. Upon completion of 5 cycles of Induction therapy, a
disease evaluation is completed to determine how well the treatment worked. If the tumor
responds to therapy, patients receive a tandem transplantation with stem cell rescue. If the
tumor has little improvement or worsens, patients receive chemoimmunotherapy on Extended
Induction. During Extended Induction, dinutuximab is given with irinotecan, temozolomide.
Patients with a good response to therapy move on to Consolidation therapy, when very high
doses of chemotherapy are given at two separate points to kill any remaining cancer cells.
Following, transplant, radiation therapy is given to the site where the cancer originated
(primary site) and to any other areas that are still active at the end of Induction. The
final stage of therapy is Post-Consolidation. During Post-Consolidation, dinutuximab is given
with isotretinoin, with the goal of maintaining the response achieved with the previous
therapy. Adding dinutuximab to Induction chemotherapy along with standard of care surgical
resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy may
be better at treating children with newly diagnosed high-risk neuroblastoma.
Description:
PRIMARY OBJECTIVE:
I. To determine if the event-free survival (EFS) of patients with newly diagnosed high-risk
neuroblastoma assigned to early chemoimmunotherapy during Induction differs from that of
patients who are not assigned to treatment that includes early chemoimmunotherapy.
SECONDARY OBJECTIVES:
I. To determine if early chemoimmunotherapy during Induction therapy improves end of
Induction (EOI) response rates and overall survival (OS) for patients with newly diagnosed
high-risk neuroblastoma.
II. To determine response rates, EFS, and OS following an Extended Induction regimen with
chemoimmunotherapy in patients with progressive disease or a poor response to Induction
therapy.
III. To compare the toxicities experienced by patients treated with chemoimmunotherapy during
Induction versus those experienced by patients treated with standard Induction and to
describe toxicities experienced during Extended Induction.
IV. To determine GD2 expression on tumor tissue and tumor cells in bone marrow and assess for
associations with response and outcome.
EXPLORATORY OBJECTIVES:
I. To describe the association between tumor and host factors and outcomes in patients
receiving protocol therapy.
II. To evaluate circulating biomarkers and markers of minimal residual disease at baseline
and during therapy, and assess for associations with response and outcome.
III. To compare patterns of failure between patients treated with and without dinutuximab
during induction.
IV. To determine the effect of telomere maintenance mechanisms on end of Induction response
rates, EFS, and OS.
V. To explore the impact of high-risk neuroblastoma (HRNBL) and its therapy, including the
addition of dinutuximab to Induction chemotherapy, on functional and quality of life outcomes
in patients with HRNBL, as measured by caregiver (parent/legal guardian) and patient
questionnaires.
VI. To describe the adequacy of diagnostic biopsy specimens, including those obtained by
percutaneous core needle biopsy.
VII. To explore the associations between family-reported adverse social determinants of
health and both clinical outcomes and biology.
VIII. To develop and validate deep learning predictors of Induction response based on
diagnostic MIBG scans. (Imaging Objective) IX. To compare institutional versus central
determination of overall response, individual response components (primary tumor, soft tissue
and bone metastatic disease, and bone marrow metastatic disease), and poor end of induction
response (PEIR) and good end of induction response (GEIR) determination. (Imaging Objective)
X. To describe late toxicities (including impaired organ function, neuropsychiatric toxicity,
and incidence of secondary malignancy) in patients treated with dinutuximab during Induction
or Extended Induction to late toxicities in patients who have not received dinutuximab during
these phases of therapy.
XI. To evaluate whether reduced dose radiotherapy to the primary site clinical target volume
(CTV) in patients with complete response of the primary site at EOI results in comparable
local control relative to historical cohorts.
XII. To compare post-transplant complications between treatment arms, and assess for
associations with outcome.
XIII. To assess for associations between EOI response (including good end of Induction
response [GEIR] and poor end of Induction response [PEIR]) and individual response components
(primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease)
with outcome (EFS and OS).
XIV. To describe and compare the changes in image-defined risk factors (IDRFs) between
patients treated with and without dinutuximab during Induction and associate with surgical
outcomes and local failure rates following primary tumor resection.
XV. To bank serial samples of blood, bone marrow, and tumor tissue for future research.
OUTLINE: Patients receive Induction cycle 1 and are then randomized to 1 of 2 treatment arms.
INDUCTION CYCLE 1: Patients receive cyclophosphamide intravenously (IV) over 30 minutes and
topotecan IV over 30 minutes on days 1-5 in the absence of unacceptable toxicity.
ARM A:
INDUCTION CYCLES 2-5: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV
over 30 minutes on days 1-5 of cycle 2 in the absence of unacceptable toxicity. Patients then
undergo stem cell harvest via apheresis. Patients then receive cisplatin IV over 4 hours and
etoposide IV over 2 hours on days 1-3 of cycles 3 and 5, and vincristine IV on day 1,
doxorubicin IV over 15 minutes, and cyclophosphamide IV over 1 hours on days 1-2 of cycle 4
in the absence of unacceptable toxicity. Patients undergo primary tumor resection after
Induction cycle 4 or 5. Following Induction cycle 5, patients undergo testing to determine
response to Induction therapy. Patients with a good tumor response proceed to Consolidation,
while patients with a poor tumor response proceed to Extended Induction.
EXTENDED INDUCTION: Patients with a poor tumor response or progression during Induction
receive temozolomide orally (PO), via nasogastric tube (NG), or via gastric tube (G-tube) on
days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximab IV over 10 hours.
Treatment repeats every 21 days for up to a maximum of 6 cycles in the absence of disease
progression or unacceptable toxicity. If at any time during Extended Induction testing shows
a good tumor response, patients proceed to Consolidation. If after 6 cycles of Extended
Induction or if at any time progression is noted, patients are removed from the study.
CONSOLIDATION: Patients undergo two autologous stem cell transplantations (HSCTs) during
Consolidation. Patients receive thiotepa IV over 2 hours on days -7 to -5 and
cyclophosphamide IV over 1 hour on days -5 to -2 during HSCT 1. Patients then receive stem
cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion, patients receive
melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4,
and carboplatin over 24 hours on days -7 to -4 during HSCT 2. Patients receive stem cell
infusion IV on day 0. Between day +42 and day +80 after HSCT 2. Patients receive radiation
daily for 12 treatments in the absence of disease progression or unacceptable toxicity.
POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and
isotretinoin PO twice daily (BID) on days 11-24 of cycles 1-5. Treatment repeats every 28
days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.
Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle, cycle 6.
Patients undergo bone marrow aspiration and/or biopsy, computed tomography (CT) scan,
magnetic resonance imaging (MRI), iodine-123 meta-iodobenzylguanidine (I-MIBG) scan and
possible fluorodeoxyglucose position emission tomography (FDG-PET) scan throughout the study.
ARM B:
INDUCTION CYCLES 2-5: Patients receive cyclophosphamide IV over 30 minutes, topotecan IV over
30 minutes on days 1-5, and dinutuximab IV over 10 hours on days 2-5 of cycle 2 in the
absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis.
Patients receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 and
dinutuximab IV over 10 hours on days 2-5 of cycles 3 and 5, and vincristine IV on day 1,
doxorubicin IV over 15 minutes, and cyclophosphamide IV over 1 hour on days 1-2, and
dinutuximab IV over 10 hours on days 2-5 of cycle 4 in the absence of unacceptable toxicity.
Patients undergo primary tumor resection after Induction cycle 4 or 5. Following Induction
cycle 5, patients undergo testing to determine response to Induction therapy. Patients with a
good tumor response proceed to Consolidation, while patients with a poor tumor response
proceed to Extended Induction.
EXTENDED INDUCTION: Patients with a poor tumor response or progression during Induction
receive temozolomide PO, via NG tube, or via G-tube on days 1-5, irinotecan IV over 90
minutes on days 1-5, and dinutuximab IV over 10 hours. Treatment repeats every 21 days for up
to a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. If
at any time during Extended Induction testing shows a good tumor response, patients proceed
to Consolidation. If after 6 cycles of Extended Induction or if at any time progression is
noted, patients are removed from the study.
CONSOLIDATION: Patients undergo two autologous HSCTs during Consolidation. Patients receive
thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to
-2 during HSCT 1. Patients then receive stem cell infusion IV on day 0. Between 6 and 10
weeks after stem cell infusion patients receive melphalan IV over 30 minutes on days -7 to
-5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to
-4 during HSCT 2. Patients receive stem cell infusion IV on day 0. Between day +42 and day
+80 after HSCT 2, patients receive radiation daily for 12 treatments in the absence of
disease progression or unacceptable toxicity.
POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and
isotretinoin PO BID on days 11-24 of cycles 1-5. Treatment repeats every 28 days for up to 5
cycles in the absence of disease progression or unacceptable toxicity. Patients then receive
isotretinoin PO BID on days 15-28 for 1 additional cycle, cycle 6.
Patients undergo bone marrow aspiration and/or biopsy, CT scan, MRI, I-MIBG scan and possible
FGD-PET scan throughout the study.
After completion of study treatment, patients are followed up at 3, 6, 9,12, 15, 18, 24, 30,
36, 42, 48, 54, and 60 months and then periodically for up to 10 years from enrollment.
