Main objective:The main objective is to evaluate the efficacy of two intensified consolidation strategies in very-high risk neuroblastoma (VHR-NBL) patients in terms of event-free survival from randomisation date. Thisevaluation will follow a…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the 3 years Event-Free Survival from the date of
randomisation into the
VERITAS trial, considering as events: disease progression or relapse, death
from any cause, and secondary malignancy. Patients without event are censored
at the date of their last follow up evaluation.
Secondary outcome
a - Overall survival, defined as the time from randomisation to death from any
cause.
b - Adverse events, evaluated using NCI-CTCAE v4.0 toxicity grading system,
reported by treatment
phase and overall over the whole treatment duration (maximum grade). The
stopping rule for
toxicity will be based on the occurrence of adverse events leading to
ventilation in an ICU and
treatment-related deaths. These events will be specifically monitored over the
first 6 months after
randomisation.
c - Disease response after BuMel and at the end of treatment
d - For the Q-TWiST analysis: time spent with severe toxicity after
randomisation and before
progression/relapse (duration of hospitalisation will be used as a surrogate of
time with toxicity);
time spent without progression/relapse and without toxicity; and time from
progression until death.
e - Logistical issues raised by 131I-mIBG and topotecan or Thiotepa therapy in
a multicenter setting
f - Event-Free Survival from the date of start of the consolidation phase
g - Event-Free Survival from the date of the neuroblastoma diagnosis
Background summary
High-risk neuroblastoma remains one of the major challenges in paediatric
oncology. Despite the introduction of high-dose chemotherapy with haemopoietic
stem cell support, the outcome of these patients remains poor. This is
particularly so for patients who respond poorly to initial chemotherapy. If
metastatic CR is achieved after induction, patients proceed directly to the
consolidation therapy consisting of BuMel and peripheral blood stem cells
transplantation (PBSCT).
Patients with primary refractory or poorly responding disease need effective
salvage treatment if they are to be cured. At the present time there is no
salvage therapy generally recognized as sufficiently effective for this patient
group, and the prognosis remains very poor. For these patients with primary
refractory or poorly responding disease, there are no current guidelines for
treatment. Audits of care have shown a range of different treatment approaches.
Separate national or institutional groups have piloted alternative treatment
strategies, some of which appear to be promising, and a formal comparison of
these is appropriate.
Study objective
Main objective:
The main objective is to evaluate the efficacy of two intensified consolidation
strategies in very-high risk neuroblastoma (VHR-NBL) patients in terms of
event-free survival from randomisation date. This
evaluation will follow a hierarchical testing procedure: each experimental
treatment will be first evaluated as a single-arm phase 2 study, and in case of
positive conclusion, the relative efficacy of both arms will then be evaluated
comparatively.
Secondary objectives:
a - To estimate and compare the overall survival (OS) of patients treated in
the two treatment
strategies
b - To evaluate and compare the safety of the two treatment strategies in terms
of toxic death and
non-fatal toxicities rates.
c - To estimate and compare the disease response after BuMel and at the end of
treatment of the two
treatment strategies
d - To evaluate the between-treatment differences in Quality adjusted Time
Without Symptoms and
Toxicity (Q-TWIST approach)
e - To evaluate the feasibility and document the logistical issues raised by
131I-mIBG and topotecan
therapy in a multicenter setting
f - To estimate and compare the Event-Free Survival of the two treatment
strategies from the start of
the intensified consolidation chemotherapy
g - To estimate and compare the Event-Free Survival of the two treatment
strategies from the date of
the neuroblastoma diagnosis
Study design
Prospective, open-label, randomised, multi-centre, phase-II trial
Intervention
The trial will evaluate two randomised arms. Each arm includes three cycles of
Temozolomide-Irinotecan (similar in both arms), a specific consolidation course
detailed hereinafter, a BuMel sequence, followed by an autologous stem cell
transplant (similar in both arms), external radiotherapy as appropriate, and/or
local surgery of the tumour residues as appropriate.
The specific consolidation courses differ between the randomised arms as
follows: Two courses 131-I- mIBG and Topotecan with peripheral blood stem cell
rescue (ARM A) or High dose thiotepa with peripheral blood stem cell rescue
(ARM B).
Study burden and risks
The VERITAS protocol is an intensification of the already very intensive HR-NBL
standard protocol, for patients with insufficient response after the induction
chemotherapy. The treatment within VERITAS is very intensive. For the high dose
chemotherapy + ASCR and MIBG therapy, patients are hospitalized for a long
time. Patients are cared in isolation during the MIBG therapy and isolation
guidelines are in place. All patients suffer from side effects during treatment
and possibly with late effects long after treatment.
Not everything in the VERITAS is an additional burden. Many parts of the
treatment are also part of the standard high-risk treatment or the individual
treatment plan for patients who need treatment intensification.
Intensification of the treatment gives patients a chance to achieve a better
result and gives the possibility to continue with the standard protocol
maintenance. It gives a possible last chance of long-term disease control, cure
and survival.
Rue Edouard Vaillant 114
Villejuif F-94805
FR
Rue Edouard Vaillant 114
Villejuif F-94805
FR
Listed location countries
Age
Inclusion criteria
1. Metastatic neuroblastoma (NBL).
2. Previously treated within the ongoing High Risk Neuroblastoma SIOPEN study.
3. 131I-mIBG scintigraphy positive at diagnosis and after induction
chemotherapy (before high-dose BuMel + ASCT).
4. Metastatic response after induction chemotherapy lower to the ongoing High
Risk Neuroblastoma
SIOPEN trial criteria to be eligible for High Dose Chemotherapy; metastatic
response worse than
partial response (< PR) or SIOPEN score >= 3.
5. Females of childbearing potential must have a negative serum pregnancy test
within 7 days prior
to initiation of treatment. Sexually active patients must agree to use
acceptable and appropriate
contraception while on study drug and for one year after stopping the study
drug. Acceptable
contraception are defined in CTFG Guidelines *Recommendations related to
contraception and
pregnancy testing in clinical trials*. Female patients who are lacting must
agree to stop breastfeeding.
6. Written informed consent from parents/legal representative, patient, and
age-appropriate assent
before any study-specific screening procedures are conducted according to
local, regional or
national guidelines.
7. Patient affiliated to a social security regimen or beneficiary of the same
according to local
requirements.
Exclusion criteria
1. Parenchymal brain metastasis(es) (even one)
2. Progressive disease at study entry
3. Previous high-dose therapy and PBSCT
4. Performance status (Karnofsky or Lansky) <70%
5. Patient having received other therapy for cancer treatment than those
allowed as per the ongoing
High Risk Neuroblastoma SIOPEN trial or as defined in the future frontlines
protocol (for HRNBL1
trial : after induction + 2 TVD)
6. Impaired organ function (liver, kidney, heart, lungs) according to the
following definitions
o Shortening fraction <28%, or ejection fraction <55%, or clinical evidence of
congestive heart
failure or uncontrolled cardiac rythm disturbance
o Dyspnea at rest and/or pulse oxymetry <95% in air.
o ALT, Bilirubin >= 2 ULN
o Creatinine clearance and/or GFR <= 60 ml/min/1.73m2 and serum creatinine < 1.5
mg/dl
7. Any uncontrolled intercurrent illness or infection that in the
investigator*s opinion would impair
study participation
8. Concomitant use with yellow fever vaccine and with live virus and bacterial
vaccines
9. Patient allergic to peanut or soya
10. Chronic inflammatory bowel disease and/or bowel obstruction
11. Pregnant or breastfeeding women
12. Known hypersensitivity to the active substance or to any of the excipients
of study drugs
13. Known hypersensitivity to dacarbazine
14. Concomitant use with St John's Wort
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003130-27-NL |
| ClinicalTrials.gov | NCT03165292 |
| CCMO | NL68701.041.19 |