Relapsed and refractory high-risk neuroblastoma Cancer
Conditions
Interventions
Participants will be treated with a drug called talazoparib (a PARP inhibitor) in combination with 131I-MIBG therapy. The participants will be split into two groups, depending on whether they have spe
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients must be >1 year of age at time of registration on study. 2. Patients must have a diagnosis of neuroblastoma either by histological verification of neuroblastoma and/or demonstration of tumour cells in the bone marrow with increased urinary catecholamines. 3. Patients must have high-risk neuroblastoma according to COG risk classification 2021 at the time of study registration. 4. Patients must have at least ONE of the following: recurrent/progressive disease; refractory disease; persistent disease 5. Patients must have evidence of abnormal mIBG uptake at one site (primary tumour, bone or soft tissue) within the 28 days prior to entry on study and following any intervening therapy. 6. Patients must have an available archival tissue sample OR an available genetic sequencing report from an approved laboratory detailing cancer-specific alterations in somatic and germline DNA 7. Patients require a minimum available stem cell dose of 1.5 x 10e6/kg CD34+ cells/kg. If patients receive a second cycle of treatment, they must have a further 1.5 x 10e6/kg CD34+ cells/kg available for use. 8. Patients must have a Lansky (16 years) score of 60. 9. Patients must have adequately recovered from clinically significant acute toxic effects of all prior therapy prior to study registration. Patients must not have received the therapies indicated below within the specific time period prior to study registration on this study: 9.1. Last dose of any myelosuppressive chemotherapy was given at least 2 weeks before study enrolment 9.2. Biologic (anti-neoplastic agent; includes retinoids): must have received last dose at least 7 days prior to study enrolment. 9.3. Monoclonal antibodies: must have received last dose at least 7 days or 3 half-lives, whichever is longer, prior to study enrolment. 9.4. Radiation: Patients must not have received radiation for a minimum of 2 weeks prior to study enrolment. 9.5. Prior 131I-mIBG: Patients previously treated with 131I-mIBG are eligible if: 9.5.1. at least 6 months from the date of last 131I-mIBG 9.5.2. Response other than progressive disease on first restaging after 131I-mIBG 9.5.3. Cumulative lifetime dose of 131I-mIBG at enrolment /=55%) or Fractional shortening (>/=28%) 10.5. Total bilirubin <=1.5x ULN 10.6. SGPT (ALT) and SGOT (AST) </=3x ULN 11. Written informed consent for trial participation must be obtained from patient or parent/guardian
Exclusion criteria
Exclusion criteria: 1. Patients who are pregnant, breastfeeding or unwilling to use effective contraception during the study. 2. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study. 3. Patients with disease of any major organ system that in the opinion of the investigator would compromise their ability to withstand therapy. 4. Previous allogeneic or solid organ transplant. 5. Patients who are on haemodialysis. 6. Patients with active or uncontrolled infection. Patients on prolonged antifungal therapy are still eligible if they are culture negative, afebrile, and meet other organ function criteria. 7. Known active infection with HIV, hepatitis B or hepatitis C (routine testing of patients is not required) 8. The maximum total allowance dose of 131I-mIBG that can be given per institutional guidelines must be at least 90% of the calculated 131I-mIBG dose or the patient is not eligible. 9. Patients and/or families who are physically and psychologically unable to cooperate with the radiation safety isolation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Incidence of dose-limiting toxicities (DLTs), where a DLT is defined as any of the following occurring from day 1 of treatment for 8 weeks (until Day 56), which is not attributable to the disease or disease-related processes under investigation and is considered at least possibly related to talazoparib or 131I-mIBG treatment: Dose-limiting non-haematological toxicity: Any Grade 3 or 4 non-haematological excluding: 1.1. Grade 3 nausea, vomiting and dehydration 1.2. Grade 3 anorexia or weight loss resulting from anorexia 1.3. Grade 3 fatigue 1.4. Grade 3 liver enzyme elevation that returns to =grade 1 or baseline by day 56 1.5. Grade 3 electrolyte abnormality requiring less than 24 hours of inpatient management 1.6. Grade 3 or 4 serum amylase elevation that resolves to =grade 2 within 14 days and is not accompanied by lipase elevation or grade =3 salivary gland toxicity 1.7. Grade 3 infection 1.8. Grade 3 fever 1.9. Grade 3 febrile neutropenia Dose-limiting haematological toxicity (in the absence of progressive bone marrow disease): 2.1. Neutrophil (ANC) <0.5 x 10e9/L at or after 28 days following PBSC reinfusion (Day 45) 2.2. Platelet count <20 x 10e9/L at or after 56 days following PBSC reinfusion (Day 73) 2.3. Infusion of additional PBSC for any medical reason after the initial stem cell reinfusion has been given AND prior to engraftment of neutrophils or platelets after that initial PBSC reinfusion. Measured using a one-stage Bayesian Continual Reassessment Method (CRM) at 8 weeks following one course of treatment. 2. Incidence of adverse events (AEs) and serious adverse events (SAEs) measured from day 1 of trial treatment through to day 84 will be summarised through tabulation and reviewed at 8 weeks, 1 year and 2 years following one course of treatment by the Safety Review and Dose Decision Committee (SRDD). | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Disease response to treatment, assessed by the NANT Criteria at 8 weeks following the initiation of 1 course of treatment 2. Overall survival, defined as the time from enrolment to death from any cause, will be measured as point estimate of the response rate along with an associated confidence interval for the overall patient population after at least 2 years following 1 course of treatment. 3. Progression-free survival, defined as the time from enrolment to disease progression or relapse | — |
Countries
Canada, England, Germany, Netherlands, Scotland, Spain, United Kingdom
Outcome results
None listed