Study in children and adolescents of 177Lu DOTATATE (Lutathera®) combined with the PARP inhibitor olaparib for treatment of recurrent or relapsed solid tumours expressing somatostatin receptors (SSTR) (LuPARPed)
Relapsed/refractory (R/R) solid tumours at the paediatric age have a dismal prognosis \[5-year overall survival (OS) less than 20%. There is growing evidence about the somatostatin receptor (SSTR) expression in paediatric tumours, which opens a new diagnostic and therapeutic tool. Somatostatin receptor-targeted therapy with 177Lu-DOTA0-Tyr3-octreotate (177\[Lu\]Lu DOTA-TATE, 177Lu-DOTATATE, Lutathera®) has been approved by the EMA (2017) and the FDA (2018) for the treatment of adults with midgut neuroendocrine tumours after the excellent results achieved in the phase III NETTER-1 study. 177Lu-DOTATATE is already being explored as monotherapy in children with R/R high-risk neuroblastoma, CNS tumours or meningiomas in 2 pilot studies and 4 clinical trials (ISRCTN98918118, NCT04903899, NCT03966651, NCT05278208). There are two on going clinical trials exploring the recommended phase 2 dose (RP2D) of 177Lu-DOTATATE in children younger than12 years old, but results are still pending. The results show promising but insufficient results. Because of its beta particle emission, 177Lu-DOTATATE mainly produces DNA single-strand breaks (SSBs) that are easily repaired by the organism. In order to enhance its effect, the investigators propose its combination with PARP inhibitors (iPARP) so that the SSBs could not be repaired and would lead to the formation of DNA double strand breaks (DSBs) and, subsequently, to cell death. This combination is already being explored in different clinical trials in adults with neuroendocrine tumours and prostate cancer. An interesting study analysed the perfect scheme for the 177Lu-DOTATATE and olaparib combination and concluded that olaparib should be delayed 24 hours after 177Lu-DOTATATE administration in order to facilitate normal tissue repair without decreasing antitumoural activity. It also concludes that there is no benefit in continuing olaparib after 4 weeks of continuous treatment. Olaparib has also been administered in children and there is today a recommended phase 2 dose (187.5 mg/m2 BID). The 177LUDOTATATE and olaparib combination is already being explored in different clinical trials in adults with neuroendocrine tumors and prostate cancer 19-21. One of these studies (NCT04375267) has already published results, showing that, when combined with 177LUDOTATATE, olaparib recommended starting dose is 200 mg BID instead of the normal 300 mg BID dose.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
25
7Lu-DOTATATE will be administered intravenously, on day 1, every 8 weeks, at a fixed dose of 200 mCi (7.4 GBq) for children \>= 12 years old infused intravenously over a period of 30 minutes. For children younger than 12 years old, the dose that will be administered is 200 MBq per kilogram of body weight (maximum 7.4 GBq) infused intravenously over a period of 30 minutes. Concomitant to 177Lu-DOTATATE, patients will receive IV fluids and an IV infusion of amino acid solution for renal protection23. Patients will receive four infusions every 8 weeks (maximum cumulative radioactivity, 29.6 GBq \[800 mCi\]). Olaparib will be administered PO, BID, days 2-29, every 8 weeks at a fixed dose of 187.5mg/m2 twice daily (BID).
HM Monteprincipe
Boadilla del Monte, Madrid, Spain
RECRUITINGTo estimate the safety of the combination of 177LUDOTATATE and olaparib.
Measured by incidence of DLTs; finding of MTD and RP2D
Time frame: Through first cycle, an average of 8 weeks
To estimate the preliminary activity of the combination of 177LUDOTATATE and olaparib.
ORR
Time frame: From enrollment to the end of treatment, up to 24 months
To test the activity of the combination of 177LUDOTATATE and olaparib
DCR, DOR, TTR, PFS, OS, quality of life assessment
Time frame: Through study completion, up to 24 months
To test the safety of the combination of 177LUDOTATATE and olaparib
AEs, SAEs
Time frame: Through study completion, up to 24 months
To test the tolerability of the combination of 177LUDOTATATE and olaparib
Frequency of treatment reductions, need of drug holidays and delays on treatment administration
Time frame: Through study completion, up to 24 months
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