177lu-dota-tate and olaparib in somatostatin receptor positive tumours

Conditions: Clinical Trial, Phase I; Neuroendocrine Tumors; Thymoma; Mesothelioma

Summary: this is a phase i study of 177lu-dota-tate in combination with the parp-inhibitor olaparib for treatment of patients with somatostatin receptor positive tumours detected by 68ga-dota-tate/toc pet. the combination of a parp inhibitor that will specifically target the repair mechanism, with ionising radiation causing ssb's might overcome the repair dependent survival of the tumour cells, making them more sensitive to β-emission and increase the probability of tumour cell death.


Eligibility criteria:
inclusion criteria: * histological or cytological diagnosis of neoplasia (not mandatory for meningioma) * gepnets grade 3 or aggressive grade 2 tumours with a poor prognosis and a ki67 \> 15% or neuroendocrine tumours nos after standard therapy or thymomas/tumours of other origin after standard therapy or meningiomas after standard therapy not suitable for surgery or radiotherapy * evidence of regional or distant metastases or localised disease not accessible for complete resection * measurable disease according to recist 1.1 * evidence of somatostatin receptor positive disease detected by 68ga-dota-tate/toc pet * progressive disease during the last 14 months based on ct or new lesions detected by 68ga-dota-tate pet. * performance status ecog 0 - 1 * life expectancy \> 6 months * age \>18 years, no upper age limit. * neutrophil count \>1,5 x 109/l * platelet count \>100 x 109/l * normal liver function regarding transaminases, pk and albumin. a raised bilirubin which can be considered an isolated effect of liver metastases is not a contraindication as long as the levels remain \<1.5 x uln. * gfr \> 50 ml/min * written informed consent from patients * evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal subjects. women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. the following age-specific requirements apply: * women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). exclusion criteria: * performance status ecog \> 1 * well differentiated gepnets grad 1 and 2 (except aggressive grade 2 tumours with a poor prognosis and a ki67 \> 15%) * loco-regional treatment during the last 3 months involving all of the measurable lesions * chemotherapy during the last 8 weeks or longer until no persisting toxicity exists. earlier treatment with mtori or tki the last 4 weeks or until no persisting toxicity exists * previous treatment with 177lu-dota-tate or cis-/carboplatin * other concomitant nephrotoxic treatment * serious heart disease (nyha iii-iv) * previous radiotherapy including \>25% of active bone marrow volume * pregnancy and lactation * extensive liver metastases combined with impaired liver function (i.e. abnormal laboratory parameters (\> grad 1 ctcae) or ascites) * symptomatic cns metastases (e.g. requiring corticosteroid treatment) symptomatic treatment for meningiomas or corticosteroids due to treatment related swelling is however allowed * ongoing treatment with interferon. this treatment should be suspended a minimum of 4 wees before treatment with 177lu-dota-tate, or longer if there is persisting signs of toxicity * patients who have a another metastatic tumor diagnosis * known or expected hypersensitivity to 177lu-dota-tate, 68ga- dota-tate/toc or any of their excipients * history of psychiatric disease/condition that may interfere with the objectives and assessments of the study * female subjects who are pregnant or breastfeeding or subjects of reproductive potential who are not willing to employ effective birth control methods (pearl index \<1) from screening to 6 months after the last dose of olaparib