177Lu-DOTA-TATE and Olaparib in Somatostatin Receptor Positive Tumours

Phase I Trial With 177Lu-DOTA-TATE and Olaparib in Somatostatin Receptor Positive Tumours

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.

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