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

Study Overview
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Brief Summary
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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.

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

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

Intervention / Treatment
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* Drug: 177Lu-DOTA-TATE + olaparib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-DOTA-TATE and olaparib<br> | Drug: 177Lu-DOTA-TATE + olaparib<br>* 177Lu-DOTA-TATE in four cycles in combination with escalated doses of olaparib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | To assess the number of participants with toxicity of 177Lu-DOTA-TATE in combination with olaparib measured by NCI Common Toxicity Criteria v 5.0 | up to 6 months after last treatment cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TTP | Time to progression | 3 years | 
| Response rate | Response rate (RECIST) at 3 and 12 months | 12 months after last treatment cycle | 
| OS | Overall survival | 3 years | 
| DOR | Duration of response | 3 years |