Clinical Trial, Phase I, Mesothelioma, Neuroendocrine Tumors, Thymoma
Conditions
Brief 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.
Interventions
DRUG177Lu-DOTA-TATE + olaparib
177Lu-DOTA-TATE in four cycles in combination with escalated doses of olaparib
Sponsors
Vastra Gotaland Region
Advanced Accelerator Applications
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | up to 6 months after last treatment cycle | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TTP | 3 years | Time to progression |
| Response rate | 12 months after last treatment cycle | Response rate (RECIST) at 3 and 12 months |
| OS | 3 years | Overall survival |
| DOR | 3 years | Duration of response |
Countries
Sweden
Outcome results
None listed