Clinical trial NCT04375267: 177Lu-DOTA-TATE and Olaparib in Somatostatin Receptor Positive Tumours
Official title: Phase I Trial With 177Lu-DOTA-TATE and Olaparib in Somatostatin Receptor Positive Tumours
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Clinical Trial, Phase I
Neuroendocrine Tumors
Thymoma
Mesothelioma
Lead sponsor: Vastra Gotaland Region
Sponsor class: OTHER_GOV
Collaborators: name: Advanced Accelerator Applications
First posted: 2020-05-05
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: up to 6 months after last treatment cycle
Secondary outcomes:
measure: TTP
timeFrame: 3 years
measure: Response rate
timeFrame: 12 months after last treatment cycle
measure: OS
timeFrame: 3 years
measure: DOR
timeFrame: 3 years
Other outcomes:
Locations:
city: Gothenburg
country: Sweden
facility: Dept of Oncology
Study officials:
References:
citation: Hallqvist A, Svensson J, Hagmarker L, Marin I, Ryden T, Beauregard JM, Bernhardt P. Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale. Biomedicines. 2021 Oct 29;9(11):1570. doi: 10.3390/biomedicines9111570.