Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)

Description

Background:

* Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are a rare and heterogeneous, but clinically important, group of neoplasms with unique tumor biology, natural history, and clinical management issues.
* While the treatment of localized NETs is surgical resection, a variety of therapeutic options are available for patients with advanced NETs. These include medical control of excess hormone levels and associated symptoms, cytoreductive surgery for patients with advanced disease, radioembolization, chemoembolization, systemic chemotherapy, interferon, longacting somatostatin analogs, receptor-targeted radionuclide therapy, and or liver transplantation.
* Somatostatin receptors (SSTR) have been shown to be overexpressed in a number of human tumors, including neuroblastoma, prostate cancer, pheochromocytomas, paragangliomas, and NETs, among many others.
* Lu-177-DOTATATE (Lutathera) is a SSTR-agonist agent which emits ionizing radiation that causes DNA damage to its target cells through both direct and indirect mechanisms. In addition, ionizing radiation has also been shown to induce cell death through what is known as the bystander effect, a phenomenon where cellular signaling from irradiated cells towards non-irradiated cells induces cellular damage and eventually death in nearby surrounding cells.
* Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Olaparib has an established safety

profile and it is under investigation in several different cancers.

– The rationale behind using combination therapies in cancer stems from the potential of synergistic mechanisms of action of the involved agents. Olaparib is a PARP-inhibitor which blocks the repair of single-stranded DNA breaks and is especially effective when combined with other agents which induces DNA damage.

Objectives:

* Phase I:

* Characterize the safety profile and tolerability of the olaparib + Lu-177-DOTATATE combination.
* Determine the maximum tolerated dose (MTD) dose of the combination using the 3+3 dose escalation design.
* Phase II:

* Measure the Best Overall Response Rate (BOR) by RECIST 1.1 at the MTD dose at completion of 4 cycles of treatment.

Eligibility:

* Clinical diagnosis of GEP-NET disease, histologically confirmed to be consistent with neuroendocrine tumor.
* Inoperable disease (metastatic, non-candidate for surgery with curative intent, locally advanced into vessels or other critical structures, etc.).
* Age >=18 years.
* Must have presence of SSTR+ disease as documented by positive Ga-68-DOTATATE PET scan within 12 weeks prior to anticipated treatment.
* ECOG Performance Status <= 1.

Design:Design:

* Open-label, single-arm, single-center, phase I/II study evaluating the safety and efficacy of the Lu-177-DOTATATE + olaparib combination in patients with inoperable GEP-NET.
* Each cycle consists of 30 days of olaparib, one infusion of Lu-177 followed by 4 weeks off drug. There will be a total of 4 cycles for each patient, in both phase I and II.
* For the Phase I portion, Lu-177-DOTATATE will be given at the fixed, FDA-approved dose regimen of 200 mCi (7.4 GBq) IV every 8 (+/- 2) weeks for a total of 4 administrations, while olaparib will be evaluated as a radiosensitizer and be dose-escalated from a starting total dose of 100 mg PO up to total dose of 600 mg PO. Administration of olaparib will start 2 days prior to each administration of Lu-177-DOTATATE and will continue daily until 4 weeks after each administration of Lu-177-DOTATATE, and will be restarted 2 days prior to next administration of Lu-177-DOTATATE.
* For the Phase II portion, patients will receive Lu-177-DOTATATE at a fixed dose of 200 mCi (7.4 GBq) in combination with olaparib at the MTD dose as determined in Phase I.
* All patients will be contacted by phone within a week after each Lu-177-DOTATATE treatment for a toxicity assessment. They will also be seen in the NIH clinic every 4 (+/- 1) weeks.
* Approximately 30 days (+/- 1 week) after last dose of study drug, patients will be invited for a safety end of treatment (EOT) visit. After the EOT visit, patients will continue to be invited to NIH CC every 12 weeks until 3 years after the end of treatment visit. Thereafter, all participants will be contacted yearly through any NIH approved platform to assess for disease status.