Phase I/II Study of Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)
Background: A neuroendocrine tumor is a rare type of tumor. It comes from body cells called neuroendocrine cells. Sometimes, these tumors develop in the gastrointestinal tract and pancreas. Researchers want to find out if a combination of drugs can shrink these tumors.
Objective: To learn if people with certain neuroendocrine tumors can take a combination of 2 drugs, Lutathera and Olaparib, without having severe side effects, and if this treatment makes the tumors shrink.
Eligibility: Adults 18 and older who have a neuroendocrine tumor in the pancreas or intestine that cannot be cured by surgery and has somatostatin receptors on the cells.
Design: Eligible participants will get Lutathera through an intravenous (IV) infusion every 8 weeks for 4 cycles. One cycle is 8 weeks. Each cycle includes a follow-up visit at week 4. For the IV, a small plastic tube is put into an arm vein. Participants will also take Olaparib by mouth twice a day for 4 weeks of each cycle. They will use a medicine diary to track the doses. During the study, participants will have physical exams. They will have blood and urine tests. They will fill out questionnaires about their general well-being and function. Their heart function will be tested. They will have scans of their chest, abdomen, and pelvis. One type of scan will use an IV infusion of a radioactive tracer. Participants will have a follow-up visit about 4 weeks after treatment ends. Then they will have follow-up visits every 12 weeks for 3 years. Then they will have yearly phone calls.
• Clinical diagnosis of GEP-NET disease, histologically consistent with neuroendocrine tumor.
• Inoperable disease (metastatic, non-candidate for surgery with curative intent, locally advanced into vessels or other critical structures, etc.)
⁃ NOTE: Presence of at least one non-irradiated index lesion (Phase II only).
• Patients on somatostatin analogue therapy (e.g., but not only limited to sandostatin or lanreotide therapy) must have initiated and been on a consistent dose of therapy for at least 3 months prior to study enrollment.
• Patients on short-term octreotide must have dose held for 24 hours without octreotide because this is necessary for study Lu-177-DOTATATE therapy.
• Age \>=18 years. Because no dosing or adverse event data are currently available on the use of Lu-177-DOTATATE in combination with olaparib in patients \<18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
• Must have presence of somatostatin receptors (SSTR) positive disease as documented by positive Ga-68-DOTATATE PET scan within 12 weeks prior to enrollment. NOTE: Positivity of Ga-68-DOTATATE PET scan is defined as having at least one RECIST 1.1 measurable lesion that has an SUV higher than or equal to liver and is qualitatively higher and distinguishable from background activity.
• Known BRCA mutation status (Cohort 3 only).
• Progressive disease by RECIST 1.1, as compared to previous anatomic imaging no more than 36 months from the date of study enrollment, with at least 1 measurable lesion by RECIST 1.1.
• ECOG Performance Status of \<=1.
• Patients must have normal organ and bone marrow function measured within 28 days prior to enrollment as defined below:
‣ Hemoglobin \>= 10.0 g/dL with no blood transfusion in the past 28 days
⁃ Absolute neutrophil count (ANC) \>= 1.5 x 10(9)/L
⁃ Platelet count \>= 100 x 10(9)/L
⁃ Total bilirubin \<= 1.5 x institutional upper limit of normal (ULN)
⁃ Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) \<= 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be \<= 5x ULN
⁃ Patients must have creatinine clearance estimated of \>= 51 mL/min using the Modification of Diet in Renal Disease (MDRD) study equation or based on a 24 hour urine test: eGFR = 175 x (SCr)\^-1.154 x (age)\^-0.203 x 0.742 \[if female\] x 1.212 \[if Black\]
• Ability to understand and willingness to sign informed consent.
• Postmenopausal or evidence of non-childbearing status. For individuals of childbearing potential (IOCBP): negative urine or serum pregnancy test within 28 days of study enrollment. Postmenopausal is defined as:
‣ Amenorrheic for 1 year (12 months in a row) or more without an alternative medical cause; if the individual received exogenous hormonal treatments, must be amenorrheic for 1 year or more following cessation of the same
⁃ Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post-menopausal range for individuals under 50
⁃ Radiation-induced oophorectomy with last menses \>1 year ago
⁃ Chemotherapy-induced menopause with \>1 year interval since last menses
⁃ Surgical sterilization for IOCBP participants (bilateral oophorectomy or hysterectomy) and/or participants with partners that can bear children.
• NOTE: An individual is not of childbearing potential if a prior history of hysterectomy with bilateral oophorectomy or other procedure has rendered the patient surgically sterile, or \>1 years since last menstruation. Must have outside endocrinologist/medical oncologist who can follow the patient for standard of care follow-ups after receiving PRRT at the NIH.
• Study drugs can have adverse effects on embryofetal survival and development. It is further not known whether olaparib or its metabolites are found in seminal fluid. For these reasons:
‣ Individuals of childbearing potential and their partners, who are sexually active, must agree to the use of 2 highly effective forms of contraception in combination (condom plus one of the methods listed below) or must totally/truly abstain from any form of sexual intercourse. This should be started from the signing of the informed consent, throughout study treatment and for at least 7 month for individuals of childbearing potential after the last dose of the study drugs.
⁃ Patients with partners that can bear children must use a condom during treatment and for 4 months after the last dose of study drugs when having sexual intercourse with a pregnant individual or with an individual of childbearing potential. Partners of patients should also use a highly effective form of contraception (see below) if they are of childbearing potential. Patients should not donate sperm throughout study treatment and for 4 months following the last dose of study drugs.
⁃ Acceptable birth control methods include:
• Total sexual abstinence i.e., refrain from any form of sexual intercourse in line with the patients usual and/or preferred lifestyle. Abstinence must be for the total duration of the study treatment and for at least 7 months (for IOCBP) or 4 months (for patients with partners of child bearing potential) after the last dose of study treatment. Periodic abstinence (e.g., calendar ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
∙ Vasectomised sexual partner PLUS condom (with participant assurance that partner received post-vasectomy confirmation of azoospermia)
∙ Tubal occlusion PLUS condom
∙ Intrauterine Device (provided coils are copper-banded) PLUS condom
∙ Mini pill PLUS condom: Progesterone-based oral contraceptive pill using desogestrel. Cerazette (Merck Sharp \& Dohme) is currently the only highly efficacious progesterone- based pill available
∙ Combined pill PLUS condom: Normal and low-dose combined oral pills
∙ Injection PLUS condom: Medroxyprogesterone injection (eg, Depo-Provera \[Pfizer\])
∙ Implants PLUS condom: Etonorgestrel-releasing implants (eg, Nexplanon \[Merck Sharp \& Dohme\])
∙ Patch PLUS condom: Norelgestromin/ethinyl estradiol transdermal system (eg, Xulane)
∙ Intravaginal device (eg, ethinyl estradiol-/etonogestrel-releasing intravaginal devices such as NuvaRing \[Merck Sharp \& Dohme\]) PLUS condom
∙ Levonorgestrel-releasing intrauterine system (eg, Mirena \[Bayer\]) PLUS condom.