- -
INCLUSION CRITERIA:
- 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.
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.
- - 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 women of childbearing
potential: 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 woman 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 women under 50.
- - Radiation-induced oophorectomy with last menses >1 year ago.
- - Chemotherapy-induced menopause with >1 year interval since last menses.
- - Surgical sterilization for female participants (bilateral oophorectomy or
hysterectomy) and/or male participants.
- - NOTE: A female 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:
- - Women of childbearing potential and their partners, who are sexually active, must
agree to the use of 2 highly effective forms of contraception in combination
(male 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 months for
women of childbearing potential after the last dose of the study drugs.
- - Male patients must use a condom during treatment and for 4 months after the last
dose of study drugs when having sexual intercourse with a pregnant woman or with
a woman of childbearing potential.
Female partners of male patients should also
use a highly effective form of contraception (see below) if they are of
childbearing potential. Male patients should not donate sperm throughout study
treamement 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
female patients) or 4 months (for male patients) 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 male condom (with participant assurance
that partner received post-vasectomy confirmation of azoospermia)
- Tubal occlusion PLUS male condom.
- - Intrauterine Device (provided coils are copper-banded) PLUS male condom.
- - Mini pill PLUS male 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 male condom: Normal and low-dose combined oral pills.
- - Injection PLUS male condom: Medroxyprogesterone injection (eg, Depo-Provera
[Pfizer])
- Implants PLUS male condom: Etonorgestrel-releasing implants (eg, Nexplanon
[Merck Sharp & Dohme])
- Patch PLUS male condom: Norelgestromin/ethinyl estradiol transdermal system
(eg, Xulane)
- Intravaginal device (eg, ethinyl estradiol-/etonogestrel-releasing
intravaginal devices such as NuvaRing [Merck Sharp & Dohme]) PLUS male
condom.
- - Levonorgestrel-releasing intrauterine system (eg, Mirena [Bayer]) PLUS male
condom.
EXCLUSION CRITERIA:
- - Patients who have any GEP-NET lesions that are negative by Ga-68-DOTATATE-PET imaging
but positive by FDG-PET imaging, unless they have progressed on at least one other
line of prior systemic treatment (such as chemotherapy or tyrosine kinase inhibitor)
and the majority of their tumor lesions are Ga-68-DOTATATE-avid.
- - Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with study drugs, breastfeeding should be
discontinued if the mother is treated with study drugs.
- - Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in
situ of the uterine cervix, unless definitively treated and proven no evidence of
recurrence for 5 years.
- - Patients who are receiving any other investigational agents.
- - Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 4 weeks prior to study enrollment.
- - Patients with persistent toxicities (>= CTCAE grade 2) with the exception of alopecia,
caused by previous cancer therapy and toxicities deemed irreversible/stable expected
to interfere with study drug administration in the opinion of the Principal
Investigator.
- - Patient s weight exceeding PET table tolerance (> 400 lbs).
- - Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
hypertension (>180/110), arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.
- - Patients with symptomatic, uncontrolled brain metastases.
NOTE: Patients with
previously treated brain metastases are eligible if asymptomatic and may be on a
stable dose of corticosteroids as long as these were started at least 4 weeks prior to
treatment.
- - Patients with spinal cord compression unless considered to have received definitive
treatment for this and evidence of clinically stable disease by imaging and clinical
assessment as assessed by the treating investigator for 28 days before enrollment.
- - Concomitant use of known strong or moderate CYP3A inhibitors within 2 weeks before
enrollment.
- - Concomitant use of known strong or moderate CYP3A inducers within 5 weeks (for
enzalutamide or phenobarbital) and 3 weeks for other agents before enrollment.
- - Patients that have had major surgery within 4 weeks prior to study enrollment and have
not recovered from any effects of any major surgery.
- - Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
- - Previous allogeneic hematopoietic stem cell transplant, allogeneic bone marrow
transplant or double umbilical cord blood transplant (duCBT).
- - Patients with a known hypersensitivity to olaparib or Lutathera or any excipients of
these products.
- - Resting ECG indicating uncontrolled cardiac conditions, as judged by the investigator
(e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart
failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with
congenital long QT syndrome.
- - Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of MDS/AML.
- - Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV).
HIV-positive patients on combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with study drugs. In addition, these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy. Appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when
indicated.
- - Patients with known active hepatitis (i.e., Hepatitis B or C).
- - Any previous treatment with PARP inhibitor, including olaparib and/or any previous
treatment with any systemic radionuclide agents.
- - Involvement in the planning and/or conduct of the study.
- - Previous treatment with Lu-177-DOTATATE.
