Phase I/II Study of Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)

  • STATUS
    Recruiting
  • End date
    Jan 1, 2026
  • participants needed
    37
  • sponsor
    National Cancer Institute (NCI)
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Updated on 28 October 2022
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Summary

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

Participants will be screened under protocol 01-C-0129. They may have a tumor biopsy.

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....

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
  • 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.
  • For phase I, a standard 3+3 design will be used to determine MTD. It is estimated that approximately 15 to 24 patients will be required. Phase II will involve the use of a Simon optimal two-stage design to determine sample size and interim stopping rule.
  • Assuming a combination of inevaluable patients or loss-to-follow-up of 10%, up to 24 patients will be accrued to phase I and 15 patients to phase II including the 6 phase I patients at MTD, with a total accrual ceiling of 37 patients to allow for a small number of inevaluable patients.

Details
Condition Gastroenteropancreatico Tumors, Neuroendocrine Tumors, Neuroendocrine Neoplasms
Treatment olaparib, Lu-177-DOTATATE, Ga dotatate scanning, FDG-PET scanning, Amino Acid infusion, Amino Acid infusion
Clinical Study IdentifierNCT04086485
SponsorNational Cancer Institute (NCI)
Last Modified on28 October 2022

Eligibility

 Yes No Not Sure

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
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
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)) <=
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 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 (bilateral oophorectomy or hysterectomy)
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
Pre-clinical data indicate that the 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 their participation in the study 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 the
period of taking olaparib and for 4 months following the last dose of the 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 PLUS male condom. Provided coils are copperbanded
Etonogestrel implants (e.g., Implanon , Norplant ) PLUS male condom
Normal and low dose combined oral pills PLUS male condom
Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom
Intrauterine system device (e.g., levonorgestrel-releasing intrauterine
system -Mirena(R)) PLUS male condom
Norelgestromin/ethinyl estradiol transdermal system PLUS male condom
Intravaginal device (e.g., ethinyl estradiol and etonogestrel) PLUS male
condom
Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only
highly efficacious progesterone based pill

Exclusion Criteria

Patients who have any GEP-NET lesions that are negative by Ga-68-DOTATATE-PET imaging
but positive by FDG-PET imaging
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
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