Description:
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....
Title
- Brief Title: Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)
- Official Title: Phase I/II Study of Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)
Clinical Trial IDs
- ORG STUDY ID:
190138
- SECONDARY ID:
19-C-0138
- NCT ID:
NCT04086485
Conditions
- Gastroenteropancreatico Tumors
- Neuroendocrine Tumors
- Neuroendocrine Neoplasms
Interventions
Drug | Synonyms | Arms |
---|
Lu-177-DOTATATE | | 1/Lu-177-DOTATATE + Olaparib escalation |
Olaparib | | 1/Lu-177-DOTATATE + Olaparib escalation |
Purpose
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....
Detailed 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 1:
- 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 2:
- 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 1/2 study evaluating the safety and
efficacy of the Lu-177-DOTATATE + olaparib combination in patients with inoperable
GEP-NET
- For phase 1, a standard 3+3 design will be used to determine MTD. It is estimated that
approximately 15 to 24 patients will be required. Phase 2 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 1 and 15 patients to phase 2 including the 6 phase 1
patients at MTD, with a total accrual ceiling of 37 patients to allow for a small number
of inevaluable patients
Trial Arms
Name | Type | Description | Interventions |
---|
1/Lu-177-DOTATATE + Olaparib escalation | Experimental | Lu-177-DOTATATE and escalating doses of olaparib to determine the maximum-tolerated dose (MTD) | |
2/Lu-177-DOTATATE + Olaparib fixed dose | Experimental | Lu-177-DOTATATE and olaparib at the MTD | |
Eligibility Criteria
- 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)) <=
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 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 month 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 month (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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Phase 1: Maximum Tolerated Dose |
Time Frame: | End of cycle 1 |
Safety Issue: | |
Description: | Depending on what the speed of dose escalation and the final MTD dose, it is estimated that for 4 dose levels with up to 6 patients at each level, approximately 12 to 24 patients will be required for the phase I portion of the study. Standard 3+3 design will be used. |
Secondary Outcome Measures
Measure: | Phase 2: PFS and OS |
Time Frame: | Death |
Safety Issue: | |
Description: | Kaplan-Meier curves of PFS and OS will be constructed. Median PFS and OS will be reported with 95% confidence intervals. |
Measure: | Phase 1: BOR and PFS |
Time Frame: | Disease progression |
Safety Issue: | |
Description: | -Preliminary information on the BOR will be presented as a percentage with 95% confidence intervals. Only evaluate patients will be included.-Kaplan-Meier curves of PFS will be constructed. Median PFS will be reported with 95% confidence intervals. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Carcinoids
- Somatostatin Receptors
- Ionizing Radiation
Last Updated
September 1, 2021