PRIMARY OBJECTIVE:
I. To evaluate the safety and to determine the recommended phase 2 dose (RP2D) of lutetium Lu
177 dotatate in combination with triapine.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To determine the overall response rate
(ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at 2, 4, 6, and 8 months
post therapy in dose escalation cohort.
III. To determine the best overall response rate (ORR) by Response Evaluation Criteria In
Solid Tumors (RECIST) 1.1 in dose expansion cohort.
IV. To measure duration of response (DOR) associated with the combination. V. To evaluate
progression-free survival (PFS), 24-month PFS, and overall survival (OS).
CORRELATIVE OBJECTIVES:
I. Measure baseline 68 gallium-dotatate (or copper 64 dotatate) biodistribution.
II. Evaluate oral triapine plasma pharmacokinetics and corresponding methemoglobin level by
venous blood gas proportion.
III. Evaluate NETest at baseline and disease progression to correlate result with clinical
outcome.
IV. Describe the tumor molecular profile using whole exome sequencing (WES), as well as
ribonucleic acid sequencing (RNAseq) by the National Clinical Laboratory Network (NCLN)
Genomics Lab, and correlate it with treatment outcome.
V. Collect plasma for circulating deoxyribonucleic acid (DNA) (ctDNA) assessment.
OUTLINE: This is a dose-escalation study of triapine.
Patients receive lutetium Lu 177 dotatate intravenously (IV) over 30-40 minutes on day 1 and
triapine orally (PO) once daily (QD) on days 1-14. Treatment repeats every 8 weeks (56 days)
for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 3 months for 24 months.
Inclusion Criteria:
- Metastatic, histologically confirmed well-differentiated neuroendocrine tumor with
positive dotatate scan (gallium-68 or copper-64) within 6 months. Lesions on dotatate
scan (gallium-68 or copper-64 dotatate scan) will be considered positive if the
maximum standard uptake value (SUVmax) is > 2 times SUV mean of normal liver
parenchyma
- Failure of at least one prior systemic cancer treatment, including somatostatin
analogs
- Patients must have progressive disease based on RECIST criteria, version 1.1 evidenced
with computed tomography (CT) scans/magnetic resonance imaging (MRI) obtained within
24 months from enrollment
- Patients must have measurable disease per RECIST 1.1
- No prior exposure to peptide receptor radionuclide therapy
- Recovered from adverse events of previously administered therapeutic agents to grade 2
or less toxicity according to Common Terminology Criteria for Adverse Events (CTCAE)
version 5.0
- Archival tissue no longer than 6 months old should be present, otherwise baseline
research biopsy is needed for WES
- Eastern Cooperative Oncology Group (ECOG) performance status 0,1, or 2 (Karnofsky >=
60%)
- Leukocytes >= 2,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 75,000/mcL
- Total bilirubin =< 3 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Glomerular filtration rate (GFR) >= 50 mL/min using Cockcroft-Gault method
- Hemoglobin >= 8.0 g/dL
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen, in the opinion of the enrolling physician, are eligible for
this trial
- Pregnancy precaution: Men and women should avoid pregnancy for seven months after the
date of their last treatment with lutetium Lu 177 dotatate. It is noteworthy that
beta-human chorionic gonadotropin (HCG) may be secreted by a small percentage of
neuroendocrine tumors (NETs), such that, in addition to being a pregnancy marker, it
also is a tumor marker. Consequently, NET female patients with positive beta-HCG at
baseline can be eligible to enter the study and receive treatment if pregnancy can be
excluded by lack of expected doubling of beta-HCG and negative pelvic ultrasound.
Normally, in pregnant subjects beta-HCG doubles every 2 days during the first 4 weeks
of pregnancy and every 3.5 days by weeks 6 to 7. Women of childbearing potential
include any female who has experienced menarche and who has not undergone successful
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral
ovariectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive months,
and for women on hormone replacement therapy, only with a documented plasma
follicle-stimulating hormone [FSH)] level > 35 mIU/mL). Even women who are using oral,
implanted, or injected contraceptive hormones, an intrauterine device (IUD), or
barrier methods (diaphragm, condoms, spermicidal) to prevent pregnancy, are practicing
abstinence or where the partner is sterile (e.g., vasectomy) should be considered to
be of childbearing potential. Postmenopausal women who have fertilized eggs implanted
are also considered to be of childbearing potential. Acceptable methods of
contraception may include total abstinence at the discretion of the Investigator in
cases where the age, career, lifestyle, or sexual orientation of the patient ensures
compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Reliable contraception (hormonal or barrier method of birth control; abstinence)
should be maintained throughout the study and for 7 months after study treatment
discontinuation. All women of childbearing potential and male partners must use a
double-barrier method of birth control or practice continuous abstinence from
heterosexual contact throughout the study and for seven months after the end of the
last treatment
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
Exclusion Criteria:
- Patients who have had major surgical procedures in the prior 6 weeks
- Patients with an inability to swallow oral medications or gastrointestinal disease
limiting absorption of oral agents
- Patients who have received prior external beam radiotherapy to more than 50% of bone
marrow, as determined by a radiation medicine physicist who will calculate the volume
of bone marrow exposure in prior radiotherapy portals divided by the volume of total
bone marrow harboring tissues. This ratio must be less than 50 percent
- Uncontrolled congestive heart failure (New York Heart Association [NYHA] III, IV)
- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to triapine or lutetium Lu 177 dotatate
- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection; symptomatic decompensated congestive heart failure; unstable
angina pectoris; cardiac arrhythmia; and known inadequately controlled hypertension
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because triapine is a ribonucleotide
reductase (RNR) inhibitor and lutetium Lu 177 dotatate is a peptide receptor
radionuclide therapy with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with triapine and lutetium Lu 177 dotatate,
breastfeeding should be discontinued if the mother is treated with triapine and
lutetium Lu 177 dotatate and for 2.5 months following the last treatment
- Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) for at
least 4 weeks prior to initiating lutetium Lu 177 dotatate. Long-acting somatostatin
analog will be allowed to continue if patient has history of carcinoid syndrome and
requires long-acting somatostatin analog for control of his/her functional syndrome
