This phase I trial studies the side effects and best dose of triapine when given together with lutetium Lu 177 dotatate in treating patients with neuroendocrine tumors. Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radioactive drugs, such as lutetium Lu 177 dotatate, may carry radiation directly to tumor cells and not harm normal cells. Giving triapine and lutetium Lu 177 dotatate together may work better to treat patients with neuroendocrine tumors.
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. Collect blood at baseline and at disease progression to correlate result with clinical outcome. (NOTE: originally this blood was collected to analyze hPG80 but will now the frozen blood samples will be biobanked for future correlative analysis) 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), and correlate it with treatment outcome. V. Collect plasma for circulating deoxyribonucleic acid (DNA) (ctDNA) assessment. VI. Assess the effect of triapine on single deoxyribonucleoside concentrations by a liquid chromatography-mass spectrometry (LC/MSMS) assay in baseline (pre-treatment) and disease progression blood samples (processed to plasma). OUTLINE: This is a dose-escalation study of triapine followed by a dose-expansion study. Patients receive lutetium Lu 177 dotatate intravenously (IV) for 30 to 40 minutes on day 1 of each cycle and triapine orally (PO) on days 1 throughout 14 of each cycle. Cycles repeat every 56 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) scan throughout the trial. Patients undergo blood specimen collection on study. Patients are followed up every 3 months for 24 months from the time of enrollment. Patients removed from study for unacceptable adverse event(s) are followed until resolution or stabilization of the adverse event.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
31
Correlative studies
Undergo CT
Given IV
Undergo MRI
Given PO
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
Mayo Clinic in Florida
Jacksonville, Florida, United States
Moffitt Cancer Center
Tampa, Florida, United States
Northwestern University
Chicago, Illinois, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
...and 1 more locations
Maximum Tolerated Dose (MTD) of Triapine and Recommended Phase 2 Dose (RP2D)
The MTD and RP2D will be estimated using isotonic regression based on observed dose limiting toxicity from all patients enrolled in the phase 1 portion and expansion cohort. All patients who received study drugs will be included in the safety analysis.
Time frame: 8 weeks (56 days)
Dose Limiting Toxicity (DLT)
DLTs will be summarized descriptively at each dose level. Will be summarized based on Common Terminology Criteria for Adverse Events version 5.0. The maximum grade of toxicity for each adverse event category of interest will be recorded for each patient and the summary results will be tabulated by category and grade. Will describe all serious (\>= grade 3) toxicity events on a patient-by-patient basis. Frequency and incidence tables of toxicity and adverse events will be generated in the overall patient group and by dose level depending on patient enrollment.
Time frame: 8 weeks (56 days)
Overall Response Rate (ORR)
ORR will be estimated along with 95% exact binomial confidence interval.
Time frame: From the start of the treatment until disease progression/recurrence, assessed up to 24 months
Progression Free Survival (PFS)
Will be estimated using the Kaplan-Meier curve and median estimates and confidence intervals will be calculated.
Time frame: Time from registration to time of progressive disease as defined by Response Evaluation Criteria in Solid Tumors 1.1 criteria or death from any cause, whichever occurs first, assessed up to 24 months
Overall Survival
Will be estimated using the Kaplan-Meier curve and median estimates and confidence intervals will be calculated.
Time frame: The time from date of enrollment to the date of death due to any cause, assessed up to 24 months
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