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Testing the Addition of an Anti-cancer Drug, Triapine, to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Neuroendocrine Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04234568
Recruitment Status : Active, not recruiting
First Posted : January 21, 2020
Last Update Posted : March 8, 2023
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Digestive System Neuroendocrine Neoplasm Metastatic Neuroendocrine Tumor Procedure: Biospecimen Collection Procedure: Computed Tomography Drug: Lutetium Lu 177 Dotatate Procedure: Magnetic Resonance Imaging Drug: Triapine Phase 1

Detailed Description:


I. To evaluate the safety and to determine the recommended phase 2 dose (RP2D) of lutetium Lu 177 dotatate in combination with triapine.


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).


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) and triapine orally (PO) on study. Patients undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) scan throughout the trial. Patients undergo blood specimen collection on study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Triapine and Lutetium Lu 177 Dotatate in Combination for Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
Actual Study Start Date : June 29, 2020
Estimated Primary Completion Date : January 15, 2024
Estimated Study Completion Date : January 15, 2024

Arm Intervention/treatment
Experimental: Treatment (lutetium Lu 177 dotatate, triapine)
Patients receive lutetium Lu 177 dotatate IV and triapine PO on study. Patients undergo CT scan or MRI scan throughout the trial. Patients undergo blood specimen collection on study.
Procedure: Biospecimen Collection
Correlative studies
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Drug: Lutetium Lu 177 Dotatate
Given IV
Other Names:
  • 177 Lu-DOTA-TATE
  • 177 Lu-DOTA-Tyr3-Octreotate
  • 177Lu-DOTA0-Tyr3-Octreotate
  • Lutathera
  • Lutetium Lu 177 DOTA(0)-Tyr(3)-Octreotate
  • Lutetium Lu 177-DOTA-Tyr3-Octreotate
  • lutetium Lu 177-DOTATATE
  • Lutetium Oxodotreotide Lu-177

Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

Drug: Triapine
Given PO
Other Names:
  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • 3-AP
  • 3-Apct
  • OCX-0191
  • OCX-191
  • OCX191
  • PAN-811

Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of triapine and recommended phase 2 dose (RP2D) [ Time Frame: 8 weeks (56 days) ]
    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.

  2. Dose limiting toxicity (DLT) [ Time Frame: 8 weeks (56 days) ]
    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.

Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: From the start of the treatment until disease progression/recurrence, assessed up to 24 months ]
    ORR will be estimated along with 95% exact binomial confidence interval.

  2. Progression free survival (PFS) [ 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 ]
    Will be estimated using the Kaplan-Meier curve and median estimates and confidence intervals will be calculated.

  3. Overall survival [ Time Frame: The time from date of enrollment to the date of death due to any cause, assessed up to 24 months ]
    Will be estimated using the Kaplan-Meier curve and median estimates and confidence intervals will be calculated.

Other Outcome Measures:
  1. Expression of somatostatin receptors [ Time Frame: Up to 24 months ]
    Will be summarized using descriptive statistics and changes from baseline versus follow-up time points will be assessed using paired test methodologies.

  2. Whole exome sequencing [ Time Frame: Up to 24 months ]
    Will be processed using the data processing and data analysis pipelines from the Biostatistics and Bioinformatics shared resource of Markey Cancer Center to identify candidate mutated genes with adjustment for false discovery rate.

  3. Pharmacokinetic (PK) studies [ Time Frame: Up to 24 months ]
    PK parameters will be estimated from patients enrolled in the dose escalation portion of the phase 1 trial. PK parameters will be compared with historical controls, and exploratorily, we may correlate exposure to toxicity, and incorporate data into a population PK model.

  4. Krenning score from the gallium 68 dotatate [ Time Frame: Up to 24 months ]
    Will be summarized by calculating the proportion of patients in each Krenning score category and exploratory assessments for association with clinical response (ORR) will be performed using Fisher's exact test. Median, interquartile range will be calculated for quantitative image measurements from gallium 68 dotatate and exploratory comparison of levels with clinical response (ORR) will be performed using two sample t-test or nonparametric analogs. Correlative endpoint analyses will be based on patients who received the recommended phase 2 dose from the dose escalation portion and expansion cohort.

  5. Change in deoxyribonucleoside concentrations [ Time Frame: Baseline up to 24 months ]
    Will be assessed by paired t-test or other methods. Deoxynucleoside plasma concentration as a predictor of clinical outcomes will explored by linear (progression free survival) and logistic regression (response).

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 CT scans/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 1 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
  • Age >= 18 years. Because no dosing or adverse event data are currently available on the use of triapine in combination with lutetium Lu 177 dotatate in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
  • 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 (> 5 mIU/mL) 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04234568

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United States, Arizona
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, United States, 85054
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Kentucky
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States, 40536
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic in Rochester
Rochester, Minnesota, United States, 55905
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States, 15232
United States, Utah
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Susanne M Arnold Ohio State University Comprehensive Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04234568    
Other Study ID Numbers: NCI-2020-00170
NCI-2020-00170 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10388 ( Other Identifier: Ohio State University Comprehensive Cancer Center LAO )
10388 ( Other Identifier: CTEP )
UM1CA186712 ( U.S. NIH Grant/Contract )
First Posted: January 21, 2020    Key Record Dates
Last Update Posted: March 8, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Lutetium Lu 177 dotatate
Molecular Mechanisms of Pharmacological Action