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

• ClinicalTrials.gov Identifier: NCT04234568
• Recruitment Status: Active, not recruiting
• First Posted: January 21, 2020
• Last Update Posted: March 8, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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:

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) 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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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).

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

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)

Investigators

• Principal Investigator: Susanne M Arnold; Ohio State University Comprehensive Cancer Center LAO

More Information

• 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) ); NCI-CIRB-10388-PMC; 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
• 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Lutetium Lu 177 dotatate; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals