Clinical trial NCT05724108: Testing the Effectiveness of an Anti-cancer Drug, Triapine, When Used With Targeted Radiation-based Treatment (Lutetium Lu 177 Dotatate), Compared to Lutetium Lu 177 Dotatate Alone for Metastatic Neuroendocrine Tumors
Official title: A Phase II Randomized Control Trial of Triapine Plus Lutetium Lu 177 Dotatate Versus Lutetium Lu 177 Dotatate Alone for Well-Differentiated Somatostatin Receptor-Positive Neuroendocrine Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Metastatic Neuroendocrine Tumor
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2023-02-13
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase II trial compares the effect of adding triapine to lutetium Lu 177 dotatate versus lutetium Lu 177 dotatate alone (standard therapy) in shrinking tumors or slowing tumor growth in patients with neuroendocrine tumors that have spread from where they first started (primary site) to other places in the body (metastatic). Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for deoxyribonucleic acid synthesis and cell growth. Lutetium Lu 177 dotatate is a radioactive drug. It binds to a protein called somatostatin receptor, which is found on some neuroendocrine tumor cells. Lutetium Lu 177 dotatate builds up in these cells and gives off radiation that may kill them. It is a type of radioconjugate and a type of somatostatin analog. Giving triapine in combination with lutetium Lu 177 dotatate may be more effective at shrinking tumors or slowing tumor growth in patients with metastatic neuroendocrine tumors than the standard therapy of lutetium Lu 177 dotatate alone.

Detailed description: PRIMARY OBJECTIVE:

I. Evaluate the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of combination triapine + lutetium Lu 177 dotatate (treatment arm 1) versus standard of care lutetium Lu 177 dotatate alone (treatment arm 2).

SECONDARY OBJECTIVE:

I. Evaluate progression-free survival (PFS) between the two treatment arms (combination arm 1 versus standard of care arm 2).

EXPLORATORY OBJECTIVES:

I. Evaluate plasma hPG80 as a biomarker of treatment response. II. Evaluate plasma deoxyribonucleosides as a biomarker of triapine resistance. III. Collect plasma for circulating deoxyribonucleic acid (DNA) (ctDNA) assessment.

IV. Evaluate triapine plasma pharmacokinetics (PK) in the combination arm (treatment arm 1 only).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive triapine orally (PO) once daily (QD) on days 1-14 of each cycle and lutetium Lu 177 dotatate intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 8 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) and collection of blood samples throughout the trial.

ARM 2: Patients receive lutetium Lu 177 dotatate IV over 30 minutes on day 1 of each cycle. Cycles repeat every 8 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up at 8 and 12 months, then every 6 months for 2 years.

Eligibility criteria: Inclusion Criteria:

* Patients must have metastatic, histologically confirmed well-differentiated neuroendocrine tumor with positive gallium 68 DOTATATE or copper 64 DOTATATE scan. Lesions on dotatate scan will be considered positive if the standardized uptake value maximum (SUVmax) of target lesion is \> 2 times standardized uptake value (SUV) mean of normal liver parenchyma. Patients with lung neuroendocrine tumors (NETs) are excluded from the trial
* 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
* Failure of at least one prior systemic cancer treatment with somatostatin analogs
* No prior exposure to peptide receptor radionuclide therapy
* Recovered from adverse events of previously administered therapeutic agents (i.e., to grade 2 or less toxicity) according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0
* 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
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* Absolute neutrophil count \>= 1,500/mcL
* Platelets \>= 100,000/mcL
* Total bilirubin =\< 1.5 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
* Serum creatinine =\< 1.5 institutional ULN. Creatinine \> 1.5 ULN will require a measured creatinine clearance (CrCl) \> 50 ml/min to qualify
* Hemoglobin \> 5.0 mmol/L (\> 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 and off steroids are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for at least 4 weeks prior to enrollment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to enrollment in the study
* 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 are eligible for this trial
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
* 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 (beta-HCG) may be secreted by a small percentage of 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 men and 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

Exclusion Criteria:

* Patients who have not recovered from adverse events of previously administered therapeutic agents (i.e., have residual toxicities \> grade 2) according to CTCAE 5.0, 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
* Uncontrolled congestive heart failure (New York Heart Association \[NYHA\] III, IV)
* 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
* Inability to swallow oral medications or gastrointestinal disease limiting absorption of oral agents
* Patients with any other significant condition, currently uncontrolled by treatment, which may interfere with completion of the study

Primary outcomes:
measure: Overall response rate
timeFrame: Up to 5 years
Secondary outcomes:
measure: Progression free survival (PFS)
timeFrame: Time from the date of randomization to the date of first documented progression or death due to any cause, assessed up to 5 years
Other outcomes:
measure: Plasma hPG80
timeFrame: Up to 5 years
measure: Plasma deoxyribonucleosides
timeFrame: Pre- to post-triapine administration
measure: Circulating deoxyribonucleic acid (ctDNA)
timeFrame: Up to 5 years
measure: Triapine plasma pharmacokinetics (PK): Maximum concentration
timeFrame: Up to 5 years
measure: Triapine plasma PK: Area under the concentration-time curve
timeFrame: Up to 5 years
measure: Triapine plasma PK: Half-life
timeFrame: Up to 5 years
measure: Triapine plasma PK: Apparent clearance
timeFrame: Up to 5 years
measure: Triapine plasma PK: Apparent volume of distribution
timeFrame: Up to 5 years
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Irvine
country: United States
facility: UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Aventura
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Aventura
state: Florida
city: Coral Gables
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Coral Gables
state: Florida
city: Deerfield Beach
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Deerfield Beach
state: Florida
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Miami
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Kendall
state: Florida
city: Plantation
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Plantation
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: NYP/Weill Cornell Medical Center
state: New York
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center LAO
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Conroe
country: United States
facility: MD Anderson in The Woodlands
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson West Houston
state: Texas
city: League City
country: United States
facility: MD Anderson League City
state: Texas
city: Sugar Land
country: United States
facility: MD Anderson in Sugar Land
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
Study officials:
affiliation: Ohio State University Comprehensive Cancer Center LAO
name: Lowell B Anthony
role: PRINCIPAL_INVESTIGATOR
References: