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
Overview
- Phase
- Phase 2
- Intervention
- Lutetium Lu 177 Dotatate
- Conditions
- Metastatic Neuroendocrine Tumor
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 94
- Locations
- 45
- Primary Endpoint
- Overall response rate
- Status
- Active, not recruiting
- Last Updated
- 19 days ago
Overview
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.
Investigators
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
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
Arms & Interventions
Arm 1 (triapine, lutetium Lu 177 dotatate)
Patients receive triapine PO QD on days 1-14 of each cycle and 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.
Intervention: Lutetium Lu 177 Dotatate
Arm 1 (triapine, lutetium Lu 177 dotatate)
Patients receive triapine PO QD on days 1-14 of each cycle and 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.
Intervention: Biospecimen Collection
Arm 1 (triapine, lutetium Lu 177 dotatate)
Patients receive triapine PO QD on days 1-14 of each cycle and 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.
Intervention: Computed Tomography
Arm 1 (triapine, lutetium Lu 177 dotatate)
Patients receive triapine PO QD on days 1-14 of each cycle and 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.
Intervention: Magnetic Resonance Imaging
Arm 2 (lutetium Lu 177 dotatate)
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.
Intervention: Biospecimen Collection
Arm 2 (lutetium Lu 177 dotatate)
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.
Intervention: Computed Tomography
Arm 2 (lutetium Lu 177 dotatate)
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.
Intervention: Magnetic Resonance Imaging
Arm 2 (lutetium Lu 177 dotatate)
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.
Intervention: Lutetium Lu 177 Dotatate
Arm 1 (triapine, lutetium Lu 177 dotatate)
Patients receive triapine PO QD on days 1-14 of each cycle and 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.
Intervention: Triapine
Outcomes
Primary Outcomes
Overall response rate
Time Frame: Up to 5 years
Estimated along with exact 95% binomial confidence intervals in each arm and compared between arms using the z-test statistic.
Secondary Outcomes
- Progression free survival (PFS)(Time from the date of randomization to the date of first documented progression or death due to any cause, assessed up to 5 years)