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.
Primary:
To evaluate the overall response rate (ORR) by RECIST 1.1 of combination triapine + Lutetium Lu 177 Dotatate and standard of care Lutetium Lu 177 Dotatate alone.
Secondary:
To evaluate progression-free survival (PFS) in study and control arm.
Exploratory:
- To evaluate plasma hPG80 as a biomarker of treatment response.
- To evaluate plasma deoxyribonucleosides as a biomarker of triapine resistance.
- Collect plasma for circulating DNA (ctDNA) assessment.
Prostate
Small Intestine
TRIAPINE
- Rutgers Cancer Institute of New Jersey
- Principal Investigator
- Matthew Deek
- Principal Investigator
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
volume 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 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
- Serum creatinine =< 1.5 x 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
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.