Investigators are evaluating the combination of telotristat ethyl and Lutathera with a goal to improve progression-free survival in patients with well-differentiated neuroendocrine tumors in a randomized, phase 2 study that was highlighted during the 2020 NANETs Virtual Symposium.
Investigators are evaluating the combination of telotristat ethyl (Xermelo) and Lutathera (lutetium Lu 177 dotatate) with a goal to improve progression-free survival (PFS) in patients with well-differentiated neuroendocrine tumors (NETs) in a randomized, phase 2 study that was highlighted during the 2020 NANETs Virtual Symposium.1
The trial (NCT04543955), which is expected to open for accrual in October 2020, will compare 2 different dose levels of telotristat ethyl in combination with Lutathera in this patient population.
“The reason why we wanted to conduct this study is that we believe that blocking serotonin would have a cytostatic effect and would result in improved outcomes in NET patients,” lead study author Aman Chauhan, MD, an assistant professor at the University of Kentucky, said in an interview with OncLive. “This trial will help us find out whether this combination makes sense—if we [will see] some improved efficacy signal. We can also prospectively look into the safety profile of the combination, and thirdly, it will help us figure out which dose to go forward with in terms of a more definite phase 3 trial. This is a very crucial trial to help answer these critical questions.”
Telotristat ethyl is a tryptophan hydroxylase (TPH) inhibitor; TPH is a rate-limiting enzyme in serotonin biosynthesis. The agent has been approved by the FDA since February 2017 for use in combination with a somatostatin analog (SSA) as a treatment for carcinoid syndrome diarrhea in patients with metastatic NETs that cannot be adequately controlled by SSA therapy alone.
The approval was based on findings from the phase 3 TELESTAR trial, in which, after 12 weeks of follow-up, the average daily bowel movements were reduced by 29% and 35% with 250- mg and 500-mg doses of telotristat ethyl, respectively.2 At week 12, significant reductions in u5-HIAA from baseline were reported; the Hodges–Lehmann estimators of median treatment differences with placebo of −54.0% (95% confidence limits, −85.0% to −25.1%, P < .001) and −89.7% (95% confidence limits, −113.1% to −63.9%, P < .001) for telotristat ethyl 250 mg and 500 mg.
Moreover, serotonin has been shown to stimulate proliferation in typical (NCI-H727), atypical (NCI-H720), bronchopulmonary NET, small intestinal NET (KRJ-I), and human pancreatic carcinoid (BON) cell lines. This stimulation, investigators added in the poster that was presented during the conference, can be performed in an autocrine fashion.
Lutathera was approved by the FDA in January 2018 for the treatment of patients with somatostatin receptor—positive GEP-NETs. The approval was based on the phase 3 NETTER-1 trial, which compared Lutathera with high-dose octreotide long-acting release for patients with grade 1/2 metastatic midgut NETs. In initial findings of the trial, there was a 79% reduction in the risk of progression or death with Lutathera versus octreotide.3
In updated findings of the NETTER-1 study, which were presented during the 2018 ESMO Congress, results showed that the median PFS in the Lutathera arm was 28.35 months versus 11.04 months in those with low liver tumor burden (LTB; HR, 0.218, 95% CI 0.120-0.394), not reached (NR) compared with 8.67 months in moderate LTB (HR, 0.202; 95% CI 0.077-0.525). and 19.38 months versus 5.52 months in high LTB (HR, 0.193; 95% CI 0.079-0.474; respectively).4
Regarding the rationale for the randomized phase 2 study, investigators hypothesized that inhibition of serotonin production will lead to a cytostatic effect on NETs but will also complement the clinical activity of Lutathera.
Additionally presented from the 2020 NANETS Virtual Symposium were retrospective results of a safety analysis of 24 patients with NETs who received concomitant telotristat ethyl and peptide receptor radionuclide therapy, of which Lutathera is a type, which suggested that the safety profile of the combination was consistent with the known toxicity profiles of each approved agent alone.5
In the investigator-initiated, single-center, open-label, randomized, parallel-arm, phase 2 trial, investigators are exploring oral telotristat ethyl at 250 mg 3 times daily or 500 mg orally 3 times daily in combination with Lutathera intravenously in 70 patients with well-differentiated NETs.
All patients will receive Lutathera for 8 weeks. In both arms, telotristat will be administered until disease progression. On day 1 of each cycle, telotristat and Lutathera will be given together.
To be eligible for enrollment, patients must have metastatic or unresectable well-differentiated grade 1/2 NETs with a positive Gallium-68 Dotatate scan within 6 months prior to study enrollment, a baseline CT scan or MRI with measurable progressive disease via RECIST v1.1 criteria, failure on at least 1 prior systemic therapy for their cancer, have recovered from adverse effects of prior therapy that were of grade 2 or lower, have an ECOG performance status of 0 to 2, and normal organ and marrow function.
Those who previously received Lutathera, a history of allergic reactions related to similar chemical or biologic compounds of telotristat or Lutathera, have unstable angina or myocardial infarction, NYHA class 3/4 heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia, or grade 3 conduction system abnormalities, were excluded from enrollment.
The primary end point is 20-month PFS rate and noninferiority compared with historical control from the NETTER-1 trial. Secondary end points include objective response rate (ORR) by RECIST v1.1 criteria at 6 and 12 months, safety, median PFS, and quality of life as measured by the QLQ-C30 and QLQ-GI.NET21.