Clinical Trial: Triapine and Lutetium Lu 177 Dotatate for Neuroendocrine Tumors
Updated 31st July 2024 to add Phase 1 results and info regarding Phase 2.
Clinical Trial: Triapine and Lutetium Lu 177 Dotatate for Neuroendocrine Tumors
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What is PRRT?
I’m guessing most of my readers know what Peptide Receptor Radiotherapy (PRRT) is. But for those new to this field, read more here
What is Triapine?
Triapine is a ribonucleotide reductase (RNR) inhibitor, I.e. it helps repair DNA. When I research this drug, I can see it is used in numerous examples of clinical trials in an anti-cancer setting alongside radiotherapy and chemotherapy, in many cancers.
Triapine in NET
There is currently a trial of Triapine with Lutathera (PRRT) (11 major US hospitals). This study was testing the hypothesis that triapine is an effective radiation sensitizer that can be safely combined with peptide receptor radionuclide therapy and can improve antitumor activity of Lutetium Lu 177 Dotatate, e.g. increase the objective response rate (ORR) above that found in standalone clinical trials, e.g. NETTER-1. A trial sponsored by Markey Cancer Center has recently completed Phase 1 and has been granted permission to progress to a randomised phase 2 study, a clear indication the Phase 1 study was successful and warranted further progression. Phase 2 has been approved and is sponsored by NIH. See below.
The Clinical Trial Document (phase 1) – NCT04234568
Phase 1 trial data
Results: Overall, 31 patients were enrolled between 6 sites, 15 in the dose escalation phase and 16 in the dose expansion phase. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. One DLT in dose level 1, seven DLTs in dose level 2, and one grade 5 DLT in dose level 3 were observed. The RP2D of the combination is triapine 150 mg QD (dose level 2) on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Detailed safety and adverse event data will be presented at the meeting. There were 28 patients evaluable for efficacy, of which 6 (21%) achieved a partial response. At 12 months, 6 patients had progressed, while 22 (86%) remained progression free. Median PFS has not been reached. PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-infwas 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent.
Conclusion: The combination of triapine and Lu-177 DOTATATE was safe with preliminary efficacy signals, which will be further evaluated in ETCTN 10558, a randomized phase 2 study that is comparing the effectiveness of triapine and Lu-177 DOTATATE to Lu-177 DOTATATE alone.
Read more by clicking here
The Clinical Trial Document (phase 2) – NCT05724108
Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium 177 DOTATATE (Lutathera) is a beta-emitting radionuclide, FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 14% ORR. Peptide receptor radionuclide therapy (PRRT) also doesn’t seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis and repair of DNA, making RNR-targeted therapy a rationale therapeutic strategy for radiosensitization. ETCTN 10388 (NCT04234568) evaluated safety and efficacy of the combination of lutetium 177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. The combination of triapine and Lu-177 DOTATATE was safe with preliminary efficacy signals.
Methods: This study is an investigator initiated, NCI sponsored, multicenter randomized phase 2 trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive neuroendocrine tumor. A total of 94 patients will be equally randomized to either Lu-177 dotatate or Triapine + Lu-177 dotatate arm. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Triapine will be administered orally from D1-14 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate overall response rate (ORR). Secondary endpoint is to evaluate median PFS. We are also evaluating triapine PK, plasma deoxyribonucleosides, circulating DNA and plasma hPG80, a novel blood based diagnostic biomarker. Clinical trial information: 05724108.
This study has 23 locations: See map.
Additional Information
The phase 1 trial also evaluated NETest, a novel blood-based test that evaluates levels of 51 neuroendocrine tumor gene transcripts. In addition, the study will correlate clinical outcome with baseline somatostatin receptor density, somatic tumor mutations and germline mutations. I could not find data on that from Phase 1.
Read more about NETest by clicking here.
The phase 2 trial is also evaluating triapine PK, plasma deoxyribonucleosides, circulating DNA and plasma hPG80, a novel blood based diagnostic biomarker.
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Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact. If you need questions, the articles here is very useful Questions to Ask About Clinical Trials | Cancer.Net
The inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan.
Whenever I post about a trial or study, some people get excited without understanding that these new treatments and capabilities can very often take years to come to fruition and it’s also possible that clinical trials can be halted, or that national approval agencies will not approve the final product. Plus, not everyone will be eligible, so always check the exclusion and inclusion criteria in the relevant clinical trials document. Please bear that in mind when reading studies/clinical trials posted on RonnyAllan.NET
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