On September 30, 2019 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company discovering and developing a new class of potent and selective precision oncology medicines for the treatment of patients with a wide range of solid tumor malignancies, reported the presentation of Phase 1 data from an ongoing Phase 1/2a study of PEN-866 at the at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019 (Press release, Tarveda Therapeutics, SEP 30, 2019, View Source [SID1234539951]). The results presented, which are based on a data cutoff date of July 10, 2019, show that PEN-866 was well tolerated and demonstrated preliminary evidence of anti-tumor activity. Three patients remained on study at the time of data cutoff.
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"Results of the Phase 1 study in heavily treated, advanced patients show that overall PEN-866 was well tolerated with encouraging, early signs of anti-tumor activity," said Dr. Jeffrey D. Bloss, Chief Medical Officer of Tarveda. "Based on these results, we have progressed to an expansion cohort to determine the recommended Phase 2 dose. We are excited about the profile of PEN-866 for its development in solid tumors where new, effective treatments are truly needed. Further, the attributes of PEN-866 are indicative of the opportunity we have with our HSP90 binding miniature drug conjugate platform to enable a wide range of compelling, anti-cancer payloads that are promising but require enhanced penetration, accumulation and residence time in tumor to be effective."
PEN-866 is a small molecule miniature drug conjugate linked to a potent topoisomerase 1 inhibitor (SN-38) payload which targets and binds to Heat Shock Protein 90 (HSP90). HSP90 is activated and upregulated in tumor cells compared to normal tissue allowing the HSP90 miniature drug conjugate to accumulate and be retained in tumor cells. The HSP90 miniature drug conjugate is designed with a slowly cleaving linker resulting in a sustained release of SN-38 in tumor. The Phase 1 study established a MTD and assessed the safety, tolerability, pharmacokinetics and efficacy of PEN-866.
"Investigating new treatment options for patients who are not responding to standard therapies is central to our research efforts," said Johanna Bendell, M.D., Chief Development Officer and Director of the Drug Development Unit at Sarah Cannon Research Institute in Nashville, Tenn. "With PEN-866’s innovative approach to targeting solid tumors, we observed promising early results with stable disease after treatment for some of the participants and a partial response for one additional participant. These preliminary results support the further investigation of PEN-866 for patients living with these difficult-to-treat cancers."
Phase 1 Trial Design
Patients were enrolled in seven dose escalating cohorts of two to six patients with advanced solid tumor malignancies, the most common of which were pancreatic and colon tumor types. Patients received PEN-866 weekly for three of four weeks in a 28-day cycle, and in cohorts 1-5, patients were initially treated with flat dosing. Cohorts 6 and 7 were switched to body surface area dosing based on emerging data indicating variable exposure.
Safety Data
Results of the study show that PEN-866 was well tolerated with no dose limiting toxicities (DLTs) in the first four cohorts (30-240 mg). One DLT was observed in cohort 5 (360 mg) and was resolved with dose reduction. 2 DLTs were observed in cohort 7 (200 mg/m2). One fatal event of dehydration occurred 11 days following the last dose of PEN-866. The most frequent adverse events observed were nausea, fatigue, diarrhea, vomiting, and alopecia and the most common Grade 3 adverse event was neutropenia. The maximum tolerated dose for PEN-866 monotherapy was determined to be 175 mg/m2.
Efficacy Data
There was preliminary evidence of antitumor activity observed in the trial. One patient (5.9%) of 17 evaluable patients per RECIST v1.1, achieved partial response and remains on therapy. Five patients of the 17 patients (29.4%) experienced stable disease (SD). Of the patients who experienced stable disease:
Two patients with pancreatic cancer had prolonged SD (~4 and 5 months, respectively).
One patient with liposarcoma had prolonged SD (>12 months).
One patient with acinar cell cancer of the pancreas remained on therapy after 6 months with SD.
About PEN-866
PEN-866 is a small molecule miniature drug conjugate that selectively binds to the activated form of the intracellular target Heat Shock Protein 90 (HSP90) linked to a topoisomerase 1 inhibitor (SN-38), a potent anti-cancer payload. HSP90 is activated and upregulated in tumor cells compared to normal tissue allowing the HSP90 miniature drug conjugate to accumulate and be retained in tumor cells. The HSP90 miniature drug conjugate is designed with a slowly cleaving linker resulting in a sustained release of SN-38 in tumor which has been shown to cause prolonged DNA damage and tumor regressions in multiple patient-derived and other xenograft tumor models. PEN-866 is in a Phase 1/2a trial and the first miniature drug conjugate from Tarveda’s HSP90 binding conjugate platform.