“We are excited to share the first clinical data from our HPN424 clinical program. Early data suggest that this novel, half-life extended T cell engager can be administered safely. Several patients remained on treatment for 24 weeks or more, which is notable in this late-stage cancer population,” said Natalie Sacks, M.D., Chief Medical Officer of Harpoon. “We will continue dose escalation, and plan to open an expansion cohort later in 2020. Our goal is to develop an effective immunotherapy treatment option for patients with prostate cancer.”
Trial Design and Interim Results from the HPN424 Phase 1 Clinical Trial
This Phase 1 trial is a multicenter, open-label study designed to evaluate the safety, tolerability, pharmacokinetics and activity of HPN424 in patients with mCRPC who are progressing at the time of enrollment and have had at least two prior systemic treatments for metastatic disease. The initial ongoing phase of the trial is dose escalation, with the goal of determining a recommended dose for the expansion phase. The escalation phase began with single patient cohorts and transitioned to a 3x3 design when Grade 2 toxicity was observed. HPN424 is being administered to patients once weekly by intravenous infusion. The primary outcome measures are an assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics. Secondary endpoints include duration of response, progression free and overall survival. Tumor assessments include PSA, CT and bone scans performed every 9 weeks.
As of the May 11, 2020cut-off date, 44 patients have been treated in 11 cohorts with doses ranging from 1.3 to 120 ng/kg. Enrolled patients had a median of 7 prior therapies, including 73% with prior chemotherapy, and a median of two prior novel hormonal agents. Median PSA level was 244, with a range of0.1-5000 ng/ml. The most frequent adverse events were chills ((all grade n= 32 (73%), grade>3 n=0 (0%)), pyrexia (all grade n=21 (48%), grade > 3 n=0 (0%)), and cytokine release syndrome (CRS) (all grade n=14 (32%), grade>3 n=3 (7%)). Cytokine-related adverse events were transient, and all patients with these adverse events were retreated successfully with HPN424. Dexamethasone premedication was instituted in cohort 4 (24 ng/kg) and has been successfully administered to mitigate cytokine-related symptoms in patients treated with higher doses in subsequent cohorts. One DLT of asymptomatic Grade 3 serum lipase elevation was observed which resolved and the patient was retreated successfully as scheduled. The most common reasons for study discontinuation were due to progressive disease (72%) and unrelated adverse events (9%).
HPN424 demonstrated dose proportional increase in Cmax and AUC with a current estimate of median T1/2 of 24.9 hours (range: 9.0 – 312 hours). Dose-dependent, transient increases in peripheral cytokine and chemokine levels were observed, including increases in interleukin 6, peaking at 5 hours post infusion and returning to baseline 24 hours post-administration. Maximal cytokine/chemokine levels attenuated with each successive dose within six weeks. Baseline circulating tumor cells (CTC) ranged from0-160 cells/ml of whole blood. Reduction in CTC was seen in 12 of 27 patients with evaluable CTC compared to baseline.
Eight of 26 patients (31%) with at least 24 weeks infollow-up remained on study beyond 24 weeks. Eight patients showed a PSA decline from baseline ranging from-4 to-76%, including patients with initial rises in PSA after study entry. Two patients had confirmed PSA partial responses with declines of 50% or greater.
Patients continue to be enrolled in the escalation phase of the trial, with a goal to identify a dose for an expansion phase planned for the second half of 2020. The expansion phase of the trial will further evaluate the safety and activity of HPN424 in patients with mCRPC. The trial is titled, “A Phase 1 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN424 in Patients with Advanced Prostate Cancer Refractory to Androgen Therapy”. For additional information about the trial, please visitwww.clinicaltrials.gov using the identifier NCT03577028.
