CHICAGO—Phase I of dose escalation trial PT2385 for patients with advanced renal cell carcinoma was examined at the 2016 American Society of Clinical Oncology Annual Meeting in Chicago during a presentation by Kevin Dale Courtney, MD, PhD, Assistant Professor, UT Southwestern Medical Center and a member of the Harold C. Simmons Comprehensive Cancer Center, Dallas. Courtney shared his findings that the first-in-class oral HIF2-α inhibitor is well-tolerated and offers reduction in disease burden after 6 weeks.
The primary objective of the trial was to prove that continuous PT2385 oral use was safe, demonstrate early evidence of clinical activity in heavily pre-treated patients with advanced ccRCC, and establish an effective dose level.
What Is PT2385?
In the vast majority of renal cell carcinoma cases, inactivation of the von Hippel-Lindau (VHL) tumor suppressor occurs. The resulting VHL deficiency stabilizes the transcription factor hypoxia-inducible factor (HIF)-2α, an oncogenic driver of ccRCC. Enter the oral PT2385 tablet, a selective small molecule inhibitor of HIF-2α that disrupts the heterodimerization of HIF-2α with HIF-1b and blocks the transcription of several genes involved in oncogenesis.
This oral inhibitor had already demonstrated anti-tumor efficacy in mouse models. “The toxicity evaluation in large animals in pre-clinical data showed it was well-tolerated and validated a reduction in the HIF-2 alpha target,” noted Courtney.
Patients with advanced renal cell carcinoma who had already undergone at least one prior therapy with a VEGF inhibitor took PT2385 twice daily in a 3 + 3 Phase I design. Plasma PK was measured on days 1 and 15 and PD, primarily erythropoietin (EPO), a downstream gene regulated by HIF-2α weekly.
In each cohort, 3-6 patients ingested PT2385 at a single dose level twice daily, starting at 100 mg. The team increased dose levels at 100 percent until the first patient reported a grade 2 or higher side effect, at which point the dose levels increased by no more than 50 percent. The aim was finding a dose level for phase II investigation. Patients experienced 3 weeks of treatment before enrolling at the next dose level.
Frequent monitoring included physical examinations, vital sign measurements, electrocardiograms, hematology and chemistry laboratory studies, and recording all adverse events. Blood samples were gathered at week 1, 2, 4, 5, 6, 7, 10, 13, and 16 appointments. Anti-tumor activity was studied by CT and MRI at baseline, week 6, and every subsequent 9-week appointment interval.
According to Courtney, the majority of this clinical trial's patients were male and the median number of prior therapies was four. Per study criteria, eligible patients were required to have progressed with at least one prior therapeutic regimen including a VEGF inhibitor, a life expectancy of 3 months or longer, ECOG performance status of 0-1, and adequate organ function.
Eligible bone marrow status was defined as those with absolute neutrophil count (ANC) >= 1.5 x 109/L; hemoglobin level >= 9 g/dL without transfusion support within 2 weeks prior to enrollment; platelet count>= 100,000/μL. Hepatic conditions for participation were limited to those with transaminase levels (aspartate aminotransferase (AST)/alanine aminotransferase (ALT)) <= 2.5 x upper limit of normal (ULN) (<= 5 x ULN if liver metastases present); total bilirubin (TBILI) <= 2.0 mg/dL in the absence of Gilbert's disease. Renal serum creatinine level had to be less than 2 x ULN or calculated creatinine clearance (CrCL) >= 50 mL/min (Cockcroft-Gault formula). Prothrombin time/activated partial prothrombin time (PT/aPTT) was limited to <= 1.2 x ULN.
Prospective female participants were required to produce a negative serum pregnancy test result within the past 7 days. If not post-menopausal, females had to be surgically sterile or consent to physician-approved birth control throughout the study duration and for 30 days thereafter. Men were required to take the same family planning precautions.
Phase I Results
Courtney was optimistic the drug would be well-tolerated because of the promising pre-trial data and his hypothesis was correct. The team reported no dose-limiting toxicity observed at any dose level, up to 1,800 mg twice daily.
“At doses exceeding 800 mg, no further reduction in EPO was found and PT2385 was rapidly absorbed,” he continued.
Therefore, based on safety, PK, and EPO PD data, 800 mg was determined to be the RP2D.
The most frequent adverse side effects—largely grade 1 and 2—were asymptomatic anemia, fatigue, and peripheral edema. In a small percentage of patients older than 65 with other co-morbidities, or treated at high altitudes, hypoxia was observed and resolved without treatment.
“The side effect reports were interesting to us since we did not predict hypoxia,” remarked Courtney. “When patients came in for visits, they'd get oxygen saturation and we'd note the hypoxia, but it was asymptomatic.”
Courtney pointed out patients with co-morbid conditions requiring additional ventilation may lag their ventilatory response upon dosing with PT2385. This observation is supported by a rodent study that reported a harder time mounting a ventilatory response. Taking this into consideration for the next clinical study, a combination with immuno-oncology agent nivolumab, researchers are recording any evidence of low-oxygen saturation.
Nonetheless, Courtney told audiences the phase I trial was encouraging. “PT2385 was tolerated at doses far above what we'd recommend,” he concluded. “It has a promising side effect profile with few grade 3 or 4 all-cause adverse effects, which opens possibilities for combination therapy. Additionally, approximately one-third of patients had stable disease for longer than 16 weeks, and four responders. If you can take a drug with a novel mechanism of anti-tumor action that's well-tolerated and combinable, that spells real promise.”
Robin Hocevar is a contributing writer.