Abstract 3014 describes a classic phase 1 cancer trial for IPI-926. Data are only included as of 12/2010 (actual poster should have more up to date results and will report the dose chosen for phase 2). Of 79 pts, an expanded group of 31 had basal cell carcinoma (BCC). Safety was acceptable and INFI reports a 26% (6 of 22) PR rate in a specified subgroup of hedgehog inhibitor-naive pts assigned to doses of at least 130 mg.
Abstract 4114 desribes the phase 1b portion of a combination trial of IPI-926 with gemcitabine for metastatic pancreatic cancer, and again only thru 12/2010. No additive toxicity has been observed. The trial is ongoing in a randomized phase 2 portion that will be enrolled by year-end 2011 (see INFI page for more info). No efficacy data is given[EDIT-sorry to be inaccurate, the abstract notes 3 potential PRs among the 1st 9 pts- but note these are not RECIST official PRs at this point, but certainly are encouraging].
Saturday June 4th: Poster Presentation Abstract #3014
"A phase I study of IPI-926, a novel hedgehog pathway inhibitor, in patients (pts) with advanced or metastatic solid tumors."
Charles M. Rudin, MD, PhD
Background: IPI-926 is a novel, selective, oral, natural- product derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting Smoothened (Smo). Inhibition of Smo can repress malignant activation of the Hh pathway, making Smo a target for treatment of a broad range of cancers. We conducted a phase I dose-escalation study to evaluate the safety, maximum tolerated dose and anti-tumor activity of IPI-926.
Methods: Eligible pts had advanced or metastatic solid tumors and adequate bone marrow, hepatic and renal function. IPI-926 was administered orally, daily (QD), in 1 to 6 pt cohorts. A cycle was 28 days in length. An expanded cohort in basal cell carcinoma (BCC) was implemented. All pts were evaluated for safety, pharmacokinetics, pharmacodynamics (PD) and tumor response. Dose-limiting toxicities (DLTs) were evaluated during Cycle 1.
Results: As of December 2010, 79 pts had been enrolled at dose levels of IPI-926 ranging from 20-210 mg QD. 31 pts had locally-advanced (LA) or metastatic (M) BCC. The median age for all patients was 60 years (range 40-87) and median number of cycles received was 3 (range 1-22), with 3 (1 LA-BCC and 2 M-BCC) pts receiving IPI-926 for > 12 months. No grade 4/5 related adverse events (AEs) have been observed. The most common IPI-926–related AEs to date include fatigue (29% total, 2.5% grade 3), ALT increased (20%, 7.6% grade 3), AST increased (19%, 3.8% grade 3) and nausea (19%, 0% grade 3). DLTs noted to date were asymptomatic grade 2/3 increased transaminases and/or bilirubin (1 pt at 160 mg, 4 pts at > 160 mg), all of which resolved when drug was held. IPI-926 exposure generally increased with increasing dose. 41 (72%) pts demonstrated a PD effect in normal skin. 6 (27%) clinical or radiologic partial responses have been observed in the 22 pts with Hh-inhibitor naive BCC treated at doses ≥ 130 mg, with 18 of these patients still on study, with a median of 7 cycles received (1-10). 27 pts in total are currently on study.
Conclusions: IPI-926, a potent and selective Smo inhibitor, was well tolerated up to 160 mg in pts with advanced or metastatic solid tumor malignancies. Evidence of clinical activity has been observed in BCC pts. The recommended dose for phase II studies will be presented.
Saturday June 4th: Poster Presentation Abstract #4114
"The safety of IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine in patients (pts) with metastatic pancreatic cancer."
Joe Stephenson, MD
Background: IPI-926 is a novel, selective, oral, natural product-derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting Smoothened (Smo). Inhibition of Smo can repress malignant activation of the Hh pathway, resulting in decreased desmoplasia and improved delivery of chemotherapy to pancreatic tumors.
Methods: A phase Ib/II trial is underway to evaluate the safety profile and efficacy of IPI-926 in combination with gemcitabine. Eligible pts with previously untreated metastatic pancreatic cancer and ECOG performance status 0-1 had IPI-926 administered orally daily (QD) for a 28-day cycle, in 3 to 6 pt cohorts. IV gemcitabine (1,000 mg/m2) was administered once weekly for 3 weeks followed by 1 week off. DLTs were evaluated during Cycle 1.
Results: As of Dec 2010, 15 pts with a median age of 67 years (range 58-83) have been enrolled in the phase Ib portion of this trial at dose levels of IPI-926 ranging from 110-160 mg QD, and a median of 3 cycles completed (1-6). No Grade 4/ 5 adverse events (AE) have been observed related to either study drug, and no IPI-926-related serious AEs have been noted. The most common IPI-926-related AEs observed include fatigue (40% total, 0% Grade 3), nausea (40%, 0%), ALT increased (13%, 7%), AST increased (13%, 7%), anemia (13%, 0%), and vomiting (13%, 0%). The observed safety profile for gemcitabine has been consistent with published data. The one DLT observed to date (130 mg of IPI-926) was Grade 3 AST increase, which was asymptomatic, resolved with dose interruption, and did not recur after dose reduction. No apparent drug interaction between IPI-926 and gemcitabine has been observed to date. Preliminary data include 3 radiographic partial responses in the 9 pts with post-baseline scans.
Conclusions: IPI-926 in combination with gemcitabine has been well tolerated to date in patients with metastatic pancreatic cancer, without unexpected toxicity, and preliminary evidence of clinical activity has been observed. The phase Ib portion of this trial is now fully enrolled with ongoing pt treatment and data collection. Clinical evaluation of this combination continues in a randomized, double blind, placebo controlled phase II trial.