Abstract No. 4010

Title: A phase Ib study of gemcitabine plus PEGPH20 (pegylated recombinant human hyaluronidase) in patients with stage IV previously untreated pancreatic cancer.

Background: PEGPH20 is a PEGylated version of human recombinant hyaluronidase. In preclinical studies, PEGPH20 depleted pancreatic cancers of their high hyaluronan (HA) content. In a genetically-engineered murine model of PDA, PEGPH20 + gemcitabine (Gem) significantly prolonged survival compared to Gem alone. In Ph1 PEGPH20 monotherapy studies, the MTD was 3.0 ug/kg. The most common AEs were musculoskeletal events (MSEs).

Methods: This was a dose-escalation study to find the recommended Phase 2 dose (RP2D) of PEGPH20 in combination with Gem in patients (pts) with Stage IV previously untreated pancreatic cancer. Pts received PEGPH20 at 1, 1.6, or 3 ug/kg IV twice a week for Wks 1-4, weekly for Wks 5-7, then 1 wk rest. Dose escalation was based on safety. Gem was given at 1000 mg/m2 IV once a week for Wks 1-7, then 1 wk rest. Thereafter, PEGPH20 + Gem were given once a week for 3 wks in 4-wk cycles. Dexamethasone was given pre and post PEGPH20 doses.

Results: Of the 28 pts enrolled, the majority had a Karnofsky performance status of 80%, and 85%/19%/26% of pts had liver/lung/visceral metastases. The median age was 58 yrs. Four pts received PEGPH20 at 1 ug/kg, 4 at 1.6 ug/kg, and 20 at 3 ug/kg. The RP2D was 3 ug/kg. Treatment duration ranged from 1-274 days; 5 pts remain on study. Treatment was generally well tolerated. Ten pts had 1 Gem dose reduction, 2 pts had 1 PEGPH20 dose reduction (3 to 1.6 ug/kg), but no pt had a DLT. The most common PEGPH20-related AEs were MSEs (25% Gr1; 18% Gr2) and fatigue (21% Gr1; 11% Gr2). Objective response was assessed by an independent central radiologist using RECIST 1.1. Of the 21 pts evaluable for efficacy, 7 had partial response (PR) for an overall response rate (ORR) of 33%, and 9 had stable disease for greater than or equal to 2 mo. Tumor biopsies from 12 pts were evaluable for HA staining. HA was high in 9 and low in 3. Of the 9 with high HA staining, 5 had PR (56% ORR); HA data were not available for the other 2 PR pts. PK results show dose-dependent exposure consistent with data from PEGPH20 monotherapy studies.

Conclusions: PEGPH20 in combination with Gem is generally well tolerated in advanced pancreatic cancer and shows promising efficacy, especially in pts with high intratumoral HA content.

Infinity Pharmaceuticals

Abstract No. 8518

Title: Preliminary safety and efficacy of IPI-145, a potent inhibitor of PI3-K delta, gamma in patients with relapsed/refractory lymphoma.

Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3K delta and PI3K gamma isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory lymphoma from an ongoing Phase 1 study are reported here.

Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) less than MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on standard disease-specific criteria.

Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with complete inhibition of PI3K-delta at doses greater than 15 mg BID and increasing suppression of PI3K-gamma with increasing dose. In the 36 pts with lymphoma who received 15 mg to 75 mg BID, the median range number of cycles was 2.4 0.1-10 and 67% remain on study. Treatment-related adverse events (TRAEs) occurred in 50% of pts with lymphoma. Neutropenia and increased ALT were the most common greater than or equal to Grade 3 TRAEs (4 pts each) and were not associated with increasing dose. Greater than Grade 3 ALT elevations were more common in lymphoma pts (18%) compared to non-lymphoma pts (5%). Among evaluable pts with lymphoma (n=27), early clinical activity was observed in T-cell (n=6, 1 CR, 1 PR, 1 SD) and aggressive/indolent B-cell (n=21, 2 CR, 9 PR, 5 SD) lymphoma pts at less than or equal to 75 mg BID. 92% of responses were observed by 3 months.

Conclusions: IPI-145 appeared well tolerated and has shown clinical activity in pts with relapsed/refractory advanced B- and T-cell lymphoma across the range of doses examined. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with lymphoma enrolled in dose escalation or ECs evaluating 25 mg BID and a higher dose (less than MTD) of IPI-145 will be presented.

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