A phase Ib/2, dose-escalating, safety, and efficacy study of imprime PGG, cetuximab and irinotecan in patients with advanced colorectal cancer (CRC)

Abstract

e15062 Background: Imprime PGG (Imprime PGG Injection) is a ß-glucan polymer being developed for treatment of cancer in combination with complement-activating monoclonal antibodies. This trial evaluates the safety and efficacy of Imprime PGG in combination with cetuximab and irinotecan in CRC patients (pts). Methods: Pts with recurrent/progressive CRC (Karnofsky > 70%) previously treated with 5-FU (alone or combined with other therapies) were treated with Imprime PGG (weekly), cetuximab (weekly; loading dose 400 mg/m2, then 250 mg/m2), and irinotecan (wks 1–4 of each 6-wk cycle; 125 mg/m2). In a 3 + 3 design, Imprime PGG dosing started at 2 mg/kg and escalated to 4 and 6 mg/kg after safety review. Safety (primary endpoint) was assessed by adverse events (AEs) and efficacy (secondary endpoint) by RECIST. Results: Imprime PGG was dosed in 3 pts at 2 mg/kg, 6 pts at 4 mg/kg and 1 pt at 6 mg/kg. Median age was 56. One pt remains on therapy at wk 49; other pts exited due to progressive disease (5 pts), irinotecan intolerance (2 pts), investigator discretion (1 pt), and withdrawn consent (1 pt). Median duration of treatment was 17.5 wks. No protocol-defined dose-limiting toxicities were observed. AEs experienced by > 50% of pts included diarrhea (90%), hypokalemia, neutropenia (80%), weight loss (70%), anemia, anorexia, leucopenia (60%), alopecia, dry skin, hypomagnesemia, increased amylase, vomiting (50%). Grade 4 SAEs included increased amylase, increased lipase, and neutropenia. Partial response (PR) occurred in 3 pts (30%) and stable disease (SD) in 7 pts (70%), yielding a disease control rate (PR + SD) of 100%. The median time to progression was 22.3 wks. Conclusions: Imprime PGG combined with cetuximab and irinotecan in CRC pts was safe and efficacy warrants further investigation. [Table: see text]

Management of dermatologic toxicities associated with monoclonal antibody epidermal growth factor receptor inhibitors: A case review

“…Based on this speculation, pharmaceutical companies are developing biochemical compounds able to augment this immune response for use in combination with anti-EGFR therapy. [ 31 32 ]…”

“…Based on this speculation, pharmaceutical companies are developing biochemical compounds able to augment this immune response for use in combination with anti-EGFR therapy. [31,32] Lastly, the well-established correlation between rash and clinical outcome imposes that management strategies of skin toxicities do not interfere with antitumor activity of EGFRIs. In this regard, two randomized studies [6,26] have demonstrated that preventive use of systemic oral doxycycline or minocycline decreases the risk of Grade 2 and higher skin toxicity, without reducing anti-EGFR efficacy.…”

The mechanisms and cross-protection of trained innate immunity

“…This combined therapy was well tolerated in patients [136]. Another trial conducted by Biothera et al showed that conducting Imprime PGG (a β-glucan polymer) combined with cetuximab and irinotecan increased the response rate in advanced colorectal cancer [137]. In conclusion, the BCG vaccine and β-glucan in antitumor activity have been summarized in Table 2.…”

Dermatologic Toxicities from Monoclonal Antibodies and Tyrosine Kinase Inhibitors against EGFR: Pathophysiology and Management

“…The rash and survival correlation also makes one think of the possible immune mechanism behind the rash and the tumor response, where a possible increase in systemic cytokines/chemokines results in immunomodulation at the tumor level resulting in a better response. Various biochemical compounds are under development to actually augment this immune response to be used in conjunction with the EGFRI therapy [ 68 ], most prominently Imprime PGG (Biothera) has shown to improve survival even in the KRAS mutant colorectal cancer patients when used in combination with cetuximab (Erbitux) [ 69 , 70 ].…”