A combination of the new drug candidate Imprime PGG? (Biothera) and cetuximab (Erbitux?, ImClone/Bristol-Myers Squibb and Merck KGaA ) doubled the overall response rates for second- and third-line metastatic colorectal cancer patients participating in a Phase Ib/IIa clinical trial. The completed trial results were released at the 35th European Society for Medical Oncology (ESMO) Congress in Milan, Italy (October 8 – 12, 2010).
Imprime PGG, which is currently in multiple Phase II clinical trials for lung and colorectal cancer, is a Phase II cancer drug candidate that triggers neutrophils, the largest population of immune cells in the body (50-70%), to kill cancer cells. While some immunomodulatory drugs trigger a broad proinflammatory response, Imprime PGG selectively targets and activates neutrophils without inducing systemic pro-inflammatory cytokines that are attributed to adverse reactions.
As a platform therapeutic in oncology, this novel immunotherapy represents a significant enhancement over monoclonal antibodies alone and can be used to treat multiple cancers. The drug the potential to improve patient response rates for existing monoclonal antibody therapies in approved indications, create new indications for these drugs and enhance the efficacy of development-stage monoclonal antibody drugs
The data presented during the 35th ESMO congress showed the latest trial results of Imprime PGG in combination with cetuximab. The sequential, dual-arm, open-label, dose-escalation study evaluated the safety and efficacy of Imprime PGG plus cetuximab and irinotecan (Camptosar, Pfizer) or Imprime PGG plus cetuximab alone. The trial includes 32 patient and was conducted in Asia. In both arms of the trial, patients were dosed with 2 mg/kg, 4 mg/kg or 6 mg/kg of Imprime PGG in combination with standard doses of cetuximab and irinotecn. Imprime PGG was safe and well tolerated.
All tumor responses and duration of responses were based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.0.
Study Arm 1 Results
This portion of the study compared the combination of Imprime PGG, cetuximab and irinotecan to the standard of care of cetuximab and irinotecan alone for these late-stage patients. The trial results from this Arm demonstrated a doubling of the historical overall response rate and a two-month extension in the time to progression of these patients, compared with cetuximab and chemotherapy.
Biothera Colorectal Cancer Phase Ib/IIa Arm #1 Study
Results Compared to Historical Data
Chemotherapy + Cetuximab* | Chemotherapy + Cetuximab + Imprime PGG** | |
| Response Rate | 16% | 30% |
| Stable Disease Rate | 45% | 70% |
| Disease Control Rate | 61% | 100% |
| Progression-Free Survival | 16 weeks | 22 weeks |
| Number of patients | 648 | 10 |
*EPIC Study (Sobrero et al., JCO, 2008), ** Biothera Study
Study Arm 2 Results
The also trial compared the combination of Imprime PGG and cetuximab with cetuximab monotherapy. Chemotherapy was not administrated to avoid the unintentional destruction of immune cells that are integral to Imprime PGG?s mechanism of action. The trial results from this Arm demonstrated a doubling of the historical overall response rate and the time to progression of these patients, compared with cetuximab monotherapy.
Biothera Colorectal Cancer Phase Ib/IIa Arm #2 Study
Results Compared to Historical Data
| Cetuximab Alone* | Cetuximab + Imprime PGG | |
| Response Rate | 11% | 24% |
| Stable Disease Rate | 22% | 38% |
| Disease Control Rate | 33% | 62% |
| Progression-Free Survival | 6 weeks | 12 weeks |
| Number of patients | 111 | 21 |
* Cetuximab alone data from the BOND study, Cunningham et al., NEJM 2004.
Subpopulation Results
The study also retrospectively looked at subpopulations of the colorectal cancer patients based on those whose tumors expressed wild type versus mutated KRAS genes. In the wild type KRAS patient population responses were even more pronounced as shown below.
Biothera Colorectal Cancer Phase Ib/IIa Arm #2 Study
Results for KRAS Wild Type Patients Compared to Historical Data
| Cetuximab Alone* | Cetuximab + Imprime PGG | |
| Response Rate | 17% | 46% |
| Stable Disease Rate | 49% | 36% |
| Disease Control Rate | 66% | 82% |
| Progression-Free Survival | 11 weeks | 24 weeks |
| Number of patients | 262 | 11 |
* Cetuximab alone KRAS wild type data represent the mean of response data reported from 4 published studies (Khambata JCO 2007, DeRook Ann Oncol 2008, Lurje Clin Cancer Res 2008, Karapetis NEJM 2008; Total subjects from all Studies = 262.)
?The results of this dual arm study demonstrate the proof of concept the Imprime PGG is a novel drug that engages and directs innate immune cells to kill cancer,? said Dan Conners, president of Biothera?s Pharmaceutical Group. ?Imprime PGG’s ability to engage the innate immune system opens the door to numerous new therapeutic combinations with monoclonal antibodies targeting the vast majority of cancers.?
For more information:
– Safety/Efficacy Study of Imprime PGG With Cetuximab in Patients With Recurrent/Progressive Colorectal Carcinoma (NCT00545545)
– Efficacy/Safety of Imprime PGG? Injection With Cetuximab and Paclitaxel/Carboplatin Therapy in Patients With
Untreated Advanced Non-Small Cell Lung Cancer (NSCLC) (NCT00874848)
– Efficacy/Safety of Imprime PGG? Injection With Bevacizumab and Paclitaxel/Carboplatin in Patients With Untreated Advanced Non-Small Cell Lung Cancer (NSCLC) (NCT00874107)
– Efficacy and Safety Study of Imprime PGG With Cetuximab in Subjects With Stage IV KRAS-Mutated Colorectal Cancer (NCT00912327)
– Phase I/II, Randomized, Double-Blind, Study of the Progenitor Cell Mobilizing Effects of Imprime PGG? Injection Administered at Varied Dosing Regimens With G-CSF Versus G-CSF Alone (NCT00542529)
– Multiple-Dose, Dose-Escalation Safety, Pharmacodynamics, and Pharmacokinetics Study of Imprime PGG? Injection (NCT00542464)
– Phase Ia Dose-Escalation Safety, Pharmacodynamic and Pharmacokinetic Study of Imprime PGG? Injection ( NCT00542217)
