Efficacy and Safety Study of Imprime PGG With Cetuximab in Subjects With Stage IV KRAS-Mutated Colorectal Cancer

Study BT-CL-PGG-CRC0821 is a Phase 2, open-label, multicenter, efficacy and safety study. It will be conducted using a two-stage design with the intention of determining the initial efficacy of Imprime PGG in combination with a monoclonal antibody (MAb; cetuximab) in the treatment of KRAS-mutant colorectal cancer (CRC). Both stages will be conducted in subjects with Stage IV CRC demonstrating the KRAS gene mutation. Subjects will dose until progression of disease or discontinuation from the study for other reasons; e.g., safety, non-compliance. Approximately 56 subjects will be enrolled at three participating centers (17 into Stage 1 and 39 into Stage 2).

Study BT-CL-PGG-CRC0821 is a Phase 2, open-label, multicenter, efficacy and safety study. It will be conducted using a two-stage design with the intention of determining the initial efficacy of Imprime PGG in combination with a monoclonal antibody (MAb; cetuximab) in the treatment of KRAS-mutant colorectal cancer (CRC). Both stages will be conducted in subjects with Stage IV CRC demonstrating the KRAS gene mutation. All subjects will receive Imprime PGG at 4 mg/kg and standard doses of cetuximab; Imprime PGG and cetuximab will be administered in 6-week cycles. Subjects will dose until progression of disease or discontinuation from the study for other reasons; e.g., safety, non-compliance. The initial cetuximab dose will be 400 mg/m2 on Cycle 1/Day1 and subsequent doses of cetuximab will be 250 mg/m2 weekly. Imprime PGG will be dosed weekly at 4 mg/kg. Tumor measurements and determination of tumor responses for this study will be performed according to RECIST. Approximately 56 subjects will be enrolled at three participating centers (17 into Stage 1 and 39 into Stage 2). Final results will be determined from combined Stage 1 and Stage 2 data.

Eligibility Criteria:
Inclusion Criteria:

1. Is \>18 years old;
2. Has Stage IV carcinoma of the colon or rectum with documented histological or cytological confirmation;
3. Tumor has known KRAS mutation;
4. Has failed previous irinotecan- and oxaliplatin-containing regimens in either adjuvant or metastatic settings or is intolerant to irinotecan-based therapies;
5. Has measurable disease, defined as at least one tumor that fulfills the criteria for a target lesion according to RECIST;
6. Has not received any other treatment for colorectal cancer within the 30 days prior to first dose of study treatment under this protocol;
7. Has an ECOG score of 0-1;
8. Has a life expectancy of \> 3 months;
9. Has adequate bone marrow reserve as evidenced by:

   1. ANC ≥ 1,500/μL
   2. PLT ≥ 100,000/μL
10. Has adequate renal function as evidenced by serum creatinine ≤ 2.5X the upper limit of normal (ULN) for the reference lab;
11. Has adequate hepatic function as evidenced by:

    1. AST ≤ 3X ULN for the reference lab (≤ 5X ULN for subjects with known hepatic metastases)
    2. ALT ≤ 3X ULN for the reference lab (≤ 5X ULN for subjects with known hepatic metastases)
    3. Bilirubin \< 1.5 mg/dl, OR direct bilirubin \< 1.0 mg/dl
    4. Serum Albumin \> 3.0 gm/dl
12. Has read, understood and signed the informed consent form (ICF) approved by the Independent Review Board/Ethics Committee (IRB/EC); and
13. If the subject is a woman of childbearing potential or a fertile man, he/she must agree to use an effective form of contraception during the study and for 60 days following the last dose of study medication (an effective form of contraception is abstinence, a hormonal contraceptive, or a double-barrier method).

Exclusion Criteria:

1. Has a known hypersensitivity to cetuximab, murine proteins, or any component of cetuximab;
2. Has a known hypersensitivity to baker's yeast or has an active yeast infection;
3. Has had previous exposure to Betafectin® or Imprime PGG;
4. Has an active, uncontrolled infection;
5. Has known or suspected brain metastases;
6. Had a second malignancy within the previous 5 years, except for basal cell carcinoma, cervical intra-epithelial neoplasia or curatively-treated prostate cancer with a PSA of \< 2.0 ng/mL;
7. Has known HIV/AIDS, Hepatitis B, Hepatitis C, connective tissue disease, or other clinical diagnosis, ongoing or intercurrent illness that in the investigator's opinion should prevent participation;
8. If female, is pregnant or breast-feeding;
9. Is receiving concurrent standard and/or investigational anti-cancer therapy or has received such therapy within a period of 30 days prior to the first scheduled day of dosing (investigational therapy is defined as treatment for which there is currently no regulatory-authority-approved indication); or
10. Has previously received an organ or progenitor/stem cell transplant.