A Phase III Study of Xilonix in Patients With Advanced Colorectal Cancer (XCITE)

• Change in Lean Body Mass [ Time Frame: baseline to 8 weeks ] [ Designated as safety issue: No ]
  Change in LBM as measured by DEXA scan will be compared between the two arms
• Quality of life questionnaire [ Time Frame: baseline to 8 weeks ] [ Designated as safety issue: No ]
  EORTC-QLQ C30
• Progression Free Survival [ Time Frame: baseline to 18 months ] [ Designated as safety issue: No ]
  The difference in median PFS will be compared between the two arms
• Objective Response Rate [ Time Frame: baseline to 18 months ] [ Designated as safety issue: No ]
  The ORR will be compared between the two arms

• Change in Lean Body Tissue [ Time Frame: baseline to 8 weeks ] [ Designated as safety issue: No ]
• Quality of life questionnaire [ Time Frame: baseline to 8 weeks ] [ Designated as safety issue: No ]

In the setting of refractory, metastatic disease a complete resolution of tumor burden is not a reasonable expectation. Instead, the primary goal of anti-tumor therapy at this stage is to eliminate or reduce the symptomatic effects of the tumor, while trying to prolong survival for as long as possible. Due to treatment related morbidity however, few treatment modalities are ideal for this objective. Even with the most recent targeted agents (such as multi-kinase inhibitors), drug related toxicities frequently lead to relatively short treatment durations. With discontinuation of therapy, disease progression is uncontrolled and prognosis is poor.

New agents that control disease progression—while improving tumor-related symptoms, rather than causing significant therapy related morbidity—are vitally needed to treat patients with advanced cancer, including those with colorectal cancer. An approach has been taken to develop such an agent using a monoclonal antibody to block the chronic inflammation involved in both malignant disease progression and constitutional symptoms.

Xilonix™ is expected to inhibit tumor growth and metastasis by interrupting crucial signals that drive angiogenesis and invasiveness. The antibody therapy may also block tumor microenvironment infiltration by leukocytes (such as myeloid suppressor cells) that suppress antitumor immunity, enabling better host immune control of the disease. In addition to local effects on the tumor, Xilonix™ is expected to work systemically to correct the metabolic dysregulation, fatigue and anxiety mediated by chronic inflammatory signaling to the central nervous system.

• Drug: Xilonix
  Xilonix is a True Human Monoclonal Antibody targeting Interleukin 1 alpha, and is administered intravenously every 2 weeks with best supportive care until clinical or radiographic progression.
  Other Name: MABp1, CA-18C3
• Drug: Placebo
  Placebo plus best supportive care will be administered intravenously every 2 weeks until clinical or radiographic progression.

• Experimental: Xilonix
  MABp1 administered IV every two weeks, plus best supportive care
  Intervention: Drug: Xilonix
• Placebo Comparator: Placebo
  Placebo administered IV every two weeks, plus best supportive care
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Subjects with pathologically confirmed colorectal carcinoma that is metastatic or unresectable and which is refractory to standard therapy. To be considered refractory, a subject must have experienced progression (or intolerance) after treatment with standard approved regimens including, oxaliplatin, irinotecan flouropyrimidine, bevacizumab, and cetuximab or panitumumab if KRAS wildtype.
2. Subjects will not be treated with any radiation, chemotherapy, or investigational agents while enrolled in this protocol.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0,1, or 2.
4. At least 2 weeks since the last previous cancer treatment including: chemotherapy, radiation therapy, immunotherapy, surgery, hormonal therapy, or targeted biologics.
5. Age ≥ 18 years, male or female subjects.
6. Serum potassium and magnesium levels within institutional normal limits. Total serum calcium or ionized calcium level must be greater than or equal to the lower limit of normal.
7. Adequate renal function, defined by serum creatinine ≤ 1.5 x ULN.
8. Adequate hepatic function
9. Adequate bone marrow function
10. For women of childbearing potential (WOCBP), a negative serum pregnancy test result at Screening.
11. Signed and dated institutional review board (IRB)-approved informed consent before any protocol-specific screening procedures are performed.
12. Patients enrolled must, in the Investigator's judgment, be healthy enough to stay on the clinical trial for three months.

Exclusion Criteria:

1. Mechanical obstruction that would prevent adequate oral nutritional intake.
2. Serious uncontrolled medical disorder, or active infection, that would impair the ability of the patient to receive protocol therapy.
3. Uncontrolled or significant cardiovascular disease, including:
4. Dementia or altered mental status that would prohibit the understanding or rendering of informed consent.
5. Subjects who have not recovered from the adverse effects of prior therapy at the time of enrollment to ≤ grade 1; excluding alopecia and grade 2 neuropathy.
6. Immunocompromised subjects, including subjects known to be infected with human immunodeficiency virus (HIV).
7. Known hepatitis B surface antigen and/or positive hepatitis C antibody and presence of hepatitis C RNA.
8. History of tuberculosis (latent or active) or positive Interferon-gamma release assay (IGRA).
9. Receipt of a live (attenuated) vaccine within 1 month prior to Screening
10. Subjects with history of hypersensitivity to compounds of similar chemical or biologic composition of XILONIX™.
11. Women who are pregnant or breastfeeding.
12. WOCBP or men whose sexual partners are WOCBP who are unwilling or unable to use an acceptable method of contraception for at least 1 month prior to study entry, for the duration of the study, and for at least 3 months after the last dose of study medication.
13. Weight loss >20% in the previous 6 months.