MODULATE: This phase II trial is evaluating the combination of nivolumab (an immunotherapy drug) and two other drugs (BNC105 or BBI608) in patients with colorectal cancers that have spread to other parts of the body and have failed prior therapiesModulation Of The Tumour Microenvironment Using Either Vascular Disrupting Agents or STAT3 Inhibition in Order to Synergise With PD1 Inhibition in Microsatellite Stable, Refractory Colorectal Cancer

Inclusion

1. Patient has a histological diagnosis of adenocarcinoma of colorectal origin.
2. Has documented microsatellite stable tumour as assessed by PCR or IHC.
3. Metastatic disease that is not resectable.
4. Male or female patients > 18 years of age at screening.
5. Failed in any sequence or combination oxaliplatin, fluoropyrimidine, irinotecan with or without bevacizumab where failure is defined as progression or toxicity precluding further therapy.
6. For patients with ras/b-raf wild type tumours: failed anti EGFR therapy (cetuximab and/or panitumumab) where failure is defined as progression or toxicity precluding further therapy. Patients with b-raf mutant tumours and/or right sided primary tumours may have received anti-EGFR therapy but this is not mandated.
7. Patient has measurable disease according to RECIST 1.1.
8. Metastatic lesion(s) amenable to biopsy, this cannot be the sole site of measurable disease.
9. ECOG performance status 0 or 1.

10. Adequate organ and hematologic function within 7 days of randomisation, defined by:

    1. Neutrophils > 1.5 X 109/L
    2. Platelets > 80 X 109/L
    3. Serum aspartate transaminase (AST) or alanine transaminase (ALT) < 3 x upper limit of normal (ULN)
    4. Bilirubin < 1.5 x ULN
    5. Albumin >30g/L
    6. Creatinine clearance ≥ 50ml/min(Cockcroft-Gault).
11. Life expectancy of at least 12 weeks
12. No other concurrent uncontrolled medical conditions
13. No other malignant disease apart from non-melanotic skin cancer or carcinoma in situ of the uterine cervix or any other cancer treated with curative intent >2 years previously without evidence of relapse.
14. Female patients of childbearing potential should have a negative urine or serum pregnancy within 24 hours prior to randomisation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
15. Female patients of childbearing potential should be willing to use a reliable method of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
16. Male patients with female partners of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy.
17. Patient has provided written informed consent including consent for tumour biopsies and donation of tumour tissue for biomarker studies.