Clinical trial NCT03647839: Modulation 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
Official title: Modulation 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer Metastatic
Keywords: Microsatellite stable tumour
Refractory colorectal cancer
Tumour microenvironment
Vascular Disrupting Agent
STAT3 inhibitors
PD1 inhibitors
Unresectable colorectal cancer
nivolumab
BNC105
BBI-608
Lead sponsor: Australasian Gastro-Intestinal Trials Group
Sponsor class: NETWORK
First posted: 2018-08-27
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is an open-label, multicentre, parallel phase II study designed to assess the efficacy of the combination of nivolumab and BNC105 and the combination of nivolumab and BBI-608. Patients with microsatellite stable adenocarcinoma of colorectal origin that is not resectable are eligible and will be randomised in the ratio of 1:1 using permuted block randomisation with stratification by screening ECOG performance status (0 or 1) to receive either nivolumab and BNC105 or nivolumab and BBI-608.
Primary purpose: TREATMENT

Brief summary: This Phase II research project will test the efficacy, safety, and tolerability of an experimental drug combination: either nivolumab and BBI608 or nivolumab and BNC105 in patients with metastatic colorectal cancer who have previously failed standard of care treatment.

Detailed description: This is an open-label, multicentre, parallel phase II study designed to assess the efficacy of the combination of nivolumab and BNC105 and the combination of nivolumab and BBI-608. Patients with microsatellite stable adenocarcinoma of colorectal origin that is not resectable are eligible and will be randomised in the ratio of 1:1 using permuted block randomisation with stratification by screening ECOG performance status (0 or 1) to receive either nivolumab and BNC105 or nivolumab and BBI-608.

The expected sample size is 90 patients over a 24 month recruitment period.

Eligibility criteria: Inclusion Criteria:

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.

Exclusion Criteria:

1. Medical or psychiatric conditions that compromise the patient's ability to give informed consent or to complete the protocol.
2. Patients with any active, known, or suspected autoimmune disease, with the following exceptions:

   1. Patients with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy are permitted to enroll.
   2. Patients with suspected autoimmune thyroid disorders may be enrolled if they are currently euthyroid or with residual hypothyroidism requiring only hormone replacement.
   3. Patients with psoriasis requiring systemic therapy must be excluded from enrolment
3. Patients with a condition requiring systemic treatment with either corticosteroids (\>10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days of randomisation. Inhaled or topical steroids and adrenal replacement doses \> 10mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.
4. Patient has evidence of interstitial lung disease or active, non-infectious pneumonitis.
5. Has an active infection requiring systemic therapy.
6. Patients receiving long-term anti-coagulation or anti-platelet agents which cannot be ceased for an appropriate interval to allow mandatory tumour biopsies prior to and during therapy.
7. Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate.
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
9. Has a known history of HIV (HIV 1/2 antibodies). Formal testing is only required if there is significant clinical suspicion of HIV.
10. Known active brain metastases (unless adequately treated with surgery and/or radiotherapy \>30 d prior and asymptomatic).
11. Significant vascular events within the previous 6 months (unstable angina, myocardial infarction, TIA, CVA).

Primary outcomes:
measure: Objective response per iRECIST
timeFrame: From start of treatment up to the date when the last patient has their 6 months follow-up assessment
Secondary outcomes:
measure: Objective response per RECIST1.1
timeFrame: From start of treatment up to the date when the last patient has their 6 months follow-up assessment
measure: Progression free survival (PFS).
timeFrame: From start of treatment until the date of first documented progression or date of death from any cause, whichever occurs first, assessed up to the date when the last patient has their 6 months follow-up assessment
measure: Adverse event assessed using CTCAE version 5.0
timeFrame: Through treatment completion, maximum of 2 years
measure: Overall survival
timeFrame: From start of treatment until the date of death from any cause, assessed up to the date when the last patient has their 6 months follow-up assessment
Other outcomes:
Locations:
city: Albury
country: Australia
facility: Border Cancer Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Newcastle Private Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Northern Cancer Institute
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Kurralta Park
country: Australia
facility: Ashford Cancer Centre Research
state: South Australia
city: Woodville South
country: Australia
facility: Queen Elizabeth Hospital
state: South Australia
city: Ballarat
country: Australia
facility: Ballarat Health Service
state: Victoria
city: Box Hill
country: Australia
facility: Eastern Health
state: Victoria
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Heidelberg
country: Australia
facility: Olivia Newton-John Cancer Wellness and Research Centre
state: Victoria
city: Mornington Peninsula
country: Australia
facility: Peninsula Health/Frankston Hospital
state: Victoria
city: Saint Albans
country: Australia
facility: Western Health
state: Victoria
Study officials:
affiliation: Olivia Newton-John Cancer Wellness and Research Centre
name: Niall Tebbutt, Prof
role: STUDY_CHAIR
References: