MODULATE

Protocol 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

AIM

Primary Objective:

• To determine the response rate (Immune RECIST)

Secondary Objective:

• To determine treatment related toxicity
• To determine progression free survival
• To determine overall survival
• Exploratory studies of biomarkers

BACKGROUND

Colorectal cancer is the most commonly diagnosed cancer in the Australian population. Surgery, with or without chemotherapy and radiotherapy, can be used to cure colorectal cancer that is diagnosed early. However, cases of advanced colorectal cancer where it has spread to other organs usually cannot be cured. Advanced colorectal cancer is treated with chemotherapy and other drugs, known as targeted therapies.  This can control advanced colorectal cancer for a limited time, but inevitably these cancers will evolve to become resistant to all the standard treatments available.  By the time cancers progress to this stage, survival is poor and patients are increasingly symptomatic.  Additional therapies are therefore needed to further extend survival of patients with advanced colorectal cancer.

CLINICAL TRIAL DESIGN

This study is a prospective randomised study that will recruit 90 patients with advanced MSS colorectal cancer at approximately 15 sites in Australia. The study will recruit patients with advanced colorectal cancer who have received and failed all standard treatments.  It is hoped that these approaches will benefit patients but this is unknown.  The approaches are highly experimental, but there is no placebo or control arm.

Arm 1:

• Nivolumab (240mg every 14 days)
• BNC105 (16mg/m²/day on day 1 and 8 every 21 days)

For 24 months or until disease progression or unacceptable toxicity.

Arm 2:

• Nivolumab (240mg every 14 days)
• BBI608 (240mg bd continuous)

For 24 months or until disease progression or unacceptable toxicity.

Patients Recruited

Click to access the table and view recruitment data on all AGITG open trials:

Open Trial Recruitment Table

Key Eligibility Criteria

Inclusion criteria
i) Histological diagnosis of colorectal cancer
ii) Documented MSS tumour
iii) Metastatic disease that is not resectable
iv) Age > 18 years
v) Failed in any sequence or combination oxaliplatin, fluoropyrimidine, irinotecan with or without bevacizumab where failure is defined as progression or toxicity precluding further therapy
vi) 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 may have received anti-EGFR therapy but this is not mandated.
vii) Measurable disease as assessed by CT scan
viii) Metastatic lesion(s) amenable to biopsy, this cannot be the sole site of measurable disease
ix) ECOG performance status 0, 1.
x) Adequate bone marrow function with platelets > 80 X 109/l; neutrophils > 1.5 X 109/l
xi) Adequate renal function, with calculated creatinine clearance >50 ml/min (Cockcroft and Gault).
xii) Adequate hepatic function with serum total bilirubin < 1.5 X upper limit of normal range and ALT or AST <3 x upper limit of normal range
xiii) Life expectancy of at least 12 weeks
xiv) No other concurrent uncontrolled medical conditions
xv) 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
xvi) Women and partners of women of childbearing potential must agree to use adequate contraception
xvii) Written informed consent including consent for donation of tumour tissue for biomarker studies

Exclusion criteria

i) Medical or psychiatric conditions that compromise the patient’s ability to give informed consent or to complete the protocol
ii) Subjects with any active, known, or suspected autoimmune disease, with the following exceptions:
Subjects with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy are permitted to enroll.
Subjects with suspected autoimmune thyroid disorders may be enrolled if they are currently euthyroid or with residual hypothyroidism requiring only hormone replacement. Subjects with psoriasis requiring systemic therapy must be excluded from enrollment

iii) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent) or other immunosuppressive medications within14 days of study administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.
iv) evidence of interstitial lung disease or active, non-infectious pneumonitis
v) active infection requiring systemic therapy;
vi) history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate;
vii) 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)
viii) known history of HIV (HIV 1/2 antibodies)

Principal Investigator

A/Professor Niall Tebbutt

Detailed Information

More information available online at the ClinicalTrials.gov, Identifier: NCT03647839. Click here for more.

Funding

Bristol-Myers Squibb