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 (MODULATE)

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer Metastatic
• Intervention / Treatment: Drug: Nivolumab 10 MG/ML; Drug: BNC 105; Drug: BBI608

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Albury, New South Wales, Australia, 2640
      • Border Cancer Hospital
    • Newcastle, New South Wales, Australia
      • Newcastle Private Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Northern Cancer Institute
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
    • Kurralta Park, South Australia, Australia, 5037
      • Ashford Cancer Centre Research
    • Woodville South, South Australia, Australia, 5011
      • Queen Elizabeth Hospital
  • Victoria
    • Ballarat, Victoria, Australia
      • Ballarat Health Service
    • Box Hill, Victoria, Australia
      • Eastern Health
    • Clayton, Victoria, Australia, 3168
      • Monash Health
    • Heidelberg, Victoria, Australia, 3084
      • Olivia Newton-John Cancer Wellness and Research Centre
    • Mornington Peninsula, Victoria, Australia
      • Peninsula Health/Frankston Hospital
    • Saint Albans, Victoria, Australia, 3021
      • Western Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Nivolumab and BNC105	Drug: Nivolumab 10 MG/ML; Nivolumab will be supplied free of charge by Bristol-Myers Squibb (BMS) as sterile liquid in 10mL glass vials.; Other Names: Opdivo; Drug: BNC 105; BNC105 will be provided free of charge by Bionomics, as a sterile solution of BNC105P. BNC105P is a clear, colorless to yellow liquid presented in a clear glass vial and is intended to be diluted with commercially available sterile 0.9% saline prior to IV administration.
Experimental: Arm 2; Nivolumab and BBI-608	Drug: Nivolumab 10 MG/ML; Nivolumab will be supplied free of charge by Bristol-Myers Squibb (BMS) as sterile liquid in 10mL glass vials.; Other Names: Opdivo; Drug: BBI608; BBI-608 will be supplied free of charge by Boston Biomedical as capsules.; Other Names: Napabucasin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Objective response per iRECIST	From start of treatment up to the date when the last patient has their 6 months follow-up assessment

Secondary Outcome Measures

Outcome Measure	Time Frame
Objective response per RECIST1.1	From start of treatment up to the date when the last patient has their 6 months follow-up assessment
Progression free survival (PFS).	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
Adverse event assessed using CTCAE version 5.0	Through treatment completion, maximum of 2 years
Overall survival	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

Collaborators and Investigators

• Sponsor: Australasian Gastro-Intestinal Trials Group
• Investigators: Study Chair: Niall Tebbutt, Prof, Olivia Newton-John Cancer Wellness and Research Centre

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2018
• Primary Completion (Actual): January 29, 2021
• Study Completion (Actual): April 9, 2021

Study Registration Dates

• First Submitted: July 2, 2018
• First Submitted That Met QC Criteria: August 23, 2018
• First Posted (Actual): August 27, 2018

Study Record Updates

• Last Update Posted (Actual): August 27, 2021
• Last Update Submitted That Met QC Criteria: August 26, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: nivolumab; Microsatellite stable tumour; Refractory colorectal cancer; Tumour microenvironment; Vascular Disrupting Agent; STAT3 inhibitors; PD1 inhibitors; Unresectable colorectal cancer; BNC105; BBI-608
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: CA209-99U

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Individual participant data will not be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes