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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)

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ClinicalTrials.gov Identifier: NCT03647839
Recruitment Status : Recruiting
First Posted : August 27, 2018
Last Update Posted : February 5, 2019
Sponsor:
Information provided by (Responsible Party):
Australasian Gastro-Intestinal Trials Group

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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Metastatic Drug: Nivolumab 10 MG/ML Drug: BNC 105 Drug: BBI608 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: None (Open Label)
Masking 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
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
Actual Study Start Date : September 6, 2018
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

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 Name: 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 Name: Opdivo

Drug: BBI608
BBI‐608 will be supplied free of charge by Boston Biomedical as capsules.
Other Name: Napabucasin




Primary Outcome Measures :
  1. Objective response per iRECIST [ Time Frame: From start of treatment up to the date when the last patient has their 6 months follow-up assessment ]

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


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03647839


Contacts
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Contact: Nisha Berthon-Jones +612 8036 5223 nisha@gicancer.org.au

Locations
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Australia, New South Wales
Border Cancer Hospital Recruiting
Albury, New South Wales, Australia, 2640
Contact: Craig Underhill         
Principal Investigator: Craig Underhill         
Newcastle Private Hospital Recruiting
Newcastle, New South Wales, Australia
Contact: James Lynam         
Northern Cancer Institute Recruiting
St Leonards, New South Wales, Australia, 2065
Contact: Nick Pavlakis         
Principal Investigator: Nick Pavlakis         
Westmead Hospital Recruiting
Westmead, New South Wales, Australia, 2145
Contact: Adnan Nagrial         
Principal Investigator: Adnan Nagrial         
Australia, Queensland
Royal Brisbane Hospital Recruiting
Herston, Queensland, Australia, 4029
Contact: Matthew Burge         
Principal Investigator: Matthew Burge         
Australia, South Australia
Flinders Medical Centre Not yet recruiting
Bedford Park, South Australia, Australia, 5042
Contact: Chris Karapetis         
Principal Investigator: Chris Karapetis         
Ashford Cancer Centre Research Recruiting
Kurralta Park, South Australia, Australia, 5037
Contact: Nimit Singhal         
Principal Investigator: Nimit Singhal         
Queen Elizabeth Hospital Recruiting
Woodville South, South Australia, Australia, 5011
Contact: Tim Price         
Principal Investigator: Tim Price         
Australia, Victoria
Ballarat Health Service Recruiting
Ballarat, Victoria, Australia
Contact: Geoffrey Chong         
Principal Investigator: Geoffrey Chong         
Eastern Health Not yet recruiting
Box Hill, Victoria, Australia
Contact: Rachel Wong         
Monash Health Recruiting
Clayton, Victoria, Australia, 3168
Contact: Ben Markman         
Principal Investigator: Ben Markman         
Olivia Newton-John Cancer Wellness and Research Centre Recruiting
Heidelberg, Victoria, Australia, 3084
Contact: Niall Tebbutt         
Principal Investigator: Niall Tebbutt         
Peninsula Health/Frankston Hospital Not yet recruiting
Mornington Peninsula, Victoria, Australia
Contact: Zee Wang Wong         
Western Health Recruiting
Saint Albans, Victoria, Australia, 3021
Contact: Jeanne Tie         
Principal Investigator: Jeanne Tie         
Sponsors and Collaborators
Australasian Gastro-Intestinal Trials Group
Investigators
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Principal Investigator: Niall Tebbutt Olivia Newton-John Cancer Wellness and Research Centre

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Responsible Party: Australasian Gastro-Intestinal Trials Group
ClinicalTrials.gov Identifier: NCT03647839     History of Changes
Other Study ID Numbers: CA209‐99U
First Posted: August 27, 2018    Key Record Dates
Last Update Posted: February 5, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data will not be shared.

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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

Keywords provided by Australasian Gastro-Intestinal Trials Group:
Microsatellite stable tumour
Refractory colorectal cancer
Tumour microenvironment
Vascular Disrupting Agent
STAT3 inhibitors
PD1 inhibitors
Unresectable colorectal cancer
nivolumab
BNC105
BBI-608

Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents