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)

• ClinicalTrials.gov Identifier: NCT03647839
• Recruitment Status: Completed
• First Posted: August 27, 2018
• Last Update Posted: August 27, 2021
• Sponsor: Australasian Gastro-Intestinal Trials Group
• Information provided by (Responsible Party): Australasian Gastro-Intestinal Trials Group

Tracking Information

• First Submitted Date: July 2, 2018
• First Posted Date: August 27, 2018
• Last Update Posted Date: August 27, 2021
• Actual Study Start Date: September 6, 2018
• Actual Primary Completion Date: January 29, 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: August 23, 2018): 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 ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 23, 2018)

• 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 ]
• 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 ]
• Adverse event assessed using CTCAE version 5.0 [ Time Frame: Through treatment completion, maximum of 2 years ]
• 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 ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief 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
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

• Condition: Colorectal Cancer Metastatic

Intervention

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

Study Arms

• Experimental: Arm 1
  Nivolumab and BNC105
  Interventions:

  • Drug: Nivolumab 10 MG/ML
  • Drug: BNC 105
• Experimental: Arm 2
  Nivolumab and BBI-608
  Interventions:

  • Drug: Nivolumab 10 MG/ML
  • Drug: BBI608

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 23, 2018): 90
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: April 9, 2021
• Actual Primary Completion Date: January 29, 2021 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT03647839
• Other Study ID Numbers: CA209-99U
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Individual participant data will not be shared.

• Current Responsible Party: Australasian Gastro-Intestinal Trials Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Australasian Gastro-Intestinal Trials Group
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Niall Tebbutt, Prof; Olivia Newton-John Cancer Wellness and Research Centre

• PRS Account: Australasian Gastro-Intestinal Trials Group
• Verification Date: August 2021