Clinical Trials /

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

NCT03647839

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: CA209‐99U
  • NCT ID: NCT03647839

Conditions

  • Colorectal Cancer Metastatic

Interventions

DrugSynonymsArms
Nivolumab 10 MG/MLOpdivoArm 1
BNC 105Arm 1
BBI608NapabucasinArm 2

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalNivolumab and BNC105
  • Nivolumab 10 MG/ML
  • BNC 105
Arm 2ExperimentalNivolumab and BBI-608
  • Nivolumab 10 MG/ML
  • BBI608

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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Adverse event assessed using CTCAE version 5.0
Time Frame:Through treatment completion, maximum of 2 years
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Australasian Gastro-Intestinal Trials Group

Trial Keywords

  • Microsatellite stable tumour
  • Refractory colorectal cancer
  • Tumour microenvironment
  • Vascular Disrupting Agent
  • STAT3 inhibitors
  • PD1 inhibitors
  • Unresectable colorectal cancer
  • nivolumab
  • BNC105
  • BBI-608

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