Do Changes in ctDNA Predict Response for Patients With Oesophageal Cancer Receiving Durvalumab (CALIBRATION)

• ClinicalTrials.gov Identifier: NCT03653052
• Recruitment Status: Unknown
• First Posted: August 31, 2018
• Last Update Posted: September 3, 2019
• Sponsor: Simon C Pacey, MD
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Simon C Pacey, MD, Cambridge University Hospitals NHS Foundation Trust

Study Description

Brief Summary:

Patients with cancer are increasingly being treated with drugs designed to modulate the response of their immune system, broadly to boost their body's defences against cancer. However, there is an unmet need to identify which patients are unlikely to benefit. Deciding on benefit from therapy uses standard imaging methods (e.g. CT scans), which can take time (months) whereas DNA in the bloodstream could be measured more rapidly.

The main aim of this study is to assess whether changes in the level of circulating tumour DNA (ctDNA) can quickly determine a patients response. This would enable patients to change therapies more quickly if they are not responding and reduce exposure to unnecessary side effects.

Condition or disease	Intervention/treatment	Phase
Oesophageal Cancer	Drug: Durvalumab	Phase 2

Detailed Description:

Measuring circulating (plasma) tumour DNA has been described as a 'liquid biopsy' able to study a tumour without invasive biopsy. By measuring ctDNA at different time points the investigators can detect tumour changes that indicate if the patient is responding to treatment or not.

This trial has been designed as a prospective, open label, non-randomised trial where patient with advanced oesophageal cancer will be treated with MEDI4736 (durvalumab), a drug designed to alter the immune system response. Samples will be taken to regularly to measure ctDNA levels and compared to patients response at 6 months when undergoing standard CT scans.

The study will run at a single centre (Addenbrookes Hospital, Cambridge). Nineteen, evaluable, patients will receive durvalumab until progression while detailed studies will assess their tumour and immune response.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CALIBRATION: An Exploratory Study in Patients With Advanced Oesophageal Malignancies Receiving MEDI4736 (Durvalumab), Investigating Whether Early Changes in Circulating Tumour DNA Can Predict Tumour Response
• Actual Study Start Date: October 30, 2018
• Estimated Primary Completion Date: May 2021
• Estimated Study Completion Date: February 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Durvalumab; Patients with advanced oesophageal cancer will be administered with 1500mg of durvalumab once every 4 weeks for up to 6 months.	Drug: Durvalumab; Durvalumab will be administered via an infusion in the arm, over a duration of up to 1 hour.; Other Name: MEDI4736

Outcome Measures

Primary Outcome Measures :

1. Clinical response to therapy (durvalumab) [ Time Frame: 26 weeks ]
   Changes in ctDNA levels (from baseline to C1/C2) compared with objective RECIST radiological response at 26 weeks

Other Outcome Measures:

1. Immunological milieu in tumour samples [ Time Frame: 33 months ]
   Changes in intra-tumoural T-Cell distribution, immunostaining and other biomarkers of immune activation following exposure to durvalumab
2. ctDNA/plasma sampling [ Time Frame: 33 months ]
   Tracking immunological changes and variability in immune-cells (clonality, T-cell receptor, tumour infiltrating lymphocytes) and neoantigens; tumour specific mutation(s); and, blood-based biomarkers following exposure to durvalumab
3. ctDNA's potential to identify tumour resistance mechanisms [ Time Frame: 33 months ]
   Tracking immunological changes and variability in immune-cells (clonality, T-cell receptor, tumour infiltrating lymphocytes) and neoantigens; tumour specific mutation(s); and, blood-based biomarkers following exposure to durvalumab
4. Correlation in ctDNA levels and occurrence of clinically related adverse events [ Time Frame: 33 months ]
   Variations in tumour variant alelle frequencies (VAF) compared with the occurrences of >= Grade 2 treatment related side effects
5. Integrate the use of iRECIST criteria [ Time Frame: 33 months ]
   Compare responses by RECIST and iRECIST criteria
6. Patient stratification according to predefined genetic signatures [ Time Frame: 33 months ]
   Time taken and costs incurred from sample collection through to the generation of data and, the correlation between response to durvalumab and the genetic signature that the patient is assigned to
7. Ex-vivo effect of compounds on tumour/cell models [ Time Frame: 33 months ]
   Ex-vivo response to durvalumab using patient derived model systems

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Provide written, informed consent to participate
• Aged ≥ 18 years at time of consent
• Confirmed advanced oesophageal cancer for which the patient must have received at least one prior line of standard of care treatment
• Predicted life expectancy ≥ 3 months
• Eastern Cooperative Oncology Group (ECOG) PS 0 or 1
• Measurable disease, as defined by RECIST v1.1.
• In the investigator's opinion, have an accessible and biopsiable tumour lesion for additional research biopsy, to which the patient will have to consent at screening.

• Adequate hematologic and organ function, defined by:

  • ANC ≥ 1500 cells/μL (no GCSF support 2 weeks prior to trial entry)
  • Platelet count ≥ 100,000/μL
  • Haemoglobin ≥ 9.0 g/dL
  • AST or ALT ≤ 2.5 times the upper limit of normal (ULN), (except patients with documented liver metastases where AST and/or ALT can be ≤ 5×ULN)
  • Serum bilirubin ≤1.5 × ULN. (Except patients with confirmed Gilbert's syndrome)
  • INR and APTT ≤ 1.5×ULN.
  • Calculated creatinine clearance (CrCl) ≥ 40 mL/min (Cockcroft-Gault formula)
• Negative pregnancy test in women of child-bearing potential or evidence of postmenopausal status

Exclusion Criteria:

• Weight of ≤30kg
• Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.
• Participation in other clinical trials involving active treatment for the malignant disease.
• Received radiotherapy treatment on a wide body field, or an equivalent to more than 30% of the bone marrow, within the last 4 weeks.
• Any unresolved symptom NCI CTCAE Grade ≥2 from previous anticancer therapy (with the exception of alopecia and vitiligo).

• Active or prior documented autoimmune or inflammatory disease (except vitiligo) within the last 3 years, for example:

  • Intestinal: Inflammatory Bowel Disease (Colitis, Crohn's Disease), Diverticulitis (with the exception of Diverticulosis), Coeliac Disease, Irritable Bowel Disease
  • Vascular: any type of Vasculitic disorder, i.e.: Wegner syndrome.
  • Endocrine: any endocrine alteration related to an auto-immune process i.e.: Hashimoto syndrome. NOTE: patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement treatment may be included at the discretion of the CI.
  • Respiratory: Active Pneumonitis (of any origin: inflammatory or infectious), Sarcoidosis.
  • Dermatological: Psoriasis, Lupus/SLE.
  • Other: Rheumatoid Arthritis, Hypophysitis, Uveitis.

• History of organ transplant that requires use of immunosuppressive medications or any medical condition in which immunosuppressive agents were administered, including but, not limited to:

  • Systemic corticosteroids.
  • Methotrexate, azathioprine
  • Tumour necrosis factor alpha (TNF-α) blockers
• History of active primary immunodeficiency.
• Receipt of live, attenuated vaccine within the last 30 days.

• Other invasive malignancy within the last 3 years. Patients with previous history of malignancies with a negligible risk of metastasis or death and treated with expected curative intent are eligible at the investigator's discretion, for example:

  • Carcinoma in situ of the cervix
  • Basal or squamous cell skin cancer
  • Localized low to intermediate risk prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse; or prostate cancer (Stage T1/T2a, Gleason ≤ 6 and PSA < 10 ng/mL) undergoing active surveillance and treatment naive
• Women who are pregnant or lactating/ breast feeding.
• Male or female patients with reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab.
• Uncontrolled intercurrent illness, including but not limited to, on-going or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Brain metastases unless asymptomatic, treated and stable and not requiring steroids in the last 4 weeks. Patients with known or suspected brain metastases at screening should have a CT/ MRI of the brain prior to trial entry.
• History of leptomeningeal carcinomatosis.
• Active infection or use of antibiotics (ATB) 14 days prior to Cycle 1 Day 1 of treatment. Patients receiving prophylactic treatment are eligible.

• Active infection including tuberculosis (clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or known human immunodeficiency virus (positive HIV1/2 antibodies).

  • Subjects with a past or resolved HBV infection (defined as: presence of hepatitis B core antibody -anti-HBc- and absence of hepatitis B surface antigen -HbsAg-) are eligible.
  • Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Major surgical procedure (investigator defined) within 4 weeks prior to first dose or anticipation of the need for a major surgical procedure during the course of the trial other than for diagnosis.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to durvalumab or any of its excipients, chimeric or humanized antibodies or fusion proteins.
• Patients previously treated with immune (checkpoint inhibition) therapy
• Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical trial due to safety concerns, compliance with clinical trial procedures or interpretation of trial results.

Contacts and Locations

Contacts

Contact: Calibration Trial Coordinator; 01223 216083; calibration@addenbrookes.nhs.uk

Contact: Cambridge Cancer Trials Unit - Cancer Theme; 01223 216083; cctu.cancer@addenbrookes.nhs.uk

Locations

United Kingdom

Cambridge University Hospitals NHS Foundation Trust; Recruiting

Cambridge, United Kingdom, CB2 0QQ

Contact: Calibration Trial Coordinator 01223 216083 calibration@addenbrookes.nhs.uk

Contact: Simon Pacey simon.pacey@addenbrookes.nhs.uk

Principal Investigator: Simon Pacey

Sponsors and Collaborators

Simon C Pacey, MD

AstraZeneca

Investigators

• Principal Investigator: Simon Pacey; Cambridge University Hospitals

More Information

• Responsible Party: Simon C Pacey, MD, Chief Investigator, Cambridge University Hospitals NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT03653052
• Other Study ID Numbers: CALIBRATION
• First Posted: August 31, 2018
• Last Update Posted: September 3, 2019
• Last Verified: August 2019

• 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

Additional relevant MeSH terms:

Esophageal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Durvalumab; Antineoplastic Agents, Immunological; Antineoplastic Agents