Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer

Phase 1/2 Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer

This is an open-label, Phase 1/2 study to evaluate the safety of durvalumab (MEDI4736) in combination with oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC) and with neoadjuvant chemo(radio)therapy before surgery in operable OC. The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts. The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B, C, C-FLOT, D/D2).

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer
• Intervention / Treatment: Radiation: Radiotherapy; Drug: Capecitabine; Drug: Carboplatin; Drug: Durvalumab; Drug: Oxaliplatin; Drug: Tremelimumab; Drug: 5-fluorouracil (5-FU); Drug: Leucovorin; Drug: Docetaxel; Drug: Paclitaxel

Detailed Description

This is an open-label, Phase 1/2 study to evaluate the safety of immunotherapy in combination with chemo (radio) therapy with the following cohorts:

• Cohorts A1, A2, and B: Oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC).
• Cohort C: Neoadjuvant oxaliplatin/capecitabine chemotherapy before surgery in operable OC.
• Cohort C-FLOT: Neoadjuvant 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy before surgery in operable OC.
• Cohort D/D2: Neoadjuvant paclitaxel/carboplatin chemotherapy + radiotherapy before surgery in operable OC.

The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts for all cohorts except Cohort D.

The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B including the higher dose tremelimumab cohort from Cohort A2, C, C-FLOT, and D/D2).

Phase 1 will evaluate the safety of durvalumab alone (Cohort A1) administered before chemotherapy (oxaliplatin + capecitabine) in subjects with metastatic or locally advanced OC. After completion of Cohort A1, Phase 2 in Cohorts C, C-FLOT, and D/D2 will begin, and a safety review will determine whether to explore the tremelimumab + durvalumab combination (Cohort A2).

Phase 2 includes the expansion into Cohorts B, C, C-FLOT, and D/D2. Once Cohort A1 is cleared, there will be concurrent enrollment into Phase 2 expansion for Cohorts C, C-FLOT and D/D2 (subjects with operable OC with neoadjuvant chemotherapy or chemoradiotherapy before surgery) and the tremelimumab dose-escalation phase for Cohort A2 (37.5 mg and 75 mg). Once Cohort A2 is completed, another safety review will determine the dose of tremelimumab to be included in the recommended combination dose (RCD) to start enrollment into the Cohort B (subjects with metastatic/locally advanced OC) expansion phase. Subjects treated at the RCD in Cohort A2 (tremelimumab 75 mg) will be included in Cohort B.

Subjects in Cohorts C, C-FLOT and D/D2 will undergo surgery after completing treatment, and they will be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this is within 3 months of surgery. Subjects in Cohort C-FLOT may receive durvalumab, FLOT, or durvalumab plus FLOT at the discretion of the investigator.

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Research Facility
  • Nottingham, United Kingdom, NG5 1PB
    • Research Facility
  • Oxford, United Kingdom, OX3 9DU
    • Research Facility
  • Southampton, United Kingdom, SO16 6YD
    • Research Facility

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Histological diagnosis of oesophageal or gastrooesophageal cancer and have not received prior chemotherapy.

   • Cohorts A and B - metastatic/locally advanced cancer
   • Cohorts C/C-FLOT and D/D2 - deemed suitable for surgery with curative intent
2. Anticipated lifespan greater than 4 months.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. At the time of day 1 of the study, subjects with brain metastases must be asymptomatic for at least 4 weeks and:

   • at least 8 weeks without tumour progression after any whole brain radiotherapy
   • at least 4 weeks since craniotomy and resection or stereotactic radiosurgery
   • at least 3 weeks without new brain metastases as evidenced by MRI/CT
5. Adequate normal organ and marrow function. Laboratory parameters for vital functions should be in the normal range. Laboratory abnormalities that are not clinically significant are generally permitted.
6. Written informed consent obtained from the subject; subject been informed of other treatment options, and able to comply with study requirements.
7. Age 18 years or older.

Exclusion Criteria

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrollment in the present study.
2. Participation in another clinical study with an investigational product during the last 4 weeks.
3. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.
4. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
5. History of allogeneic organ transplant.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C, known immunodeficiency or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
7. Known history of previous clinical diagnosis of tuberculosis.
8. History of pneumonitis or interstitial lung disease.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A1: Metastatic/locally advanced OC, Durva + Chemotherapy (Chemo); Durvalumab (750 mg IV every two weeks [Q2W]) was to be given for up to 11 doses. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.	Drug: Capecitabine; orally-administered chemotherapy; Other Names: Xeloda®; Drug: Durvalumab; Anti PD-L1 antibody; Other Names: MEDI4736; Imfinzi®; Durva; Drug: Oxaliplatin; IV administered chemotherapy; Other Names: Eloxatin®
Experimental: Cohort A2: Metastatic/locally advanced OC, Durva, Treme + Chemo; Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (37.5 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.	Drug: Capecitabine; orally-administered chemotherapy; Other Names: Xeloda®; Drug: Durvalumab; Anti PD-L1 antibody; Other Names: MEDI4736; Imfinzi®; Durva; Drug: Oxaliplatin; IV administered chemotherapy; Other Names: Eloxatin®; Drug: Tremelimumab; Anti CTLA-4 antibody; Other Names: Treme
Experimental: Cohort B: Metastatic/locally advanced OC, Durva, Treme + Chemo; Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (75 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.	Drug: Capecitabine; orally-administered chemotherapy; Other Names: Xeloda®; Drug: Durvalumab; Anti PD-L1 antibody; Other Names: MEDI4736; Imfinzi®; Durva; Drug: Oxaliplatin; IV administered chemotherapy; Other Names: Eloxatin®; Drug: Tremelimumab; Anti CTLA-4 antibody; Other Names: Treme
Experimental: Cohort C: Operable OC; Durva + Chemo; Durvalumab (750 mg IV Q2W) was to be given for up to 5 doses. Two cycles of neoadjuvant oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy were to be administered before surgery. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.	Drug: Capecitabine; orally-administered chemotherapy; Other Names: Xeloda®; Drug: Durvalumab; Anti PD-L1 antibody; Other Names: MEDI4736; Imfinzi®; Durva; Drug: Oxaliplatin; IV administered chemotherapy; Other Names: Eloxatin®
Experimental: Cohort C-FLOT: Operable OC, Durva + FLOT Chemotherapy; Durvalumab (750 mg IV Q2W) was to be given for up to 6 doses. Two cycles of neoadjuvant 5-fluorouracil (5-FU) (2600 mg/m^2 24-hr IV), leucovorin (200 mg/m^2 IV), oxaliplatin (85 mg/m^2 IV), and docetaxel (50 mg/m^2 IV) chemotherapy (FLOT) were to be administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.	Drug: Durvalumab; Anti PD-L1 antibody; Other Names: MEDI4736; Imfinzi®; Durva; Drug: Oxaliplatin; IV administered chemotherapy; Other Names: Eloxatin®; Drug: 5-fluorouracil (5-FU); IV administered chemotherapy; Other Names: Adrucil®; Drug: Leucovorin; chemo-protective agent; Other Names: Folinic Acid; Leucovorin calcium; Drug: Docetaxel; IV administered chemotherapy; Other Names: Taxotere®
Experimental: Cohort D/D2: Operable OC, Durva + Neoadjuvant Chemo(radio)therapy; Durvalumab (750 mg IV Q2W) was to be given for 2 doses. This was followed by five weekly doses of neoadjuvant paclitaxel (50 mg/m^2 IV) / carboplatin (AUC 2) IV chemotherapy + radiotherapy (41.4 Gy radiotherapy given over 23 fractions) before surgery. Subjects could receive an additional dose of durvalumab after completion of chemoradiation. In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.	Radiation: Radiotherapy; Other Names: Radiation; Drug: Carboplatin; IV administered Chemotherapy; Other Names: Paraplatin®; Drug: Durvalumab; Anti PD-L1 antibody; Other Names: MEDI4736; Imfinzi®; Durva; Drug: Paclitaxel; IV administered chemotherapy; Other Names: Taxol®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Reporting Treatment Emergent Adverse Events (TEAEs)	Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) were reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 110 days after the last dose of study treatment. Treatment-emergent AEs were those that occurred or worsened after administration of the first dose of study treatment. In Cohorts A1, A2 and B, 12, 5 and 7 subjects, respectively, were monitored for dose limiting toxicities (DLTs) during the first 10 weeks of treatment (DLT evaluation period).	up to 1 year
Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)	Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), and in Cycles 1, 3, 5 and 6 in Cohorts A1, A2 and B. In the other cohorts, tumor response was assessed at baseline, post-surgery and 14 days after the last dose. In Cohorts C-FLOT and D, an additional assessment was done prior to surgery and in Cohorts C and D, an additional assessment was done in Cycle 3. Per irRECIST, measurable lesions are categorized as follows: Immune-related Complete Response (irCR): Complete disappearance of all target lesions; Immune-related Partial Response (irPR): ≥ 30% decrease from baseline in the Total Measurable Tumor Burden (TMTB); Immune-related Progressive Disease (irPD): ≥ 20% increase from nadir in TMTB; Immune-related Stable Disease (irSD): not meeting above criteria; irNon-CR/Non-PD: irNon-CR/Non-PD is preferred over SD when no lesions can be measured.	up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Metastatic/Locally Advanced Oesophageal Cancer (OC) Who Had a Response at Cycle 6 by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)	Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), and in Cycles 1, 3, 5 and 6 in Cohorts A1, A2 and B. Per irRECIST, measurable lesions are categorized as follows: irCR: Complete disappearance of all target lesions; irPR: ≥ 30% decrease from baseline in the Total Measurable Tumor Burden (TMTB); irPD: ≥ 20% increase from nadir in TMTB; irSD: not meeting above criteria; irNon-CR/Non-PD: irNon-CR/Non-PD is preferred over SD when no lesions can be measured.	Up to 23 weeks
Median Progression-free Survival (PFS) by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) as Estimated Using the Kaplan-Meier Method	Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), and in Cycles 1, 3, 5 and 6 in Cohorts A1, A2 and B. In the other cohorts, tumor response was assessed at baseline, post-surgery and 14 days after the last dose. In Cohorts C-FLOT and D, an additional assessment was done prior to surgery and in Cohorts C and D, an additional assessment was done in Cycle 3. In Cohorts A1, A2 and B, PFS was measured from the date of the first dose of study treatment to the date of earliest disease progression according to irRECIST or to the date of death, if disease progression did not occur. For Cohorts C, C-FLOT and D/D2, PFS is measured from the date of surgery. Per irRECIST, irPD was defined as a ≥ 20% increase from nadir in the TMTB.	Up to 3 years
Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method	After completion of treatment, all subjects were followed for survival every 6 months for up to 3 years from start of treatment. OS was measured from the date of the first dose of study treatment to the date of death or last follow-up. Subjects lost to follow-up were censored on the date when they were last known to be alive. Per protocol amendment 8.0, all post study follow-up for the collection of survival data was discontinued as of June 30, 2022.	Up to 3 years
One Year Survival Rate in Subjects With Operable OC	OS was measured from the date of the first dose of study treatment to the date of death or last follow-up. Subjects lost to follow-up were censored on the date when they were last known to be alive. Per protocol amendment 8.0, all post study follow-up for the collection of survival data was discontinued as of June 30, 2022.	up to 12 months
Overall Response Prior to Surgery in Operable OC (Cohorts C, C-FLOT and D/D2) Using Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST)	18F- fluorodeoxyglucose (18F-FDG) PET scans were conducted at baseline and in Cycle 3 in Cohorts C and D, and after completion of therapy in Cohort C-FLOT and D2. Complete metabolic response: 18F-FDG-avid lesions revert to background of normal tissues in which they are located; Partial metabolic response: 30% or greater reduction in measurable tumors; Stable Metabolic Response: no visible change in metabolic activity of tumor; Progressive metabolic disease: increase in intensity or extent of tumor metabolic activity or new sites of activity.	Up to 7months

Collaborators and Investigators

• Sponsor: Ludwig Institute for Cancer Research
• Collaborators: AstraZeneca
• Investigators: Study Chair: Mark Middleton, University of Oxford, UK

Publications and helpful links

General Publications

• Bohnsack O, Hoos A, Ludajic K. Adaptation of the immune related response criteria: irRECIST. Ann Oncol. 2014 Sep;25(suppl 4):iv361-iv72 [Abstract 4958]. doi: 10.1093/annonc/mdu342.23.

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2016
• Primary Completion (Actual): June 16, 2022
• Study Completion (Actual): June 16, 2022

Study Registration Dates

• First Submitted: March 17, 2016
• First Submitted That Met QC Criteria: April 11, 2016
• First Posted (Estimated): April 12, 2016

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: September 12, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Immunotherapy; Programmed death ligand 1 (PD-L1); Oesophageal Cancer; Oesophageal adenocarcinoma; Oesophageal squamous cell carcinoma; Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); Programmed cell death protein 1 (PD-1)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Docetaxel; Carboplatin; Fluorouracil; Capecitabine; Oxaliplatin; Durvalumab; Tremelimumab; Leucovorin; Levoleucovorin
• Other Study ID Numbers: LUD2015-005; 2015-005298-19 (EudraCT Number); ESR 15-10891 (Other Identifier: AstraZeneca reference number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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