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

NCT ID: NCT02735239

Last Updated: 2024-03-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 73 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-24
• Study Completion Date: 2022-06-16

Brief Summary

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).

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.

Conditions

Esophageal Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Anti PD-L1 antibody

Oxaliplatin

Intervention Type: DRUG

IV administered chemotherapy

Capecitabine

Intervention Type: DRUG

orally-administered chemotherapy

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Anti PD-L1 antibody

Tremelimumab

Intervention Type: DRUG

Anti CTLA-4 antibody

Oxaliplatin

Intervention Type: DRUG

IV administered chemotherapy

Capecitabine

Intervention Type: DRUG

orally-administered chemotherapy

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Anti PD-L1 antibody

Tremelimumab

Intervention Type: DRUG

Anti CTLA-4 antibody

Oxaliplatin

Intervention Type: DRUG

IV administered chemotherapy

Capecitabine

Intervention Type: DRUG

orally-administered chemotherapy

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Anti PD-L1 antibody

Oxaliplatin

Intervention Type: DRUG

IV administered chemotherapy

Capecitabine

Intervention Type: DRUG

orally-administered chemotherapy

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Anti PD-L1 antibody

Oxaliplatin

Intervention Type: DRUG

IV administered chemotherapy

5-fluorouracil (5-FU)

Intervention Type: DRUG

IV administered chemotherapy

Leucovorin

Intervention Type: DRUG

chemo-protective agent

Docetaxel

Intervention Type: DRUG

IV administered chemotherapy

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Anti PD-L1 antibody

Radiotherapy

Intervention Type: RADIATION

Paclitaxel

Intervention Type: DRUG

IV administered chemotherapy

Carboplatin

Intervention Type: DRUG

IV administered Chemotherapy

Interventions

Durvalumab

Anti PD-L1 antibody

Intervention Type: DRUG

Tremelimumab

Anti CTLA-4 antibody

Intervention Type: DRUG

Oxaliplatin

IV administered chemotherapy

Intervention Type: DRUG

Capecitabine

orally-administered chemotherapy

Intervention Type: DRUG

Radiotherapy

Intervention Type: RADIATION

Paclitaxel

IV administered chemotherapy

Intervention Type: DRUG

Carboplatin

IV administered Chemotherapy

Intervention Type: DRUG

5-fluorouracil (5-FU)

IV administered chemotherapy

Intervention Type: DRUG

Leucovorin

chemo-protective agent

Intervention Type: DRUG

Docetaxel

IV administered chemotherapy

Intervention Type: DRUG

Other Intervention Names

MEDI4736; Imfinzi®; Durva; Treme; Eloxatin®; Xeloda®; Radiation; Taxol®; Paraplatin®; Adrucil®; Leucovorin calcium; Folinic Acid; Taxotere®

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Ludwig Institute for Cancer Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark Middleton

Role: STUDY_CHAIR

University of Oxford, UK

Locations

Research Facility

Dundee, , United Kingdom

Research Facility

Nottingham, , United Kingdom

Research Facility

Oxford, , United Kingdom

Research Facility

Southampton, , United Kingdom

Countries

United Kingdom

References

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.

Reference Type: BACKGROUND

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2015-005298-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ESR 15-10891

Identifier Type: OTHER

Identifier Source: secondary_id

LUD2015-005

Identifier Type: -

Identifier Source: org_study_id