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Esophageal CancerPhase 1/2NCT02735239

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

A Phase 1/2 study testing Durvalumab, Tremelimumab and Oxaliplatin in people with Esophageal Cancer, run by Ludwig Institute for Cancer Research at 4 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Esophageal Cancer
What is being tested?
Durvalumab, Tremelimumab and Oxaliplatin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
73 participants
Where
4 sitesUnited Kingdom
Study dates
24 Jun 2016to 16 Jun 2022
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
  • Anticipated lifespan greater than 4 months.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • At the time of day 1 of the study, subjects with brain metastases must be asymptomatic for at least 4 weeks and:
Show all 12Show fewer
  • 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
  • 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.
  • Written informed consent obtained from the subject; subject been informed of other treatment options, and able to comply with study requirements.
  • Age 18 years or older.

Who cannot join

  • 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.
  • Participation in another clinical study with an investigational product during the last 4 weeks.
  • Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.
  • Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
  • History of allogeneic organ transplant.
  • 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.
  • Known history of previous clinical diagnosis of tuberculosis.
  • History of pneumonitis or interstitial lung disease.

Trial locations and contacts

4 sites in 1 country.

United Kingdom4 sites

  • Research Facility

    Dundee, DD1 9SY

  • Research Facility

    Nottingham, NG5 1PB

  • Research Facility

    Oxford, OX3 9DU

  • Research Facility

    Southampton, SO16 6YD

Other trials in United Kingdom

About this study

Official title: 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).

Read the 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.

Being tested
Durvalumab, Tremelimumab, Oxaliplatin, Capecitabine, Radiotherapy
Keywords
Oesophageal Cancer, Oesophageal adenocarcinoma, Oesophageal squamous cell carcinoma, Immunotherapy, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Programmed cell death protein 1 (PD-1), Programmed death ligand 1 (PD-L1)
Medical subject headings
Esophageal Neoplasms, Adenocarcinoma Of Esophagus, Esophageal Squamous Cell Carcinoma, Diabetes Mellitus, Insulin-Dependent, 12, Parkinson Disease 4, Autosomal Dominant Lewy Body

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabDrug

    Also called MEDI4736, Imfinzi®, Durva

    Anti PD-L1 antibody

  • TremelimumabDrug

    Also called Treme

    Anti CTLA-4 antibody

  • OxaliplatinDrug

    Also called Eloxatin®

    IV administered chemotherapy

  • CapecitabineDrug

    Also called Xeloda®

    orally-administered chemotherapy

  • RadiotherapyRadiation

    Also called Radiation

  • PaclitaxelDrug

    Also called Taxol®

    IV administered chemotherapy

  • CarboplatinDrug

    Also called Paraplatin®

    IV administered Chemotherapy

  • 5-fluorouracil (5-FU)Drug

    Also called Adrucil®

    IV administered chemotherapy

  • LeucovorinDrug

    Also called Leucovorin calcium, Folinic Acid

    chemo-protective agent

  • DocetaxelDrug

    Also called Taxotere®

    IV administered chemotherapy

Study groups in NCT02735239
Study groupRoleWhat they receive
Cohort A1: Metastatic/locally advanced OC, Durva + Chemotherapy (Chemo)ExperimentalDurvalumab (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.
Receives: Drug: Durvalumab; Drug: Oxaliplatin; Drug: Capecitabine
Cohort A2: Metastatic/locally advanced OC, Durva, Treme + ChemoExperimentalDurvalumab (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.
Receives: Drug: Durvalumab; Drug: Tremelimumab; Drug: Oxaliplatin; Drug: Capecitabine
Cohort B: Metastatic/locally advanced OC, Durva, Treme + ChemoExperimentalDurvalumab (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.
Receives: Drug: Durvalumab; Drug: Tremelimumab; Drug: Oxaliplatin; Drug: Capecitabine
Cohort C: Operable OC; Durva + ChemoExperimentalDurvalumab (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.
Receives: Drug: Durvalumab; Drug: Oxaliplatin; Drug: Capecitabine
Cohort C-FLOT: Operable OC, Durva + FLOT ChemotherapyExperimentalDurvalumab (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.
Receives: Drug: Durvalumab; Drug: Oxaliplatin; Drug: 5-fluorouracil (5-FU); Drug: Leucovorin; Drug: Docetaxel
Cohort D/D2: Operable OC, Durva + Neoadjuvant Chemo(radio)therapyExperimentalDurvalumab (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.
Receives: Drug: Durvalumab; Radiation: Radiotherapy; Drug: Paclitaxel; Drug: Carboplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: up to 1 year

  2. 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.

    Measured: up to 1 year

Secondary outcomes (5)

  1. 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.

    Measured: Up to 23 weeks

  2. 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.

    Measured: Up to 3 years

  3. 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.

    Measured: Up to 3 years

  4. 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.

    Measured: up to 12 months

  5. 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.

    Measured: Up to 7months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Apr 2016 (estimated)
  2. Study start24 Jun 2016
  3. Primary completion16 Jun 2022
  4. Study completion16 Jun 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
73 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02735239
Sponsor's protocol ID
LUD2015-005
Other IDs
2015-005298-19, ESR 15-10891, 2015
Status last verified
Sep 2023
First submitted
17 Mar 2016
Last updated
22 Mar 2024
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

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.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Durvalumab, Tremelimumab and Oxaliplatin in people with Esophageal Cancer, run by Ludwig Institute for Cancer Research at 4 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Subjects Reporting Treatment Emergent Adverse Events (TEAEs) (time frame: up to 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02735239, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Mar 2024.

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