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

Esophageal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02735239
• Other study ID #: LUD2015-005
• Secondary ID: 2015-005298-19ES
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 24, 2016
• Est. completion date: June 16, 2022

Study information

• Verified date: September 2023
• Source: Ludwig Institute for Cancer Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 73
• Est. completion date: June 16, 2022
• Est. primary completion date: June 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Esophageal Cancer

Intervention

Drug:
• Durvalumab
Anti PD-L1 antibody
• Tremelimumab
Anti CTLA-4 antibody
• Oxaliplatin
IV administered chemotherapy
• Capecitabine
orally-administered chemotherapy

Radiation:
• Radiotherapy

Drug:
• Paclitaxel
IV administered chemotherapy
• Carboplatin
IV administered Chemotherapy
• 5-fluorouracil (5-FU)
IV administered chemotherapy
• Leucovorin
chemo-protective agent
• Docetaxel
IV administered chemotherapy

Locations

Country	Name	City	State
United Kingdom	Research Facility	Dundee
United Kingdom	Research Facility	Nottingham
United Kingdom	Research Facility	Oxford
United Kingdom	Research Facility	Southampton

Sponsors (2)

Lead Sponsor	Collaborator
Ludwig Institute for Cancer Research	AstraZeneca

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

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.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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