Proof-of-concept Study of Ibrutinib in c-MYC and HER2 Amplified Oesophagogastric Carcinoma

NCT02884453 | Unknown Phase 2 DMC

• 1 other identifier: 4449
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

Some cancers of the oesophagus and stomach express excessive copies of either the cMYC (Myelocytomatosis oncogene) gene, the HER2 (Human epidermal growth factor receptor 2) gene or both. These genes may potentially contribute to the growth and spread of cancer.Ibrutinib is a drug that is already used in the treatment of certain cancers of the immune system. There is preclinical evidence that it shows activity against gastric and stomach cancer cells over-expressing cMYC and HER2 genes. The iMYC study will assess the activity of ibrutinib in cancers of the oesophagus and stomach which over-express these genes and which have previously been treated with standard chemotherapies. Any anti-cancer activity seen will be measured and correlated with metabolic changes on FDG (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose) - PET (positron emission tomography) scan, changes in DNA and circulating tumour cells in the blood, and molecular changes in the cancer itself through the use of optional repeat tumour biopsies. If an effect is seen it could provide justification for further research in this group of patients. Patients will be eligible if they have advanced cancer of the oesophagus or stomach and have been treated with at least one line of prior therapy. The study will be conducted at the Royal Marsden Hospital at its Sutton and Chelsea sites. It will involve an initial group of up to 17 patients. Screening, recruitment and follow up will last for 3 years in total. Patients wishing to take part must consent to having their cancer biopsied to test for cMYC and HER2 amplification, as well as a number of imaging and blood tests. There are optional further tumour biopsies whilst on study. Patients will be treated with ibrutinib until progression of their disease or unacceptable toxicity.

Conditions

Gastrooesophageal Cancer

Keywords

gastrooesophageal carcinoma

Outcome Measures

Primary Outcomes (1)

• Objective response rate in patients with c-MYC and HER2 amplified advanced pre-treated oesophagogastric carcinomas treated with ibrutinib

  Primary end point of objective overall radiological response rate, defined as confirmed complete response and partial response on CT or MRI imaging (assessed according to RECIST 1.1).

  3 years

Secondary Outcomes (7)

• Progression free survival

  3 years

• Overall survival

  3 years

• Disease control rate at 8 weeks

  8 weeks

• Safety and tolerability of ibrutinib treatment in advanced oesophagogastric cancer

  3 years

• Patient reported outcome- health related quality of life (HRQoL) as assessed by EORTC Quality of Life questionnaire QLQ-C30

  3 years

Other Outcomes (3)

• Pharmacokinetics of ibrutinib in advanced oesophagogastric cancer patients: Minimum Concentration (Cmin) of ibrutinib

  3 years

• Investigate dynamic changes in c-MYC copy number in circulating tumour DNA

  3 years

• Correlate c-MYC amplification ratio in tumour tissue with c-MYC copy number variation in serum

  3 years

Study Arms (1)

ibrutinib

EXPERIMENTAL

ibrutinib delivered orally at a dose of 560mg once daily continuously on a 4 weekly cycle until disease progression or unacceptable toxicity occurs.

Drug: ibrutinib

Interventions

ibrutinib DRUG

Ibrutinib (PCI-32765) is a first-in-class, potent, orally-administered, covalently-binding small molecule inhibitor of Bruton's tyrosine kinase (BTK) currently under development for the treatment of B-cell malignancies. Ibrutinib is being co-developed by Janssen Research \& Development, LLC and Pharmacyclics Inc.

Also known as: JNJ-54179060, IMBRUVICA, PCI-32765

ibrutinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Female or male aged 18 years or older.
• Histologically proven metastatic or locally advanced inoperable squamous or adeno carcinoma of the oesophagus,stomach or oesophago-gastric junction.
• Documented progression after at least 1 prior line of chemotherapy for advanced disease. For HER2 positive tumours documented progression after at least 1 line of chemotherapy with or without HER2 directed therapy.
• c-MYC or HER2 gene amplification as defined in trial protocol
• Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study. If female patients are taking hormonal contraceptives to prevent pregnancy then this should be combined with a barrier method of contraception. Men must agree to not donate sperm during and after the study. For both males and females restrictions apply for 3 month after the last dose of study drug. See protocol for highly effective methods of birth control.
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[b-hCG\]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
• Mandatory provision of archival or fresh tumour biopsy for confirmation of c-MYC or HER2 gene amplification.
• World Health Organisation (ECOG) performance status 0-2, minimum life expectancy of 12 weeks from proposed first dose date, no deterioration within 2 weeks of screening and first dose.
• Adequate organ and haematological function as evidenced by the following laboratory values within 14 days before enrolment:
• absolute neutrophil count (ANC) ≥1,500/mm3μL platelets ≥100,000/mm3μL (independent of transfusion support) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin serum creatinine ≤2 x ULN or estimated creatinine clearance (CCr) ≥30 mL/min/1.73m2
• At least one measurable target lesion, as per RECIST criteria 1.1

You may not qualify if:

• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Concurrent treatment within 4 weeks of study entry with any other chemotherapy, anticancer immunotherapy or experimental therapy
• No available histology for c-MYC or HER-2 amplification testing
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
• Patients with ECG abnormalities considered by the investigator to be clinically significant, or repeated baseline prolongation of the rate-corrected QT interval (QTc)
• Any actively bleeding gastrooesophageal tumour
• History of stroke or intracranial haemorrhage within 6 months prior to enrolment
• Symptomatic brain metastases
• Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
• Ongoing anticoagulation with a vitamin K antagonist
• Requiring use of strong P450 (CYP) 3A4 inhibitors
• Major surgery within 4 weeks of enrolment
• Vaccinated with live, attenuated vaccines within 4 weeks of enrolment
• Any pre-existing medical condition of sufficient severity to prevent full compliance with the study

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Janssen, LP: collaborator

Study Sites (1)

The Royal Marsden NHS Trust

Sutton, Surrey, SM2 5PT, United Kingdom

RECRUITING

Related Publications (2)

• Butler M, van Ingen Schenau DS, Yu J, Jenni S, Dobay MP, Hagelaar R, Vervoort BMT, Tee TM, Hoff FW, Meijerink JP, Kornblau SM, Bornhauser B, Bourquin JP, Kuiper RP, van der Meer LT, van Leeuwen FN. BTK inhibition sensitizes acute lymphoblastic leukemia to asparaginase by suppressing the amino acid response pathway. Blood. 2021 Dec 9;138(23):2383-2395. doi: 10.1182/blood.2021011787.

  PMID: 34280258 DERIVED

• Chong IY, Aronson L, Bryant H, Gulati A, Campbell J, Elliott R, Pettitt S, Wilkerson P, Lambros MB, Reis-Filho JS, Ramessur A, Davidson M, Chau I, Cunningham D, Ashworth A, Lord CJ. Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer. Gut. 2018 Oct;67(10):1780-1792. doi: 10.1136/gutjnl-2017-314408. Epub 2017 Aug 22.

  PMID: 28830912 DERIVED

MeSH Terms

Interventions

ibrutinib

Study Officials

• Ian Chau

  Royal Marsden NHS Foundation Trust

  STUDY CHAIR

Central Study Contacts

Annette Bryant

CONTACT

0208 642 6011; annette.bryant@rmh.nhs.uk

Michael Davidson

CONTACT

020 8642 6011; michael.davidson@rmh.nhs.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2016
• First Posted: August 31, 2016
• Study Start: July 19, 2016
• Primary Completion: December 30, 2021
• Study Completion: December 30, 2021
• Last Updated: September 18, 2019

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)