A Randomised Phase III Double-Blind Placebo-Controlled Study of regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)

• Register: ANZCTR
• Last refreshed on: 26 October 2021
• Main ID: ACTRN12616000420448
• Date of registration: 01/04/2016
• Prospective Registration: Yes
• Primary sponsor: The Australasian Gastro-Intestinal Trials Group (AGITG)
• Public title: A Randomised Phase III Double-Blind Placebo-Controlled Study of regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)
• Scientific title: A Randomised Phase III Double-Blind Placebo-Controlled Study to determine if regorafenib improves overall survival in refractory Advanced Gastro-Oesophageal Cancer (AGOC)
• Date of first enrolment: 10/11/2016
• Target sample size: 350
• Recruitment status: Recruiting
• URL: https://anzctr.org.au/ACTRN12616000420448.aspx
• Study type: Interventional
• Study design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel;Type of endpoint: Safety/efficacy;
• Phase: Phase 3

Countries of recruitment

Australia, Canada, Japan, Korea, Republic Of, New Zealand, Taiwan, Province Of China, United States of America

Contacts

• Name: Mr Anthony Jaworski (Project Manager)

• Name: Mr Anthony Jaworski (Project Manager)

Key inclusion & exclusion criteria

Inclusion criteria: 1. Adults (18 years or over) with metastatic or locally recurrent gastro-oesophageal cancer which:
a. has arisen in any primary gastro-oesophageal site (oesophago-gastric junction (GOJ) or stomach); and
b. is of adenocarcinoma or undifferentiated carcinoma histology , and
c. is evaluable according to Response Evaluation Criteria in Solid Tumours (RECIST Version 1.1) by computed tomography (CT) scan performed within 21 days prior to randomisation. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrolment; and
d. has failed or been intolerant to a minimum of 2 lines of prior anti-cancer therapy for recurrent/metastatic disease which must have included at least one platinum agent and one fluoropyrimidine analogue, Note: Neoadjuvant or adjuvant chemotherapy or chemoradiotherapy will be considered as first line treatment where people have relapsed or progressed within 6 months of completing treatment; Radiosensitising chemotherapy given solely for this purpose concurrent with palliative radiation will not be considered as a line of treatment. Ramucirumab monotherapy, or immunotherapy with a checkpoint inhibitor, will be considered a line of treatment.
e. HRE2- positive participants mush have received trastuzumab.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
3. Ability to swallow oral medication.
4. Adequate bone marrow function (Platelets greater than or equal to 100x109/L; Absolute Neutrophil Count (ANC) greater than or equal to 1.5x109/L and Haemoglobin greater than or equal to 9.0g/dL).
5. Adequate renal function (Creatinine clearance greater than 50 ml/min) based on either the Cockcroft-Gault formula (Appendix 2), 24-hour urine or Glomerular Filtration Rate (GFR) scan; and serum creatinine less than or equal to 1.5 x Upper Limit of Normal (ULN).
6. Adequate liver function (Serum total bilirubin less than or equal to 1.5 x ULN, and INR less than or equal to 1.5 x ULN, and Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) less than or equal to 2.5 x ULN (less than or equal to 5 x ULN for participants with liver metastases)).
Participants being treated with an anti-coagulant, such as warfarin or heparin, will be allowed to participate provided that no prior evidence of an underlying abnormality in these parameters exists.
7. Adequate cardiac function (Left Ventricular Ejection Fraction (LVEF) greater than or equal to 50% or above the lower limit of normal (LLN) for the Institution (whichever is lower).
Cardiac function should be assessed within 3 months prior to randomisation, but after completion of any anthracycline containing chemotherapy.
8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments and follow-up.
9. Study treatment both planned and able to start within 7 days after randomisation (note: subjects randomised on a Friday should commence treatment no earlier than the following Monday)
10. Signed, written informed consent.

Exclusion criteria: 1. Known allergy to the investigational product drug class or excipients in the regorafenib
2. Poorly controlled hypertension (systolic blood pressure greater than 140mmHg or diastolic pressure greater than 90mmHg despite optimal medical management).
3. Participants with known uncontrolled malabsorption syndromes
4. Any prior anti-VEGF targeted therapy using small molecule VEGF TKIs (e.g. apatinib). Prior anti-VEGF targeted monoclonal antibody therapies (e.g. bevacizumab and ramucirumab) are permitted.
5. Treatment with any previous drug therapy within 2 weeks prior to first dose of study treatment. This includes any investigational therapy.
6. Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
7. Concurrent treatment with strong CYP3A4 inhibitors or inducers.
8. Palliative radiotherapy, unless more than 14 days have elapsed between completion of radiation and the date of registration, and adverse events resulting from radiation have resolved to less than Grade 2 according to CTCAE V4.03
9. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
10. Arterial thrombotic or ischaemic events, such as cerebrovascular accident within 6 months prior to randomization.
11. Venous thrombotic events and pulmonary embolism within 3 months prior to randomization
12. Any haemorrhage or bleeding event greater than or equal to Grade 3 according to CTCAE v4.03 within 4 weeks prior to randomization.
13. Non-healing wound, ulcer, or bone fracture.
14. Interstitial lung disease with ongoing signs and symptoms
15. Clinical hyperthyroidism or hypothyroidism. Note: non-clinically significant abnormal TFTs (abnormal TSH and abnormal T3 and/or abnormal T4) considered to be due to sick euthyroid syndrome is allowed.
16. Persistent proteinuria of greater than or equal to Grade 3 according to CTCAE v4.03
(Equivalent to greater than or equal to 3.5g of protein over 24 hours, measured on either a random specimen of 24 hour collection).
17. Uncontrolled metastatic disease to the central nervous system.
To be eligible, CNS metastases should have been treated with surgery and/or radiotherapy and the patient should have been receiving a stable dose of steroids for at least 2 weeks prior to randomization, with no deterioration in neurological symptoms during this time.
18. History of another malignancy within 2 years prior to randomization. Participants with the following are eligible for this study:
a) curatively treated cervical carcinoma in situ,
b) non-melanomatous carcinoma of the skin,
c) superficial bladder tumours (T1a [Non-invasive tumour], and Tis[Carcinoma in situ]),
d) treated thyroid papillary cancer
19. Any significant active infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated. Participants with known Hepatitis B/C infection will be allowed to participate providing evidence of viral suppression has been documented and the patient remains on appropriate anti-viral therapy.
20. Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.
21. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 d

Age minimum: 18 Years
Age maximum: No limit
Gender: Both males and females

Health Condition(s) or Problem(s) studied

Advanced (metastatic or locally recurrent) Gastro-Oesophageal Cancer (AGOC);
Advanced (metastatic or locally recurrent) Gastro-Oesophageal Cancer (AGOC)

Cancer - Oesophageal (gullet)

Cancer - Stomach

Intervention(s)

Group 1: Regorafenib will be self-administered by participants at 160mg (4 x 40mg tablets) orally once daily on days 1-21 of each 28 day cycle plus best supportive care until progression or prohibitive toxicity as defined by the protocol. The pharmacy at Participating Institutions will maintain a record of drugs dispensed for each participant and tablets returned.

Primary Outcome(s)

Overall survival (death from any cause)[Patient status updates will be sought every 2-4 weeks at clinic visit whilst on treatment and then every 8 weeks until death. ]

Secondary Outcome(s)

Safety- The NCI Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE) will be used to classify and grade the intensity of adverse events after each treatment cycle.
AEs include the following;
- All suspected adverse drug or device reactions
- All reactions from drug or device – overdose, abuse, withdrawal, sensitivity, toxicity or
failure of expected pharmacological action (if appropriate)
- Apparently unrelated illnesses, including the worsening (severity, frequency) of pre-existing illnesses
- Injury or accidents.
- Abnormalities in physiological testing or physical examination that require clinical intervention or further investigation (beyond ordering a repeat examination)
- Laboratory abnormalities that require clinical intervention or further investigation (beyond
ordering a laboratory test).
- Any untoward event that occurs after the protocol-specified reporting period, which the Investigator believes may be related to the study drug or device.[Adverse events will be reported at baseline and assessed 4 weekly whilst on study treatment, and at the 30 Day safety visit.]

Objective tumour response rate (partial or complete response) [Tumour response will be assessed according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) guidelines via CT scan within 21 days prior to randomisation and then every 8 weeks until disease progression. ]

Patient-rated quality of life (EORTC QLQ-C30, STO22, EQ5D-5L, and Patient D.A.T.A form)[Patient rated quality of life will be assessed via self-report questionnaires at baseline and every 4 weeks thereafter until disease progression.]

To evaluate progression free survival (disease progression or death)[Tumour response will be assessed according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) guidelines via CT scan within 21 days prior to randomisation and then every 8 weeks until disease progression. ]

Secondary ID(s)

AG0315OG

CTC0140

Source(s) of Monetary Support

Bayer HealthCare Pharmaceuticals Inc.

Ethics review

Status: Approved
Approval date: 31/03/2016
Contact:

Northern Sydney Local Distrct HREC

Status: Approved
Approval date: 14/10/2016
Contact:

The Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research

Status: Approved
Approval date: 10/11/2016
Contact:

St John of God Health Care Human Research Ethics Committee

Status: Approved
Approval date: 18/11/2016
Contact:

Tasmania Health and Medical Human Research Ethics Committee

Status: Approved
Approval date: 30/11/2016
Contact:

ACT Health Human Research Ethics Committee

Status: Approved
Approval date: 02/12/2016
Contact:

Southern Health and Disability Ethic Committee

Status: Approved
Approval date: 23/12/2016
Contact:

Bellberry Human Research Ethics Committee A

Status: Approved
Approval date: 20/01/2017
Contact:

Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee