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Trial registered on ANZCTR


Trial ID
ACTRN12614000950662
Ethics application status
Approved
Date submitted
19/06/2014
Date registered
4/09/2014
Date last updated
2/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised phase II trial of imatinib alternating with regorafenib compared to imatinib alone for the first line treatment of advanced gastrointestinal stromal tumour (GIST)
Scientific title
A phase II trial to determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety to warrant further evaluation as a first line treatment for metastatic GIST.
Secondary ID [1] 284561 0
AG1013GST
Secondary ID [2] 286466 0
NCT02365441
Universal Trial Number (UTN)
Trial acronym
ALT GIST
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic gastrointestinal stromal tumour (GIST) 291830 0
Condition category
Condition code
Cancer 292195 292195 0 0
Sarcoma (also see 'Bone') - soft tissue

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Those randomised to the experimental alternating arm will receive:
Imatinib 400mg (1 x 400mg tablet) orally daily for 21 to 25 days (washout period determined by treating investigator), then a 3 - 7 day washout period (no drug). In total, the days taking imatinib plus the washout period must be 28 days. This is followed by regorafenib 160 mg (4 x 40mg tablets) orally daily for 21 days, then a 7 day washout period. This combination of imatinib, regorafenib and intervening washout periods will constitute 1 cycle of study treatment (imatinib plus washout period 28 days in total; regorafenib 3 weeks on, 1 week off; cycle duration 8 weeks in total).
Treatment will continue until progressive disease or unacceptable toxicity.
A drug administration diary will be provided to patients.
Intervention code [1] 289333 0
Treatment: Drugs
Comparator / control treatment
Participants randomised to standard therapy will receive treatment with 400mg (1 x 400mg tablet) orally daily of imatinib, with no washout periods. Treatment will continue until progressive disease or unacceptable toxicity.
A drug administration diary will be provided to patients.
Control group
Active

Outcomes
Primary outcome [1] 292067 0
To determine PFS at 24 months as calculated from the commencement of treatment to the date of progression as determined by RECIST v1.1
Timepoint [1] 292067 0
Progression free survival is defined as the time from either (i) randomization (if patients have not yet commenced treatment) or (ii) commencement of therapy (if patients are randomized during the first cycle of imatinib). PFS at 24 months will be the proportion of patients potentially not progressing at 24 months. Disease progression is defined according to RECIST 1.1.
Secondary outcome [1] 308122 0
To determine objective tumour response rate following 2 cycles of treatment
Timepoint [1] 308122 0
Tumour evaluation will follow the RECIST Version 1.1 guidelines and be used to determine response status (i.e. complete response, partial response, stable disease, and progressive disease) at each assessment time point. The OTRR will be calculated by summing the number of participants assessed as having a complete or partial response within the first 16 weeks from randomisation, and dividing this by the total number of participants evaluable for response (according to RECIST Version 1.1).
Secondary outcome [2] 308123 0
To determine clinical benefit rate (SD + PR + CR) following 2 cycles of treatment
Timepoint [2] 308123 0
The Clinical benefit rate will be calculated by summing the number of participants assessed as having a complete response, partial response or stable disease within the first 16 weeks from randomisation, and dividing this by the total number of participants evaluable for response (according to RECIST Version 1.1) within the first 16 weeks.
Secondary outcome [3] 308124 0
To determine complete response rate
Timepoint [3] 308124 0
The Complete response rate will be calculated by summing the number of participants assessed as having a complete response and dividing this by the total number of participants evaluable for response (according to RECIST Version 1.1). For the first 12 months, CT scans are performed every 8 weeks after which CT scans are performed 12 weekly. CT scans should continue until progressive disease.
Secondary outcome [4] 308125 0
To determine time-to-treatment failure
Timepoint [4] 308125 0
Time to treatment failure is defined as the time from either (i) randomization (if patients have not yet commenced treatment) or (ii) commencement of therapy (if patients are randomized during the first cycle of imatinib to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, or death. This outcome will be assessed is up to 24 months.
Secondary outcome [5] 308126 0
To determine Safety/toxicity/tolerability
Timepoint [5] 308126 0
The NCI Common Terminology Criteria for Adverse Events version 4 (NCI CTCAE v4.0) will be used to classify and grade the intensity of adverse events after each treatment cycle. This outcome may be assessed until 30 days +/- 7 days after the last dose of treatment.
Secondary outcome [6] 308127 0
To determine overall survival
Timepoint [6] 308127 0
Overall survival is defined as the interval from either (i) randomization (if patients have not yet commenced treatment) or (ii) commencement of therapy (if patients are randomized during the first cycle of imatinib) to date of death from any cause, or the date of last known follow-up alive. Maximum duration that this outcome may be assessed is N/A.

Eligibility
Key inclusion criteria
-Adults (over 18 yrs) with histologically confirmed GIST. In CD-117-negative cases DOG-1 must be positive or a KIT/PDGFRA mutation must be present.
-Unresectable, metastatic disease.
-No prior TKI for metastatic disease, with the exception of those patients who have had up to 21 days of uninterrupted treatment on 400mg daily of imatinib.
-Imatinib therapy given as an adjuvant treatment and completed at least 3 months prior to entry into this trial is permitted. Patients who have progression of GIST while on adjuvant therapy are not eligible for this trial.
-ECOG performance status 0-2
-Measurable disease by RECIST version 1.1. (Note: Participants with only peritoneal disease will be eligible only if they have lesions measurable in two dimensions and have at least 1 lesion which is greater than or equal to 2 cm in size).
-Adequate bone marrow function (Haemoglobin greater than or equal to 9.0g/dL, platelet count greater than or equal to 100 x 109/L, and absolute neutrophil count greater than or equal to 1.5 x 109/L).
Adequate liver function (Serum total bilirubin less than or equal to 1.5 x ULN, INR less than or equal to 1.5, and ALT, AST, ALP less than or equal to 2.5 x ULN (less than or equal to 5 x ULN for participants with liver metastases). Lipase level must be less than or equal to 1.5 x ULN.
Adequate renal function (Creatinine clearance greater than 50ml/min) based on either the Cockcroft Gault formula, 24 hour urine or Glomerular Filtration Rate (GFR scan); and serum creatinine less than or equal to 1.5 x ULN.
-Tumour tissue available for central review.
-Willing and able to comply with all study requirements, including treatment timing and/or nature of required assessments.
-Study treatment both planned and able to start within 14 days of randomisation.
-Signed, written informed consent.


Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Concurrent GI illness which may prevent absorption of imatinib or regorafenib – please note that prior gastrectomy or bowel resection does not exclude patients from this study.
-Use of other investigational drugs within 4 weeks prior to enrolment.
-Known sensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
-Participants receiving therapeutic doses of warfarin.
-Presence of brain metastases.
-The presence of PDGFR D842V mutation or other mutation known to cause imatinib resistance.
- Inability to swallow tablets.
-Arterial thrombotic or ischaemic events, such as cerebrovascular accident or pulmonary embolism within 6 months prior to randomisation; or major venous thrombotic events requiring use of an anticoagulant such as warfarin within 6 months prior to randomisation.
-Poorly controlled hypertension (systolic blood pressure greater than 140 mmHg or diastolic pressure greater than 90 mmHg despite optimal medical management).
-Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation, or non healing wound, ulcer or fracture.
-Congestive cardiac failure (NYHA greater than or equal to grade 2), unstable angina or new onset angina within the previous 3 months, or AMI within the previous 6 months. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
-Haemorrhage or bleeding event greater than or equal to Grade 3 according to CTCAE v4.0 within 4 weeks prior to randomisation.
-Ongoing infection of greater than Grade 2 according to CTCAE v4.0.
-Active hepatitis B or C or HIV, or chronic hepatitis B or C requiring treatment with antiviral therapy. Testing for these is not mandatory unless clinically indicated.
-Interstitial lung disease with ongoing signs and symptoms.
-Persistent proteinuria of greater than or equal to Grade 3 (greater than 3.5g/24 hours) according to CTCAE v4.0
-Other significant medical or psychiatric condition judged by the investigator to interfere with protocol requirements.
-Use of biological response modifiers such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
-Patients taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinovir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg carbamazepine, phenobarbitol, phenytoin, rifampicin, St John’s wort).
-History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment.
- 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 days prior to registration. Women of childbearing potential and men must agree to use adequate contraception before entering the trial until at least 8 weeks after the last study drug administration.


Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Upon confirmation of eligibility, patients will be randomised (1:1 allocation) via central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be stratifed by site, receipt of previous adjuvant therapy (prior adjuvant therapy vs no prior adjuvant therapy), and receipt of imatinib for metastatic disease for less than 21 days. Randomisation method being used is minimisation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is a randomized Phase II design to investigate the efficacy/activity of an alternating regimen of
21-25 days of imatinib followed by a 3-7-day gap for washout followed by 21 of regorafenib and a 7-
day gap for washout. The control group will be a regimen of continuous imatinib in a 56 day cycle.
In order to demonstrate a relative increase in progression free survival at 24 months from the date of
randomisation or commencement of imatinib ( if the participant had already commence treatment),
based on A’Hern’s adjustment of Fleming’s design, approximately 110 evaluable participants in the
alternating group will provide 80% power with a 2-sided 95% confidence each to rule out a 24 month
expected PFS rate of 78% in favour of 88%. Allowing for a 1:1 randomisation, it is proposed to enrol
240 participants into the trial, allowing for approximately a 10% drop-out rate. Currently 80% of
participants are expected to achieve a clinical benefit at 24 months (CBR – rate of complete or partial
response, or stable disease). A secondary outcome would be to determine whether a minimum 25%
relative increase of the CBR (from 80% to 85%) in the experimental cohort can be attained.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Current
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 4786 0
The Canberra Hospital - Garran
Recruitment hospital [2] 4787 0
Prince of Wales Private Hospital - Randwick
Recruitment hospital [3] 4788 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [4] 4789 0
Border Medical Oncology - Wodonga
Recruitment hospital [5] 4790 0
Peninsula Oncology Centre - Frankston
Recruitment hospital [6] 4791 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [7] 4792 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [8] 4793 0
Ashford Cancer Centre: Adelaide Cancer Centre - Kurralta Park
Recruitment hospital [9] 4794 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [10] 4795 0
Royal Hobart Hospital - Hobart
Recruitment outside Australia
Country [1] 6038 0
Belgium
State/province [1] 6038 0
Country [2] 6039 0
France
State/province [2] 6039 0
Country [3] 6040 0
Sweden
State/province [3] 6040 0
Country [4] 6041 0
Finland
State/province [4] 6041 0
Country [5] 6042 0
Norway
State/province [5] 6042 0
Country [6] 7388 0
Singapore
State/province [6] 7388 0
Hong Kong

Funding & Sponsors
Funding source category [1] 289190 0
Commercial sector/Industry
Name [1] 289190 0
Bayer Global
Address [1] 289190 0
100 Bayer Boulevard, Whippany, NJ 07981
Country [1] 289190 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-Intestinal Trials Group (AGITG)
Address
Locked Bag 77
Camperdown
NSW 1450
Country
Australia
Secondary sponsor category [1] 287948 0
None
Name [1] 287948 0
Address [1] 287948 0
Country [1] 287948 0
Other collaborator category [1] 277969 0
Other Collaborative groups
Name [1] 277969 0
European Organisation for Research and Treatment of Cancer (EORTC)
Address [1] 277969 0
83/11 Avenue E. Mounier 1200 Brussels Belgium, VAT BE 408292992,
Country [1] 277969 0
Belgium
Other collaborator category [2] 277970 0
Other Collaborative groups
Name [2] 277970 0
Scandinavian Sarcoma Group (SSG)
Address [2] 277970 0
Scheelevagen 8, SE-223 81 LUND
Country [2] 277970 0
Sweden

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291036 0
SLHD Ethics Review Committee (RPAH Zone) (EC00113)
Ethics committee address [1] 291036 0
Research Development Office
RPAH Medical Centre
Suite 210A, 100 Carillon Avenue
NEWTOWN NSW 2042
Ethics committee country [1] 291036 0
Australia
Date submitted for ethics approval [1] 291036 0
15/06/2014
Approval date [1] 291036 0
29/09/2014
Ethics approval number [1] 291036 0
HREC/14/RPAH/286

Summary
Brief summary
The aim of this study is to determine whether an alternating regime of imatinib and regorafenib improves disease control in patients with metastatic gastrointestinal stromal tumours (GIST). Who is it for? You may be eligible to join this study if you aged 18 years or more and have a confirmed diagnosis of metastatic GIST. Study details Participants in this study will be randomly (by chance) allocated to one of two groups. Participants in one group will receive an alternating regime of treatment with the drugs imatinib and regorafenib (administered orally by tablet). One treatment cycle lasts for 8 weeks. Participants in the other group will receive treatment with daily imatinib tablets only. Imatinib is currently used as the initial treatment for incurable GIST. Although many people with metastatic disease initially respond to imatinib, the cancer usually becomes resistant to this drug and starts to grow. The cancer drug called regorafenib works in a similar way to imatinib and has been shown to be effective against GIST after other treatments have stopped working. Participants will be regularly monitored for a minimum of 24 months follow-up in order to determine whether the alternating treatment approach improves disease control. If it is found to have benefit and be tolerable, this alternating approach will be further evaluated in a larger study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 48182 0
A/Prof Desmond Yip
Address 48182 0
NHMCR CTC Locked Bag 77 Camperdown, NSW, 1450
Country 48182 0
Australia
Phone 48182 0
+61 2 9562 5000
Fax 48182 0
+61 2 9562 5094
Email 48182 0
altgist@ctc.usyd.edu.au
Contact person for public queries
Name 48183 0
Ms ALTGIST Trial Coordinator
Address 48183 0
NHMCR CTC Locked Bag 77 Camperdown, NSW, 1450
Country 48183 0
Australia
Phone 48183 0
+61 2 9562 5000
Fax 48183 0
+61 2 9562 5094
Email 48183 0
altgist@ctc.usyd.edu.au
Contact person for scientific queries
Name 48184 0
Ms ALTGIST Trial Coordinator
Address 48184 0
NHMCR CTC Locked Bag 77 Camperdown, NSW, 1450
Country 48184 0
Australia
Phone 48184 0
+61 2 9562 5000
Fax 48184 0
+61 2 9562 5094
Email 48184 0
altgist@ctc.usyd.edu.au