1. No category

Supplementary appendix
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Demetri GD, Reichardt P, Kang Y-K, et al, on behalf of all GRID study
investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal
tumours after failure of imatinib and sunitinib (GRID): an international, multicentre,
randomised, placebo-controlled, phase 3 trial. Lancet 2012; published online Nov 22.
http://dx.doi.org/10.1016/S0140-6736(12)61857-1.
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GRID lead investigators
AUSTRIA:
Hellmut Samonigg, MD, Medizinische Universitätsklinik Graz;
Thomas Brodowicz, MD, Alllgemeines Krankenhaus Wien, Universitätskliniken, Universitätsklinik für
Innere Medizin I;
Wolfgang Eisterer, MD, Medizinische Universitätsklinik Innsbruck;
BELGIUM: Patrick Schöffski, MD, Department of General Medical Oncology
Leuven Cancer Institute, University Hospitals Leuven;
CANADA: Martin Blackstein, MD, Mount Sinai Hospital, Toronto,
Karen Mulder, MD, Cross Cancer Institute, Edmonton,
Jawaid Younus, MD, London Regional Cancer Centre;
CHINA: Jin Li, MD, Cancer Hospital of FUDAN University,
Shukui Qin, MD, Nanjing Ba Yi Hospital,
De Sen Wan, MD, Sun Yat-Sen University Cancer Center, Guangzhou,
Jianming Xu, MD, 307 Hospital of PLA, Beijing;
FINLAND: Heikki Joensuu, MD, Helsinki University Central Hospital;
FRANCE: Jean-Yves Blay, MD, Centre Léon Bérard, Lyon,
Binh Bui Nguyen, MD, Institut Bergonié, Bordeaux,
Antoine Adenis, MD, Centre Oscar Lambret, Lille,
Axel Le Cesne, MD, Institut Gustave Roussy, Paris;
GERMANY: Peter Reichardt, MD, Helios Klinikum Bad Saarow,
Jens Chemnitz, MD, Universitätsklinik Köln,
Sebastian Bauer, MD, Universitätsklinikum Essen,
Peter Hohenberger, MD, Universitätsmedizin Mannheim,
Viktor Grünwald, MD, Medizinische Hochschule Hannover,
Frank Mayer, MD, Eberhard Karls Universität Tübingen,
Jochen Schütte, MD, Marien Hospital Düsseldorf;
ISRAEL: Ofer Merimsky, MD, Tel Aviv Souraski Medical Center;
ITALY: Paolo Casali, MD, Istituto Nazionale Tumori, Milano,
Guido Biasco, MD, Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi,
Massimo Aglietta, MD, Fondazione del Piemonte per l'Oncologia,
Giuseppe Badalamenti, MD, Azienda Ospedaliero Universitaria Policlinico
Paolo Giaccone, Palermo;
JAPAN: Toshihiko Doi, MD, National Cancer Center Hospital East, Chiba,
Tatsuo Kanda, MD, Niigata University Medical and Dental Hospital,
Toshirou Nishida, MD, Osaka Police Hospital,
Yasuhide Yamada, MD, National Cancer Center Hospital, Tokyo,
Yoshito Komatsu, MD, Hokkaido University Hospital,
Akira Sawaki, MD, Nagoya Daini Red Cross Hospital;
NETHERLANDS: Hans Gelderblom, MD, Leiden Universitair Medisch Centrum,
Winette Van der Graaf, MD, Radboud University Hospital, Nijmegen;
POLAND: Piotr Rutkowski, MD, Centrum Onkologii - Instytut im. M. Sklodowskiej-Curie, Warsaw;
SINGAPORE: Richard Quek, MD, National Cancer Centre;
SOUTH KOREA: Yoon-Koo Kang, MD, Asan Medical Center, Seoul,
Hyuk Chan Kwon, MD, Dong-A University Medical Center, Busan,
Seock-Ah Im, MD, Seoul National University Hospital,
Joon Oh Park, MD, Samsung Medical Center, Seoul,
Sun Young Kim, MD, National Cancer Center, Goyang;
SPAIN: Claudia M Valverde Morales, MD, Hospital Universitario Vall d'Hebron, Barcelona,
Xavier Garcia Del Muro, MD, Institut Català D'oncologia, Barcelona;
UK: Ian Judson, MD, Royal Marsden NHS Trust, London,
Michael Leahy, MD, Christie Hospital NHS Foundation Trust, Manchester,
Anne Thomas, MD, Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust;
USA: George Demetri, MD, Dana-Farber Cancer Institute, Boston MA,
Mary Louise Keohan, MD, Memorial Sloan-Kettering Cancer Center, NY,
Michael Heinrich, MD, Oregon Health and Sciences University, Portland OR,
Margaret von Mehren, MD, Fox Chase Cancer Center, Philadelphia PA,
Robin Jones, MD, University of Washington, Seattle WA,
Bruce Brockstein, MD, NorthShore University Health System, Evanston IL,
Pamela Kaiser, MD, Lutheran General Hospital, Chicago IL,
Keith Skubitz, MD, Masonic Cancer Center, Minneapolis, MN,
Michael Gordon, MD, Pinnacle Oncology, Scottsdale AZ.
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Online Table 1: Inclusion and exclusion criteria for participation in the GRID study (details from study protocol)
Criteria
Eligibility
Subjects with histologically proven metastatic and/or unresectable gastrointestinal stromal tumour (GIST) not amenable to surgery, radiation, or a combination of different approaches with curative intent and
who have shown objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib treatment, are eligible for inclusion in the study.
At least 50% of subjects to be enrolled must be receiving third-line therapy for GIST, i.e. no more than 50% of subjects can be receiving fourth-line or beyond treatment for GIST.
Inclusion
Inclusion criteria must be met at the time of screening unless otherwise specified.
1. Signed informed consent form obtained before any study-specific procedures. Subjects must be able to understand and be willing to sign a written informed consent.
2. Male or female subjects ≥ 18 years of age.
3. Histologically confirmed metastatic and/or unresectable GIST.
4. At least imatinib and sunitinib as prior treatment regimens, with objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib therapy. Additionally, disease
progression or intolerance to other systemic therapies, as well as investigational new agents, is allowed, except prior treatment with any other vascular endothelial growth factor receptor inhibitor.
5. Subjects must have at least one measurable lesion according to modified RECIST version 1∙1. 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 before study enrolment.
6. Eastern Cooperative Oncology Group performance status of 0 or 1.
7. Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:
–
Total bilirubin ≤ 1∙5 × the upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dl).
–
Alanine aminotransferase and aspartate aminotransferase ≤ 3∙0 × ULN (≤ 5 × ULN for subjects with liver involvement of their GIST).
–
Lipase ≤ 1∙5 × ULN.
–
Serum creatinine ≤ 1∙5 × ULN.
–
Glomerular filtration rate ≥ 30 ml/min/1∙73 m2 according to the Modified Diet in Renal Disease abbreviated formula.
–
International normalised ratio (INR) ≤ 1∙5 × ULN and partial thromboplastin time (PTT) or activated PTT ≤ 1∙5 × ULN. Subjects who are being treated with an anticoagulant, such as warfarin or
heparin, will be allowed to participate provided that no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until
INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care.
–
Platelet count ≥ 100,000/mm3, haemoglobin ≥ 9∙0 g/dl, absolute neutrophil count ≥ 1,500/mm3. Transfusion of subjects to meet the inclusion criteria will not be allowed.
–
Alkaline phosphatase limit ≤ 2∙5 × ULN (≤ 5 × ULN for subjects whose cancer involves their liver).
8. Recovery to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4∙0 grade 0 or 1 level or recovery to baseline preceding the prior treatment from any
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previous drug/procedure-related toxicity (except alopecia, anaemia, and hypothyroidism).
Exclusion
Subjects who meet any of the following criteria at the time of screening will be excluded from the study.
1. Prior treatment with regorafenib. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study.
2. Prior treatment with any vascular endothelial growth factor receptor (VEGFR) inhibitor except sunitinib.
3. Subjects who have received:
–
Any other approved tyrosine kinase inhibitor within 1 week or a minimum of 5 drug half-lives, whichever is longer (i.e. within 7 days for imatinib, or within 10 days for sunitinib);
–
Any other investigational new drugs within 4 weeks or 5 drug half-lives (if drug half-life in subjects is known), whichever is shorter.
4. Cancer other than GIST within 5 years before randomisation EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder tumours (Ta [non-invasive tumour],
and Tis [carcinoma in situ]).
5. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.
6. Pregnancy or breast feeding. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before
start of study medication and a negative result must be documented before start of study medication. Women of childbearing potential and men must agree to use adequate contraception (barrier method of
birth control) since signing of the informed consent form until at least 3 months after the last study drug administration. The definition of adequate contraception will be based on the judgment of the treating
investigator or a designated associate.
7. Congestive heart failure New York Heart Association class ≥ 2.
8. Unstable angina (angina symptoms at rest, new-onset angina, i.e. within the past 3 months) or myocardial infarction within the past 6 months before start of study medication.
9. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
10. Uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management.
11. Phaeochromocytoma.
12. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) or pulmonary embolism within the 6 months before start of study drug.
13. Venous thrombotic events such as deep vein thrombosis within the 3 months before start of study drug.
14. Ongoing infection NCI-CTCAE version 4∙0 grade > 2.
15. Known history of human immunodeficiency virus infection.
16. Seizure disorder requiring medication.
17. Symptomatic metastatic brain or meningeal tumours.
18. History of organ allograft.
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19. Evidence or history of bleeding diathesis. Any haemorrhage or bleeding event NCI-CTCAE version 4∙0 grade ≥3 within 4 weeks before the start of study drug.
20. Non-healing wound, ulcer, or bone fracture.
21. Renal failure requiring haemodialysis or peritoneal dialysis.
22. Dehydration NCI-CTCAE version 4∙0 grade ≥ 1.
23. Substance abuse or medical, psychological, or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results.
24. Known hypersensitivity to the study drug, study drug class, or excipients in the formulation.
25. Any illness or medical conditions that are unstable or could jeopardise the safety of the subject and his or her compliance in the study.
26. Interstitial lung disease with ongoing signs and symptoms at the time of screening.
27. Inability to swallow oral medications.
28. Persistent proteinuria of NCI-CTCAE version 4∙0 grade ≥ 3 (> 3∙5 g/24 hours, measured by urine protein:creatinine ratio on a random urine sample).
29. Any malabsorption condition.
30. Close affiliation with the investigational site, e.g. a close relative of the investigator or dependent person (e.g. employee of or student at the investigational site who would have access to study records and
case report form data).
31. Unresolved toxicity higher than NCI-CTCAE version 4∙0 grade 1 (excluding alopecia, anaemia, and hypothyroidism) attributed to any prior therapy/procedure.
32. Concomitant participation in another clinical study.
33. Left ventricular ejection fraction < 50% or below the lower limit of normal for the institution (whichever is higher).
34. Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE version 4∙0 grade ≥2 dyspnoea).
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Online Table 2: Prespecified dose modifications for adverse events related to study drug excluding hand–foot skin reaction, hypertension, and aspartate
aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin increases
National Cancer Institute Common
Terminology Criteria for Adverse Events,
version 4∙0 (NCI-CTCAE v4∙0) grade
Dose interruption
Dose modificationa
Dose for subsequent cycles
Grade 0–2
Treat on time
No change
No change
Grade 3
Delay until ≤ Grade 2b
Reduce by 1 dose levelc
If toxicity remains ≤ Grade 2, dose re-escalation
can be considered at the discretion of the treating
investigator. If dose is re-escalated and toxicity
(≥ Grade 3) recurs, institute permanent dose
reduction
Grade 4
Delay until ≤ Grade 2b
Reduce by 1 dose level.
Permanent discontinuation can be considered
at treating investigator’s discretion
a
Not for alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity and asymptomatic laboratory abnormalities.
Patients requiring a delay of >4 weeks should discontinue protocol therapy.
c
Dose level 0 = 160 mg, dose level –1 = 120 mg, dose level –2 = 80 mg.
b
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Online Table 3: Prespecified dose modifications for treatment-related hand–foot skin reaction
Skin Toxicity Grade
(according to NCI-CTCAE v4∙0 “Palmar–plantar
erythrodysesthesia syndrome”)
Occurrence
Suggested dose modification (more liberal management is allowed if judged medically
appropriate by the investigator)
Grade 1: Numbness, dysaesthesia, paraesthesia, tingling,
painless swelling, erythema or discomfort of the hands or
feet which does not disrupt the patient’s normal activities
Any
Maintain dose level and immediately institute supportive measures for symptomatic relief
Grade 2: Painful erythema and swelling of the hands or
feet and/or discomfort which affects the patient’s normal
activities
1st occurrence
Consider decreasing dose by 1 dose levela and immediately institute supportive measures. If
there is no improvement, interrupt therapy for ≥7 days, until toxicity resolves to Grade 0–1b
No improvement within 7 days or 2nd
occurrence
Interrupt therapy until toxicity resolves to Grade 0–1. Resume treatment at reduced dose levelb
3rd occurrence
Interrupt therapy until toxicity resolves to Grade 0–1. On resuming treatment, decrease dose by
one additional dose levela,c
4th occurrence
Discontinue treatment
1st occurrence
Institute support measures immediately. Interrupt therapy for ≥7 days until toxicity resolves to
Grade 0–1. On resuming treatment, decrease dose by one dose levela
2nd occurrence
Institute support measures immediately. Interrupt therapy for ≥7 days until toxicity resolves to
Grade 0–1. On resuming treatment, decrease dose by one additional dose levela,c
3rd occurrence
Discontinue treatment permanently
Grade 3: Moist desquamation, ulceration, blistering or
severe pain of the hands or feet, or severe discomfort that
causes the patient to be unable to work or perform
activities of daily living
a
Dose level 0 = 160 mg, dose level –1 = 120 mg, dose level –2 = 80 mg.
b
If toxicity returns to Grade 0–1 after dose reduction, re-escalation is permitted at the discretion of the investigator.
c
Patients requiring >2 dose level reductions (i.e. a reduction that would result in a dose <80 mg) should discontinue protocol therapy.
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Online Table 4: Prespecified dose modifications for treatment-related hypertension
NCI-CTCAE v4.0
grade
Definition
Antihypertensive therapy
Study drug dosing
Grade 1
Pre-hypertension (systolic blood pressure [BP] 120–
139 mmHg or diastolic BP 80–89 mmHg)
None
Continue study drug
Consider increased blood pressure monitoring
Grade 2
Systolic BP 140–159 mmHg or
diastolic BP 90–99 mmHg
or
Symptomatic increase by >20 mmHg (diastolic) if
previously within normal limits
Grade 3
Grade 4
Systolic BP ≥160 mmHg or
diastolic BP ≥100 mmHg
or
More than one drug or more intensive therapy than
previously indicated
Life-threatening consequences (e.g.,
malignant hypertension, transient
or permanent neurological deficit, hypertensive crisis)
Treat to achieve diastolic BP ≤90 mmHg
If BP previously within normal limits, start
antihypertensive monotherapy
— If patient already on antihypertensive
medication, titrate dose up
—
Treat to achieve diastolic BP ≤90 mmHg
Start antihypertensive medication
and/or
— Increase current antihypertensive medication
and/or
— Add additional antihypertensive medications
—
Continue study drug
If symptomatic, hold study drug
until symptoms resolve and
diastolic BP ≤90 mmHga
On resuming study drug,
continue at same dose level
Hold study drug until diastolic
BP ≤90 mmHg and, if symptomatic, symptoms resolvea
On resuming study drug,
continue at same dose level
If BP is not controlled with addition of new or more intensive
therapy, reduce study drug by one dose levelb,c
If Grade 3 hypertension recurs despite study drug dose
reduction and antihypertensive therapy, reduce study drug by
one additional dose levelb,d
Discontinue treatment
a
Patients requiring a delay of >4 weeks should discontinue protocol therapy.
Dose level 0 = 160 mg, dose level –1 = 120 mg, dose level –2 = 80 mg.
c
If blood pressure remains controlled for at least one full cycle, study drug dose re-escalation is permitted at the investigator’s discretion.
d
Patients requiring >2 study drug dose level reductions (i.e. a reduction that would result in a study drug dose <80 mg) should discontinue protocol therapy.
b
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Online Table 5: Prespecified dose modifications for treatment-related increases in ALT and/or AST and/or bilirubin
NCI-CTCAE v4.0 grade
Baseline Grade 0 → Grade 1
Or baseline Grade 1 → Grade 2
1st occurrence
Restart
Give study drug on time
Check AST, ALT and bilirubin
twice weekly for 2 weeks then weekly for at least
4 weeks
Reoccurrence
Give study drug on time
Check AST, ALT and bilirubin
twice weekly for 2 weeks then
weekly for at least 4 weeks
Delay study drug until ≤ Grade 1
Check AST, ALT, and bilirubin
twice weekly
Reduce study drug by 1 dose levela
Check AST, ALT, and bilirubin
twice weekly for 2 weeks then weekly for at least
4 weeksb
Discontinue study drugc
Baseline any grade → Grade 3
Delay study drug
until ≤ Grade 1 if baseline was Grade 0 or 1
or until Grade 2 if baseline was Grade 2
Check AST, ALT, and bilirubin
twice weekly
If ALT or AST >8× upper limit of normal, with
concomitant rise in bilirubin (of any degree)
versus previous bilirubin values, consider
permanent discontinuation of study drug at first
occurrencec
Reduce study drug by 1 dose levela
Check AST, ALT, and bilirubin
twice weekly for 2 weeks then weekly for at least
4 weeksb
Discontinue treatmentc
Baseline any grade → Grade 4
Discontinue treatmentc
Baseline Grade 0 → Grade 2
a
Dose level 0 = 160 mg, dose level –1 = 120 mg, dose level –2 = 80 mg.
If all values remain stable for two full cycles, study drug dose re-escalation may be considered at the discretion of the investigator. After re-escalation AST, ALT, bilirubin
should be checked twice weekly for 2 weeks then weekly for at least 4 weeks.
c
In case of discontinuation, check AST, ALT, and bilirubin twice weekly for 2 weeks then weekly until recovery to baseline.
b
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Online Table 6: Patient disposition
Placebo, n (%)
Regorafenib, n (%)
Enrolled
240 (100·0)
Screening failures
Randomised
Total, n (%)
41 (17·1)
66 (100·0)
133 (100·0)
199 (82·9)
Study drug never administered
0
1 (0·8)
1 (0·4)
Started double-blind treatment
66 (100·0)
132 (99·2)
198 (82·5)
Ongoing with double-blind treatment
3 (4·5)
53 (39·8)
56 (23·3)
Terminated double-blind treatment
7 (10·6)
38 (28·6)
45 (18·8)
Started open-label treatment
56 (84·8)
41 (30·8)
97 (40·4)
Ongoing with open-label treatment
33 (50·0)
24 (18·0)
57 (23·8)
Terminated open-label treatment
23 (34·8)
17 (12·8)
40 (16·7)
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Online Table 7: Systemic anticancer therapy during follow up
Placebo (n=66)
n (%)
Regorafenib (n=133)
n (%)
Total (n=199)
n (%)
Number of subjects (%) with at least one medication
10 (15·2)
20 (15·0)
30 (15·1)
Antineoplastic and immunomodulating agents
8 (12·1)
20 (15·0)
28 (14·1)
Anthracyclines and related substances
0
1 (0·8)
1 (0·5)
6 (9·1)
7 (5·3)
13 (6·5)
Nitrogen mustard analogues
0
1 (0·8)
1 (0·5)
Other antineoplastic agents
4 (6·1)
11 (8·3)
15 (7·5)
Protein kinase inhibitors
1 (1·5)
4 (3·0)
5 (2·5)
3 (4·5)
0
3 (1·5)
3 (4·5)
0
3 (1·5)
Antineoplastic agents
Unclassifiable
Investigational drug
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Online Figure 1: Kaplan–Meier curve for investigator-assessed progression-free survival (PFS)
CI: confidence interval
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