A Non-randomized, Open-label, Single-center Phase Ib Study of Short Cycles of SUnitinib Alternating With REgorafenib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) Progressing After Prior Therapy With Tyrosine Kinas
Phase: Phase 1
NCT ID: NCT02164240
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 14-149
The purpose of this research study is to determine the safety and tolerability of sunitinib alternating with regorafenib in participants with advanced gastrointestinal stromal tumor GIST, if the standard approved therapies (imatinib, sunitinib and regorafenib) have failed to control the disease. Additionally, this study seeks to determine the highest dose that can be given safely for this combination of drugs.
Dana-Farber Cancer Institute, Brigham and Women's Hospital
Suzanne George, MD,
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute:
Dana-Farber Cancer Institute:
- At least 18 years of age at the time of study entry.
- Histologically confirmed metastatic and/or unresectable GIST. Patients must
demonstrate prior failure to at least imatinib, sunitinib and regorafenib (4th line
and beyond). Any number of previous therapies for GIST is allowed.
Failure of imatinib is defined as either prior progression of disease on imatinib in the
metastatic setting or progression during adjuvant imatinib, or within 3 months of
completing adjuvant imatinib. Failure of sunitinib and regorafenib is defined only as
prior progression of disease on sunitinib or on regorafenib as assessed by the
- Measurable disease per modified RECIST 1.1. A lesion in a previously irradiated area
is ineligible to be considered as measurable disease unless there is objective
evidence of progression of the lesion prior to study enrollment.
- ECOG performance status 0 or 1 (see Appendix A).
- Participants must have adequate organ and marrow function as defined below (within 7
days prior to enrollment):
- Hemoglobin ≥ 9.0 g/dL (90 g/L). Previous transfusion is allowed.
- Absolute neutrophil count ≥ 1500/mm3.
- Platelets ≥100,000 /mm3. Previous transfusion is allowed.
- International normalized ratio (INR), and prothrombin time (PT) ≤1.5 x ULN
(patients who are being prophylactically anticoagulated with an agent such as
coumadin or low molecular weight heparin (LMWH) or therapeutically
anticoagulated with LMWH will be allowed to participate provided they are stable
and monitored at appropriate intervals per institutional guidelines throughout
- Alanine aminotransferanse (ALT) and aspartate aminotransferanse (AST) ≤ 2.5 x
upper limit of normal (ULN), or ≤ 5.0 x ULN if liver metastases are present.
- Alkaline phosphatase (ALP) limit < 2.5 x ULN or ≤ 5.0 x ULN if liver metastases
- Total serum bilirubin ≤1.5 x ULN. Patients with Gilbert's syndrome with
baseline serum bilirubin exceeding this limit are allowed to participate.
- Serum sodium within normal limits.
- Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to the MDRD
(modified diet in renal disease) abbreviated formula (see Appendix B).
- Serum phosphate levels ≥ 2.5 mg/dL or ≥ 0.8 mmol/L.
- Patients must be able to swallow oral medication.
- Willingness to use effective means of birth control throughout the duration of
clinical study and for at least 3 months after completion of study drug.
- Women of childbearing potential must have a negative pregnancy test performed within
7 days of the start of study drug administration.
- Ability to understand and the willingness to sign a written informed consent
- Patients will be ineligible for enrollment into the study if they meet any of the
following criteria. Unless specified, all patients in dose-escalation cohort and
dose-expansion cohort must meet all of the following inclusion criteria to be
eligible for enrollment into the study:
- Use of any approved tyrosine kinase inhibitors or investigational agents within 2
weeks or 6 half-lives of the agent, whichever is shorter, prior to receiving study
- Patients with intolerance to sunitinib and/or regorafenib.
- Participants who have had radiotherapy within 4 weeks prior to study entry.
- Major surgery, or significant traumatic injury within 4 weeks prior to study entry.
- Presence of symptomatic or uncontrolled brain or central nervous system metastases.
- Known or suspected allergy to the investigational agent or any agent given in
association with this trial.
- Individuals with a history of a different malignancy, other than cervical cancer in
situ, basal cell or squamous cell carcinoma of the skin, are ineligible, except if
they have been disease-free for at least 5 years, and are deemed by the investigator
to be at low risk for recurrence of that malignancy OR other primary malignancy is
neither currently clinically significant nor requiring active intervention.
- Clinically significant cardiac arrhythmias and/or patients who require
anti-arrhythmic therapy (excluding beta blockers or digoxin). Patients with
controlled atrial fibrillation are not exluded.
- History of clinically significant cardiac disease or congestive heart failure > NYHA
class 2 (See Appendix C). Patients must not have unstable angina (anginal symptoms at
rest) or new-onset angina within the last 3 months or myocardial infarction within
the past 6 months.
- Hypertension as defined by systolic blood pressure >140 mmHg or diastolic blood
pressure > 90 mmH despite optimal medical management.
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
within the 6 months before start of study medication (except for adequately treated
catheter-related venous thrombosis occurring more than 1 month before the start of
- Patients with evidence or history of any bleeding diathesis, irrespective of
- Ongoing infection ≥ Grade 2.
- Patients with any seizure disorder requiring medication.
- Non-healing wound, ulcer, or bone fracture.
- Persistent proteinuria Grade 2 or higher measured by urine protein:creatinine ratio
on a urine sample or during 24-hour assessment.
- HIV-positive individuals on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with sunitinib and regorafenib.
- Patients with active hepatitis B or C, or chronic hepatitis B or C requiring
treatment with antiviral therapy, because of potential risk of lethal liver toxicity.
- Interstitial lung disease with ongoing signs and symptoms at the time of informed
- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, clinically significant cardiac and pulmonary disease; liver diseases such
as cirrhosis, chronic active or persistent hepatitis; or acute/ chronic medical/
psychiatric illness/ social situations or laboratory abnormality that may increase
the risk associated with study participation or study drug administration, or limit
compliance with study requirements, or interfere with the interpretation of study
results, and in the judgment of the investigator would make the patient inappropriate
for entry into this study.
- Pregnant or lactating females.
- Presence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule;
those conditions should be discussed with the patient before registration in the
- Strong CYP3A4 inhibitors (e.g. clarithromycin, indinavir , itraconazole, ketoconazole
, nefazodone , nelfinavir , posaconazole, ritonavir, saquinavir, telithromycin,
voriconazole) or strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital,
phenytoin, rifampin, St. John's Wort) within 28 days or 5 drug half-lives (if drug
half-life in patients is known), whichever is longer, before start of study