Gastrointestinal Stromal Tumor
Conditions
Keywords
Gastrointestinal Stromal Tumor
Brief summary
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.
Detailed description
This is a non-randomized, open label, single-center, single-arm, phase Ib study to evaluate the safety and the preliminary efficacy of short cycles of sunitinib alternated with regorafenib in participants with metastatic and/or unresectable gastrointestinal stromal tumor GISTs with prior failure of tyrosine kinase inhibitors (TKI). The study consists of two cohorts: a dose-escalation, dose-finding cohort, and dose-expansion cohort. Between 6 to 15 patients are expected to be included in the escalation cohort. A total of 20 eligible and evaluable patients will be included in the expansion cohort to further assess toxicity and evaluate preliminary efficacy. Each treatment cycle lasts 28 days (4 weeks), during which time you will be taking the study drug, sunitinib, for the first 3 days of the week, followed by the study drug, regorafenib, for the last 4 days of the week. The study drugs will be taken continuously for 4 weeks each cycle, unless the study team instructs you otherwise. Each participant will receive a study diary. The diary will also include special instructions for taking the study drugs.
Interventions
DRUGSunitinib
Intervention Description: 3 days of once daily sunitinib alternating with 4 days of once daily regorafenib throughout each 28 day cycle. The starting dose level (level 1) is sunitinib 37.5 mg/d and regorafenib 120 mg/d, and doses will be escalated in subsequent cohorts following a classical 3+3 design up to sunitinib 50 mg/d and regorafenib 160 mg/d or until maximum tolerable dosage (MTD) and recommended phase II dose (RP2D) is determined. Number of Cycles: until progression or unacceptable toxicity develops.
DRUGRegorafenib
Intervention Description: 3 days of once daily sunitinib alternating with 4 days of once daily regorafenib throughout each 28 day cycle. The starting dose level (level 1) is sunitinib 37.5 mg/d and regorafenib 120 mg/d, and doses will be escalated in subsequent cohorts following a classical 3+3 design up to sunitinib 50 mg/d and regorafenib 160 mg/d or until maximum tolerable dosage (MTD) and recommended phase II dose (RP2D) is determined. Number of Cycles: until progression or unacceptable toxicity develops.
Sponsors
Bayer
Pfizer
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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. * 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 outlined in the protocol. * 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 document.
Exclusion criteria
* 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 drugs. * 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 excluded. * 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 study medication). * Patients with evidence or history of any bleeding diathesis, irrespective of severity. * 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. * Patients with active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy. * Interstitial lung disease with ongoing signs and symptoms at the time of informed consent. * Uncontrolled intercurrent illness. * Pregnant or lactating females. * Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol. * Strong CYP3A4 inhibitors within 28 days or 5 drug half-lives, whichever is longer, before start of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and Non-Serious Adverse Events | Up to Day 28 | Dose-escalation cohort is to determine the frequency and characteristics of DLTs of alternation of sunitinib and regorafenib at each dose level during the first cycle of therapy. Toxicity will be graded accordingly with NCI CTCAE version 4.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Benefit | 16 weeks | Percentage of participants who experienced complete response, partial response or stable disease per RECIST 1.1 at 16 weeks |
| Median Progression Free Survival (mPFS) | From date of registration until date of protocol-defined progression while on this protocol, assessed up to 6 months | Non-parametric Kaplan-Meier analysis to assess median progression free survival (mPFS) |
Countries
United States
Participant flow
Pre-assignment details
The Protocol Enrollment number reflects the 14 participants who completed the informed consent process, were determined eligible following screening, and were registered in the protocol registration system per study protocol. The Started in Participant Flow number reflects the 13 participants who started on the course of study drug treatment following registration (1 of the 14 enrolled participants did not).
Participants by arm
| Arm | Count |
|---|---|
| Sunitinib Alternated With Regorafenib Sunitinib: Intervention Description: 3 days of once daily sunitinib alternating with 4 days of once daily regorafenib throughout each 28 day cycle. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Sunitinib Alternated With Regorafenib |
|---|---|
| Age, Continuous | 63.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 4 / 4 | 5 / 5 | 4 / 4 |
| serious Total, serious adverse events | 2 / 4 | 3 / 5 | 2 / 4 |
Outcome results
Primary
Number of Participants With Serious and Non-Serious Adverse Events
Dose-escalation cohort is to determine the frequency and characteristics of DLTs of alternation of sunitinib and regorafenib at each dose level during the first cycle of therapy. Toxicity will be graded accordingly with NCI CTCAE version 4.0
Time frame: Up to Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sunitinib 37.5 and Regorafenib 120 | Number of Participants With Serious and Non-Serious Adverse Events | 4 Participants |
| Sunitinib 37.5 and Regorafenib 160 | Number of Participants With Serious and Non-Serious Adverse Events | 5 Participants |
| Expansion Sunitinib 37.5 Regorafenib 120 | Number of Participants With Serious and Non-Serious Adverse Events | 4 Participants |
Secondary
Median Progression Free Survival (mPFS)
Non-parametric Kaplan-Meier analysis to assess median progression free survival (mPFS)
Time frame: From date of registration until date of protocol-defined progression while on this protocol, assessed up to 6 months
Population: all patients enrolled were analyzed as a single cohort for this endpoint based on pre-planned study design
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib 37.5 and Regorafenib 120 | Median Progression Free Survival (mPFS) | 1.9 months |
Secondary
Percentage of Participants With Clinical Benefit
Percentage of participants who experienced complete response, partial response or stable disease per RECIST 1.1 at 16 weeks
Time frame: 16 weeks
Population: clinical benefit was analyzed across the entire population based on the pre-planned study design
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sunitinib 37.5 and Regorafenib 120 | Percentage of Participants With Clinical Benefit | 0 Participants |
Comparison: Clinical benefit rate of at least 30% at 16 weeks for the entire, combined population, was considered worthy of further study.95% CI: [0, 24.7]