Advanced Gastrointestinal Stromal Tumor (GIST)
Conditions
Keywords
BGJ398, Imatinib Mesylate, 14-140
Brief summary
The goal of a phase Ib clinical trial is to find the doses of drugs that are safe. Although BGJ398 has been given to patients safely on its own, it has never been given together with imatinib mesylate. In this study, we will test the safety of taking BGJ398 with imatinib mesylate. The investigators will learn this by closely checking for side effects that the patient may experience. Side effects can be seen in laboratory studies, on physical examination, or by asking the patient.Once a dose has been determined to be safe, a larger Phase II study will be done in patients with advanced GIST who have never received any prior treatments.
Interventions
DRUGBGJ398
DRUGImatinib Mesylate
Sponsors
Dana-Farber Cancer Institute
M.D. Anderson Cancer Center
University of Pittsburgh
Memorial Sloan Kettering Cancer Center
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
* Patients must have pathologically confirmed GIST. * In the Phase Ib portion, must have locally advanced or metastatic GIST and have progressed on imatinib. * In the Phase II portion, patients must be newly diagnosed or imatinib treatment naïve in the advanced/metastatic setting. Prior adjuvant imatinib therapy is allowed as long as disease recurrence was documented ≥90 days after last dose of imatinib and imatinib has not yet been restarted. * Patients must be at least 18 years of age. * Disease must be measurable by RECIST 1.1. * ECOG Performance Status 0 or 1. Adequate renal, hepatic, and hematologic function as the following: Serum Creatinine ≤ 1.5 mg/dL, Total Serum Bilirubin ≤ 1.5 x upper limit of normal (ULN) unless due to Gilbert's Disease, Serum AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x ULN (or ≤ 5.0 x ULN if considered due to tumor), ANC ≥ 1500/mm3, Platelets ≥ 100,000/mm3, and hemoglobin ≥ 10g/dL. * Patients of childbearing potential must have a negative blood pregnancy test within 14 days of treatment. Patients must agree to use a reliable barrier method of birth control during and for 3 months following the last dose of study drug. * Patient must have adequate cardiac function (left ventricular ejection fraction (LVEF) ≥50% as determined by a multigated acquisition (MUGA) scan or echocardiogram; and QTc interval ≤480 ms by Fridericia's formula (QTcF). * Patient must be able to take oral medications. * Patients must sign an informed consent document.
Exclusion criteria
* For phase I, prior intolerance to imatinib at a dose of 400 mg daily. * For phase II, any receipt of cytotoxic, biologic, or immune therapy aimed to treat GIST except for adjuvant imatinib systemic therapy that concluded at least 90 days prior to registration. For Phase I, patients are eligible regardless of prior therapy. * Chronic liver disease (e.g., cirrhosis) * Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection. * Patients have a history or current evidence of Central Serous Retinopathy (CSR) or retinal vein occlusion (RVO) or major predisposing factors to CSR or RVO (e.g. uncontrolled glaucoma or ocular hypertension) in the opinion of the study ophthalmologist. * History of retinal degenerative disease * Active corneal disorder or keratopathy (e.g. corneal abrasion, bullous keratopathy) * Severe and/or uncontrolled medical disease, including: * Uncontrolled diabetes mellitus (A1c \>8) * Chronic Kidney Disease Stage III or higher (Creatinine Clearance \<60mL/min/m2 by Modified Diet in Renal Disease (MDRD) calculation) * Active, uncontrolled infection Known active brain metastasis unless they have been treated and shown documented radiographic stability for 28 days. * Known other active malignancy (other than malignancies which the investigator determines are unlikely to interfere with treatment and safety analysis). * Patients have clinically significant cardiovascular disease, including any of the following * Any history of acute coronary syndrome including myocardial infarction, stable or unstable angina, CABG, coronary angioplasty or stenting or known obstructive coronary artery disease. * Symptomatic chronic heart failure (New York Heart Association Criteria, Class II-IV) * Evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities \< 6 months prior to screening except atrial fibrillation (AF) and paroxysmal supraventricular tachycardia (PSVT) * Any history of thrombotic cerebrovascular accident or other arterial thrombosis * Uncontrolled arterial hypertension (systolic blood pressure \>155 mmHg or diastolic \>95 mmHg) despite appropriate medical therapy. * History and/or current evidence of uncontrolled endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis, etc. * Impairment of gastrointestinal function or gastrointestinal disease (e.g., uncontrolled ulcerative disease; uncontrolled nausea, vomiting, diarrhea; chronic malabsorption syndrome). * Patients with major surgery within 3 weeks prior to study entry or who have not recovered from side effects of such procedure. * Women who are pregnant or lactating. * Sexually active males, unless they use a condom during intercourse while taking the drug and for 15 days after stopping treatment. They should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. * Patients with any significant history of non-adherence to medical regimens or with inability to grant reliable informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib Study: Number of Participants With Dose-Limiting Toxicities | 1 year | The phase Ib will be pursued in standard 3+3 format, based on toxicities encountered during the first cycle of therapy. |
| Phase Ib Portion: Response Rate (RR) | 32 weeks | (CR+PR, RECIST 1.1) and by CHOI criteria PHASE 1b PARTICIPANTS ONLY Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib Study: Response Rate (RR) | 32 weeks | defined by RECIST 1.1 criteria and by CHOI criteria,and by EORTC criteria PHASE 1b PARTICIPANTS ONLY Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b, Dose Level -1 Phase 1b, Dose Level -1: BGJ398 50 mg | 3 |
| Phase 1b, Dose Level 1 Phase 1b, Dose Level 1: BGJ398 75 mg | 8 |
| Phase 1b, Dose Level 2 Phase 1b, Dose Level 2: BGJ398 100 mg | 1 |
| Phase 1b, Dose Level -2 Phase 1b, Dose Level -2: BGJ398 25 mg | 3 |
| Phase II Phase II: BGJ398 75mg | 1 |
| Total | 16 |
Baseline characteristics
| Characteristic | Phase 1b, Dose Level -1 | Total | Phase II | Phase 1b, Dose Level -2 | Phase 1b, Dose Level 2 | Phase 1b, Dose Level 1 |
|---|---|---|---|---|---|---|
| Age, Continuous | 54 years | 54 years | 53 years | 53 years | 44 years | 58.88 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 12 Participants | 0 Participants | 3 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 10 Participants | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 3 Participants | 16 Participants | 1 Participants | 3 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 13 Participants | 0 Participants | 3 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 3 / 8 | 0 / 1 | 0 / 3 | 0 / 1 |
| other Total, other adverse events | 3 / 3 | 8 / 8 | 1 / 1 | 3 / 3 | 1 / 1 |
| serious Total, serious adverse events | 2 / 3 | 7 / 8 | 1 / 1 | 3 / 3 | 0 / 1 |
Outcome results
Primary
Phase Ib Portion: Response Rate (RR)
(CR+PR, RECIST 1.1) and by CHOI criteria PHASE 1b PARTICIPANTS ONLY Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: 32 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b, Dose Level -1 | Phase Ib Portion: Response Rate (RR) | Partial Response/PR | 1 Participants |
| Phase 1b, Dose Level -1 | Phase Ib Portion: Response Rate (RR) | Stable Disease/SD | 2 Participants |
| Phase 1b, Dose Level -1 | Phase Ib Portion: Response Rate (RR) | Progressive Disease/PD | 0 Participants |
| Phase 1b, Dose Level -1 | Phase Ib Portion: Response Rate (RR) | Not reported due to withdrawn from study | 0 Participants |
| Phase 1b, Dose Level 1 | Phase Ib Portion: Response Rate (RR) | Stable Disease/SD | 3 Participants |
| Phase 1b, Dose Level 1 | Phase Ib Portion: Response Rate (RR) | Progressive Disease/PD | 3 Participants |
| Phase 1b, Dose Level 1 | Phase Ib Portion: Response Rate (RR) | Not reported due to withdrawn from study | 2 Participants |
| Phase 1b, Dose Level 1 | Phase Ib Portion: Response Rate (RR) | Partial Response/PR | 0 Participants |
| Phase 1b, Dose Level 2 | Phase Ib Portion: Response Rate (RR) | Progressive Disease/PD | 1 Participants |
| Phase 1b, Dose Level 2 | Phase Ib Portion: Response Rate (RR) | Stable Disease/SD | 0 Participants |
| Phase 1b, Dose Level 2 | Phase Ib Portion: Response Rate (RR) | Not reported due to withdrawn from study | 0 Participants |
| Phase 1b, Dose Level 2 | Phase Ib Portion: Response Rate (RR) | Partial Response/PR | 0 Participants |
| Phase 1b, Dose Level -2 | Phase Ib Portion: Response Rate (RR) | Not reported due to withdrawn from study | 0 Participants |
| Phase 1b, Dose Level -2 | Phase Ib Portion: Response Rate (RR) | Stable Disease/SD | 0 Participants |
| Phase 1b, Dose Level -2 | Phase Ib Portion: Response Rate (RR) | Partial Response/PR | 0 Participants |
| Phase 1b, Dose Level -2 | Phase Ib Portion: Response Rate (RR) | Progressive Disease/PD | 3 Participants |
Primary
Phase Ib Study: Number of Participants With Dose-Limiting Toxicities
The phase Ib will be pursued in standard 3+3 format, based on toxicities encountered during the first cycle of therapy.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Level -1 | Phase Ib Study: Number of Participants With Dose-Limiting Toxicities | 3 Participants |
| Phase 1b, Dose Level 1 | Phase Ib Study: Number of Participants With Dose-Limiting Toxicities | 8 Participants |
| Phase 1b, Dose Level 2 | Phase Ib Study: Number of Participants With Dose-Limiting Toxicities | 1 Participants |
| Phase 1b, Dose Level -2 | Phase Ib Study: Number of Participants With Dose-Limiting Toxicities | 3 Participants |
Secondary
Phase Ib Study: Response Rate (RR)
defined by RECIST 1.1 criteria and by CHOI criteria,and by EORTC criteria PHASE 1b PARTICIPANTS ONLY Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: 32 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b, Dose Level -1 | Phase Ib Study: Response Rate (RR) | Progressive Disease/PD | 1 Participants |
| Phase 1b, Dose Level -1 | Phase Ib Study: Response Rate (RR) | Not reported due to withdrawn from study | 0 Participants |
| Phase 1b, Dose Level -1 | Phase Ib Study: Response Rate (RR) | Stable Disease/SD | 2 Participants |
| Phase 1b, Dose Level 1 | Phase Ib Study: Response Rate (RR) | Progressive Disease/PD | 2 Participants |
| Phase 1b, Dose Level 1 | Phase Ib Study: Response Rate (RR) | Not reported due to withdrawn from study | 2 Participants |
| Phase 1b, Dose Level 1 | Phase Ib Study: Response Rate (RR) | Stable Disease/SD | 4 Participants |
| Phase 1b, Dose Level 2 | Phase Ib Study: Response Rate (RR) | Stable Disease/SD | 1 Participants |
| Phase 1b, Dose Level 2 | Phase Ib Study: Response Rate (RR) | Progressive Disease/PD | 0 Participants |
| Phase 1b, Dose Level 2 | Phase Ib Study: Response Rate (RR) | Not reported due to withdrawn from study | 0 Participants |
| Phase 1b, Dose Level -2 | Phase Ib Study: Response Rate (RR) | Progressive Disease/PD | 3 Participants |
| Phase 1b, Dose Level -2 | Phase Ib Study: Response Rate (RR) | Not reported due to withdrawn from study | 0 Participants |
| Phase 1b, Dose Level -2 | Phase Ib Study: Response Rate (RR) | Stable Disease/SD | 0 Participants |