Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Conditions
Brief summary
This phase II trial studies how well dovitinib works in treating patients with recurrent or progressive glioblastoma. Dovitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
Detailed description
PRIMARY OBJECTIVES: Anti-angiogenic Therapy Naive Patients: To determine 6 month progression-free survival (PFS6) in anti-angiogenic therapy (including anti-vascular endothelial growth factor (VEGF) therapy or bevacizumab) naive patients with recurrent glioblastoma (GBM) in patients treated with dovitinib Anti-angiogenic Therapy Patients: To estimate time to progression in patients with recurrent or progressive Glioblastoma who have progressed on anti-angiogenic therapy (including anti-VEGF therapy). SECONDARY OBJECTIVES: 1. To evaluate the side effect profile of dovitinib in both patient populations. 2. To evaluate the efficacy of dovitinib as measured by objective response rate (ORR) in both patient populations. 3. To estimate time to percentage of patients free from progression at 6 months (PFS-6)in patients with recurrent or progressive Glioblastoma who have progressed on antiangiogenic therapy (including anti-VEGF therapy). (Anti-angiogenic Therapy Patients) 4. To estimate time to progression in anti-angiogenic therapy (including anti-VEGF therapy or bevacizumab) naiVe patients with recurrent glioblastoma (GBM) in patients treated with dovitinib. (Anti-angiogenic Therapy Naive Patients) 5. To evaluate the overall survival (OS) in both patient populations. EXPLORATORY OBJECTIVES: To explore association between clinical outcome and potential biomarkers that may include microparticles, PlGF, PDGF-AA, PDGF-AB, PDGF-BB, SDF-1a, thrombospondin-1, Ang1, and Il-6, IL-8 and FGF. OUTLINE: Patients receive dovitinib orally (PO) 5 days a week. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Interventions
DRUGdovitinib
Given PO
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Novartis
Manmeet Ahluwalia, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed glioblastoma, recurrent after standard external-beam fractionated radiotherapy and temozolomide chemotherapy * Patients who have NOT received any anti-angiogenic therapy (Anti-VEGF, including avastin, cediranib, or other anti-angiogenic therapies like cilengitide) on Anti-angiogenic Therapy Naive Patients Arm. No more than two recurrences are allowed on Anti-angiogenic Therapy Naive Patients Arm. * Patients who have received any anti-angiogenic therapy (Anti-VEGF, including avastin, cediranib, or other anti-angiogenic therapies like cilengitide) on Anti-angiogenic Therapy Patients Arm. Any number of recurrences are allowed on Anti-angiogenic Therapy Patients Arm. * Karnofsky performance status ≥ 60% * Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L * Platelets ≥ 100 x 10\^9/L * Hemoglobin (Hgb) \> 9 g/dL * Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN * Serum creatinine ≤ 1.5 x ULN * Minimum interval since completion of radiation treatment is 12 weeks * Minimum interval since last drug therapy 2 weeks since last non-cytotoxic therapy 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen 6 weeks since the completion of a nitrosourea containing chemotherapy regimen * Patients must be able to provide written informed consent * Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception; the anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant; female patients of child-bearing potential must have a negative pregnancy test * Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated stage I or II cancer from which the patient is in complete remission; patients with other prior malignancies must be disease-free for ≥ three years * Patients must be maintained on a stable corticosteroid regimen from the time of their baseline scan until the start of treatment and/or for at least 5 days before starting treatment
Exclusion criteria
* Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury * Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months * Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: * Impaired cardiac function or clinically significant cardiac diseases, including any of the following: * History or presence of serious uncontrolled ventricular arrhythmias * Clinically significant resting bradycardia * Left ventricular ejection fraction (LVEF) assessed by 2-dimensional (2-D) echocardiogram (ECHO) \< 50% or lower limit of normal (whichever is higher) or multi gated acquisition scan (MUGA) \< 45% or lower limit of normal (whichever is higher) * Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), and transient ischemic attack (TIA) * Uncontrolled hypertension defined by a systolic blood pressure (SBP) ≥ 160 mm Hg and/or diastolic blood pressure (DBP) ≥ 100 mm Hg, with or without anti-hypertensive medication(s) * Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dovitinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) * Cirrhosis, chronic active hepatitis or chronic persistent hepatitis * Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) * Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol * Women of child-bearing potential, who are biologically able to conceive, not employing two forms of highly effective contraception; highly effective contraception (e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used by both sexes during the study and must be continued for 8 weeks after the end of study treatment; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study; women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (e.g., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to starting study treatment * Fertile males not willing to use contraception, as stated above * Patients who are currently receiving full dose anticoagulation treatment with therapeutic doses of warfarin or anti-platelet therapy (e.g., Plavix \[clopidogrel bisulfate\]); treatment with locally accepted low molecular weight heparin and low dose of acetylsalicylic acid (i.e., 81mg or 100 mg daily) to prevent cardiovascular events or strokes is allowed * Patients unwilling or unable to comply with the protocol * Any significant hemorrhage defined as \> 1 cm diameter of blood seen on the MRI or CT scan. If \> 1 cm of acute blood is detected, the patient will be ineligible for this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arm 1: Progression Free Survival (PFS) | 6 months | Number of anti-angiogenic therapy (including anti-VEGF therapy or bevacizumab) naive patients with recurrent glioblastoma (GBM). The progression- free survival (PFS) at 6 months is defined as the time from randomization to objective tumor progression or death. So patients who have CR, PR or SD at 6 months will constitute PFS-6. Progression is defined using the Response Assessment in Neuro-Oncology (RANO) Criteria where CR = Total disappearance of lesions, PR = \>50% reduction in lesions and SD = \<25% reduction in lesions |
| Arm 2: Determine Median Time to Progression | From randomization to time of progression every 8 weeks (2 cycles of treatment) up to 32 weeks | Anti-angiogenic therapy (including anti-VEGF therapy or bevacizumab) patients with recurrent glioblastoma (GBM). Time to tumor progression (TTP), is defined as the time from randomization to time of progressive disease. So it is ongoing and will be assessed every 8 weeks …8, 16, 24, 32 …week. Progression is defined as \>25% increase in size of lesions or evidence of new lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival | 6 months | The progression- free survival (PFS) at 6 months is defined as the time from randomization to objective tumor progression or death. So patients who have CR, PR or SD at 6 months will constitute PFS-6 |
| Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Assessed until 30 days after treatment up to 32 weeks | Number of adverse events in patients in both populations (grade 1-5). Grade 1 are defined as mild events characterized as asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated. Grade 2 are moderate events with minimal, local or non invasive interventions indicated. Grade 3 are severe or medically significant events but not immediately life-threatening; hospitalization indicated. Grade 4 are life-threatening consequences with urgent intervention indicated. Grade 5 are deaths related to events |
| Overall Survival | to death, approximately 2 years | The Kaplan-Meier method will be used. Overall survival is defined as the time from randomization to death. |
| Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Up to 30 days after treatment | Number of patients (both populations) with a complete response (CR-no measurable disease), partial response (PR \>50% reduction in measurable disease), minor response (MR \>25% reduction of measurable disease), stable disease (SD \<25% reduction) and progressive disease (PD \>25% measurable disease and new lesions). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes From Baseline in Circulating Growth Factors and Soluble Receptors. | Up to 30 days after treatment | To assess the pharmacodynamic effect of dovitinib on potential plasma biomarkers that may include measuring concentrations of circulating, microparticles, PlGF, PDGF-AA, PDGF-AB, PDGF-BB, SDF-la, thrombospondin-l, Angl, and 11-6, IL-8 and FGF. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Anti-angiogenic Therapy Naive Patients Patients who have progressed without anti-angiogenic therapy. Patients receive dovitinib orally (PO) 5 days a week. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
dovitinib: Given PO
laboratory biomarker analysis: Correlative studies | 19 |
| Anti-angiogenic Therapy Patients Patients who have progressed on anti-angiogenic therapy. Patients receive dovitinib orally (PO) 5 days a week. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
dovitinib: Given PO
laboratory biomarker analysis: Correlative studies | 14 |
| Total | 33 |
Baseline characteristics
| Characteristic | Anti-angiogenic Therapy Naive Patients | Anti-angiogenic Therapy Patients | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 13 Participants | 29 Participants |
| Age, Continuous | 58 years | 51 years | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 13 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 16 Participants | 11 Participants | 27 Participants |
| Region of Enrollment United States | 19 Participants | 14 Participants | 33 Participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 12 Participants | 9 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 19 | 2 / 14 |
| other Total, other adverse events | 19 / 19 | 14 / 14 |
| serious Total, serious adverse events | 10 / 19 | 7 / 14 |
Outcome results
Primary
Arm 1: Progression Free Survival (PFS)
Number of anti-angiogenic therapy (including anti-VEGF therapy or bevacizumab) naive patients with recurrent glioblastoma (GBM). The progression- free survival (PFS) at 6 months is defined as the time from randomization to objective tumor progression or death. So patients who have CR, PR or SD at 6 months will constitute PFS-6. Progression is defined using the Response Assessment in Neuro-Oncology (RANO) Criteria where CR = Total disappearance of lesions, PR = \>50% reduction in lesions and SD = \<25% reduction in lesions
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anti-angiogenic Therapy Naive Patients | Arm 1: Progression Free Survival (PFS) | 0 Participants |
| Anti-angiogenic Therapy Patients | Arm 1: Progression Free Survival (PFS) | 0 Participants |
Primary
Arm 2: Determine Median Time to Progression
Anti-angiogenic therapy (including anti-VEGF therapy or bevacizumab) patients with recurrent glioblastoma (GBM). Time to tumor progression (TTP), is defined as the time from randomization to time of progressive disease. So it is ongoing and will be assessed every 8 weeks …8, 16, 24, 32 …week. Progression is defined as \>25% increase in size of lesions or evidence of new lesions
Time frame: From randomization to time of progression every 8 weeks (2 cycles of treatment) up to 32 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anti-angiogenic Therapy Naive Patients | Arm 2: Determine Median Time to Progression | 1.8 Months |
| Anti-angiogenic Therapy Patients | Arm 2: Determine Median Time to Progression | 1.8 Months |
Secondary
Median Progression Free Survival
The progression- free survival (PFS) at 6 months is defined as the time from randomization to objective tumor progression or death. So patients who have CR, PR or SD at 6 months will constitute PFS-6
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anti-angiogenic Therapy Naive Patients | Median Progression Free Survival | 2.0 Months |
| Anti-angiogenic Therapy Patients | Median Progression Free Survival | 1.8 Months |
Secondary
Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria
Number of patients (both populations) with a complete response (CR-no measurable disease), partial response (PR \>50% reduction in measurable disease), minor response (MR \>25% reduction of measurable disease), stable disease (SD \<25% reduction) and progressive disease (PD \>25% measurable disease and new lesions).
Time frame: Up to 30 days after treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Anti-angiogenic Therapy Naive Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Progressive Disease | 8 Participants |
| Anti-angiogenic Therapy Naive Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Unknown | 6 Participants |
| Anti-angiogenic Therapy Naive Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Stable Disease | 3 Participants |
| Anti-angiogenic Therapy Naive Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Partial Response | 2 Participants |
| Anti-angiogenic Therapy Naive Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Complete Response | 0 Participants |
| Anti-angiogenic Therapy Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Partial Response | 0 Participants |
| Anti-angiogenic Therapy Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Complete Response | 0 Participants |
| Anti-angiogenic Therapy Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Progressive Disease | 8 Participants |
| Anti-angiogenic Therapy Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Stable Disease | 2 Participants |
| Anti-angiogenic Therapy Patients | Objective Response Rate Using Modified Revised Assessment in Neuro-Oncology (RANO) Criteria | Unknown | 4 Participants |
Secondary
Overall Survival
The Kaplan-Meier method will be used. Overall survival is defined as the time from randomization to death.
Time frame: to death, approximately 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anti-angiogenic Therapy Naive Patients | Overall Survival | 8.0 Months |
| Anti-angiogenic Therapy Patients | Overall Survival | 4.3 Months |
Secondary
Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Number of adverse events in patients in both populations (grade 1-5). Grade 1 are defined as mild events characterized as asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated. Grade 2 are moderate events with minimal, local or non invasive interventions indicated. Grade 3 are severe or medically significant events but not immediately life-threatening; hospitalization indicated. Grade 4 are life-threatening consequences with urgent intervention indicated. Grade 5 are deaths related to events
Time frame: Assessed until 30 days after treatment up to 32 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anti-angiogenic Therapy Naive Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 2 | 109 Events |
| Anti-angiogenic Therapy Naive Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 4 | 2 Events |
| Anti-angiogenic Therapy Naive Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 3 | 55 Events |
| Anti-angiogenic Therapy Naive Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 5 | 1 Events |
| Anti-angiogenic Therapy Naive Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 1 | 217 Events |
| Anti-angiogenic Therapy Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 5 | 2 Events |
| Anti-angiogenic Therapy Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 1 | 119 Events |
| Anti-angiogenic Therapy Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 2 | 85 Events |
| Anti-angiogenic Therapy Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 3 | 40 Events |
| Anti-angiogenic Therapy Patients | Toxicity Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 4 | 5 Events |
Other Pre-specified
Changes From Baseline in Circulating Growth Factors and Soluble Receptors.
To assess the pharmacodynamic effect of dovitinib on potential plasma biomarkers that may include measuring concentrations of circulating, microparticles, PlGF, PDGF-AA, PDGF-AB, PDGF-BB, SDF-la, thrombospondin-l, Angl, and 11-6, IL-8 and FGF.
Time frame: Up to 30 days after treatment