Adult Glioblastoma Multiforme
Conditions
Keywords
recurrent adult brain tumor, adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma
Brief summary
RATIONALE: Monoclonal antibodies, such as ramucirumab and anti-PDGFR alpha monoclonal antibody IMC-3G3 (Olaratumab), can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. PURPOSE: This phase II trial is studying how well ramucirumab or anti-PDGFR alpha monoclonal antibody IMC-3G3 works in treating patients with recurrent glioblastoma multiforme.
Detailed description
OBJECTIVES: Primary * To assess the progression-free survival rate at 6 months after treatment with ramucirumab or anti-PDGFR alpha monoclonal antibody IMC-3G3 in patients with recurrent glioblastoma multiforme. Secondary * To evaluate the acute and late toxicities associated with these regimens. * To assess the objective tumor response rate. * To estimate the overall survival of these patients. * To describe the pharmacokinetic and pharmacodynamic profiles and immunogenicity of these regimens. OUTLINE: This is a multicenter study. Patients are sequentially assigned to 1 of 2 treatment groups. * Group 1: Patients receive ramucirumab IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. * Group 2: Patients receive anti-PDGFR alpha monoclonal antibody IMC-3G3 IV over 60-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Interventions
BIOLOGICALolaratumab
Given IV
BIOLOGICALramucirumab
Given IV
Sponsors
National Cancer Institute (NCI)
Eli Lilly and Company
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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
DISEASE CHARACTERISTICS: * Histologically confirmed supratentorial glioblastoma multiforme (GBM) * Patients with prior low-grade glioma who progressed after radiotherapy ± chemotherapy and are biopsied and found to have GBM are eligible * Progressive or recurrent disease after radiotherapy ± chemotherapy * Measurable disease by contrast-enhanced MRI or CT scan PATIENT CHARACTERISTICS: * Karnofsky performance status 60-100% * Life expectancy ≥ 3 months * Absolute neutrophil count ≥ 1,500/millimeter cubed (mm³) * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 9 gram/deciliter (g/dL) * Creatinine ≤ 1.5 milligram/deciliter (mg/dL) OR creatinine clearance \> 60 mL/min * Total bilirubin ≤ 1.5 mg/dL * Transaminases ≤ 3 times upper limit of normal (ULN) * Urine protein ≤ 2+ by dipstick or urinalysis or ≤ 1,000 mg by 24-hour urine collection * International Normalized Ratio (INR) ≤ 1.5 * Partial Thromboplastin Time (PTT) ≤ 5 seconds above ULN * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for ≥ 12 weeks after completion of study treatment * Mini Mental State Exam score ≥ 15 * Able to undergo magnetic resonance imaging (MRI) (i.e., no pacemaker, aneurysm clip, or claustrophobia) * No concurrent serious infection or medical illness that would jeopardize the ability of the patient to receive the treatment outlined in this study with reasonable safety including, but not limited to, any of the following: * Uncontrolled hypertension * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness/social situation that would limit compliance with study requirements * No other malignancy within the past 5 years, except curatively treated carcinoma in situ or basal cell carcinoma of the skin * No major bleeding episode within the past 3 months * No myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack within the past 6 months * No serious or non-healing wound, ulcer, or bone fracture * No uncontrolled or poorly controlled hypertension, despite standard medical management * No known allergy to any of the treatment components * No known HIV positivity or AIDS-related illness * No uncontrolled thrombotic or hemorrhagic disorders * No grade 3-4 gastrointestinal bleeding within the past 3 months * No gross hemoptysis (≥ ½ teaspoon) within the past 2 months PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from prior therapy * At least 3 months since prior radiotherapy * At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas) * At least 2 weeks since prior FDA-approved, non-cytotoxic agents (e.g., celecoxib, thalidomide) * At least 3 weeks since prior investigational, non-cytotoxic agents * More than 28 days since prior major surgery, including brain biopsy * More than 7 days since prior subcutaneous venous access device placement * No prior treatment with other agents that directly inhibit Platelet-Derived Growth Factor Receptor (PDGFR)α/β, Platelet-Derived Growth Factor (PDGF), Vascular Endothelial Growth Factor (VEGF), or Vascular Endothelial Growth Factor Receptor (VEGFR)s * No concurrent therapeutic anticoagulation, chronic daily treatment with aspirin (\> 325 mg/day), or other known inhibitors of platelet function * No concurrent prophylactic hematopoietic growth factors (e.g., erythropoietin, Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte-macrophage Colony Stimulating Factor (GM-CSF), or Interleukin (IL-11) during the first course of treatment * No concurrent elective or planned surgery * No other concurrent therapy for the tumor (e.g., chemotherapy or investigational agents) * Concurrent steroids allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Progression-Free Survival Rate at 6 Months (PFS-6) | Start of treatment to PD or Death Up To 6 Months | PFS was defined as the start of treatment to the earliest date of tumor progression or death from any cause based on the modified Response Assessment in Neuro-Oncology Group through the American Society of Clinical Oncology (RANO) criteria. Progression is defined by any of the following: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. RANO is a standardized response criteria using bi-dimensional measurements of the largest contrast-enhancing area (Macdonald, 1990). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants (Pts) With Complete Response (CR), Partial Response (PR) and Minor Response (MR) (Objective Response Rate [ORR]) | Start of Treatment to PD Up To 20 Months | The pts achievement of both measurement and confirmation criteria for a status of CR, PR or MR based on the modified RANO criteria.CR requires all of the following:complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks (wks);no new lesions;no corticosteroids;and stable or improved clinically.PR requires all of the following:≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 wks;no new lesions;stable or reduced corticosteroid dose;and stable or improved clinically.MR requires ≥ 25% reduction in sum of products of the perpendicular diameters of all measureable enhancing lesions sustained for at least 4 wks and no new lesions or progression of non-measurable lesions. PD is defined by any of these: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions;any new lesion;or clinical deterioration. |
| Median Overall Survival (OS) | Start of Treatment to Death Up To 27 Months | OS is the time from the start of treatment to the date of death. Participants who had not expired by the data analysis cutoff date were censored at their last date known to be alive. |
| Pharmacokinetics (PK): Concentration Maximum (Cmax) and Concentration Minimum (Cmin) of Ramucirumab | Cycle 7, Day 1: Prior to Infusion,1 hour (hr) Post Infusion | — |
| Number of Participants With Treatment Emergent Adverse Events as Assessed by NCI CTCAE v4.0 (National Cancer Institute-Common Terminology Criteria for Adverse Events) | Start of Treatment to End of Study (Up to 13 Months) | The number of participants who experienced serious adverse events (SAEs) that were considered to be related to ramucirumab or olaratumab. A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section. |
| Pharmacodynamics (PD) Profiles | Cycle 7, Day 1: Prior to Infusion, 1 hr Post Infusion | — |
| Percentage of Participants With Anti-Olaratumab Antibodies (ADA) | Start of Treatment to 30-day Post Infusion Follow Up (Up to 6 Months) | Percentage of Participants with Treatment Emergent (TE) anti-olaratumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20. |
| Percentage of Participants With Anti-Ramucirumab Antibodies (ADA) | Start of Treatment to 30-day Post Infusion Follow Up (Up to 6 Months) | Percentage of Participants with Treatment Emergent (TE) anti-ramucirumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20. |
| PK: Cmax and Cmin of Olaratumab | Cycle 3, Day 1: Prior to Infusion, 1 hr Post Infusion | — |
Countries
United States
Participant flow
Pre-assignment details
The completers include those participants with progressive disease (PD) or those who died.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Ramucirumab Participants receive ramucirumab IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | 40 |
| Group 2 Olaratumab Participants receive olaratumab IV over 60-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | 40 |
| Total | 80 |
Baseline characteristics
| Characteristic | Group 1 Ramucirumab | Total | Group 2 Olaratumab |
|---|---|---|---|
| Age, Continuous | 51.4 years STANDARD_DEVIATION 12.29 | 51.5 years STANDARD_DEVIATION 11.98 | 51.6 years STANDARD_DEVIATION 11.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 77 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 38 Participants | 75 Participants | 37 Participants |
| Region of Enrollment United States | 40 participants | 80 participants | 40 participants |
| Sex: Female, Male Female | 12 Participants | 28 Participants | 16 Participants |
| Sex: Female, Male Male | 28 Participants | 52 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 40 | 39 / 40 |
| serious Total, serious adverse events | 13 / 40 | 14 / 40 |
Outcome results
Primary
Percentage of Participants Who Achieved Progression-Free Survival Rate at 6 Months (PFS-6)
PFS was defined as the start of treatment to the earliest date of tumor progression or death from any cause based on the modified Response Assessment in Neuro-Oncology Group through the American Society of Clinical Oncology (RANO) criteria. Progression is defined by any of the following: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. RANO is a standardized response criteria using bi-dimensional measurements of the largest contrast-enhancing area (Macdonald, 1990).
Time frame: Start of treatment to PD or Death Up To 6 Months
Population: All enrolled participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 Ramucirumab | Percentage of Participants Who Achieved Progression-Free Survival Rate at 6 Months (PFS-6) | 12.5 percentage of participants |
| Group 2 Olaratumab | Percentage of Participants Who Achieved Progression-Free Survival Rate at 6 Months (PFS-6) | 7.5 percentage of participants |
Secondary
Median Overall Survival (OS)
OS is the time from the start of treatment to the date of death. Participants who had not expired by the data analysis cutoff date were censored at their last date known to be alive.
Time frame: Start of Treatment to Death Up To 27 Months
Population: All enrolled participants who received at least one dose of study drug. Participants censored in ramucirumab = 4 and olaratumab = 4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 Ramucirumab | Median Overall Survival (OS) | 49.5 Weeks |
| Group 2 Olaratumab | Median Overall Survival (OS) | 34.3 Weeks |
Secondary
Number of Participants With Treatment Emergent Adverse Events as Assessed by NCI CTCAE v4.0 (National Cancer Institute-Common Terminology Criteria for Adverse Events)
The number of participants who experienced serious adverse events (SAEs) that were considered to be related to ramucirumab or olaratumab. A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section.
Time frame: Start of Treatment to End of Study (Up to 13 Months)
Population: All enrolled participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 Ramucirumab | Number of Participants With Treatment Emergent Adverse Events as Assessed by NCI CTCAE v4.0 (National Cancer Institute-Common Terminology Criteria for Adverse Events) | SAE | 13 participants |
| Group 1 Ramucirumab | Number of Participants With Treatment Emergent Adverse Events as Assessed by NCI CTCAE v4.0 (National Cancer Institute-Common Terminology Criteria for Adverse Events) | Other adverse events (AEs) | 38 participants |
| Group 2 Olaratumab | Number of Participants With Treatment Emergent Adverse Events as Assessed by NCI CTCAE v4.0 (National Cancer Institute-Common Terminology Criteria for Adverse Events) | SAE | 14 participants |
| Group 2 Olaratumab | Number of Participants With Treatment Emergent Adverse Events as Assessed by NCI CTCAE v4.0 (National Cancer Institute-Common Terminology Criteria for Adverse Events) | Other adverse events (AEs) | 39 participants |
Secondary
Percentage of Participants (Pts) With Complete Response (CR), Partial Response (PR) and Minor Response (MR) (Objective Response Rate [ORR])
The pts achievement of both measurement and confirmation criteria for a status of CR, PR or MR based on the modified RANO criteria.CR requires all of the following:complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks (wks);no new lesions;no corticosteroids;and stable or improved clinically.PR requires all of the following:≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 wks;no new lesions;stable or reduced corticosteroid dose;and stable or improved clinically.MR requires ≥ 25% reduction in sum of products of the perpendicular diameters of all measureable enhancing lesions sustained for at least 4 wks and no new lesions or progression of non-measurable lesions. PD is defined by any of these: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions;any new lesion;or clinical deterioration.
Time frame: Start of Treatment to PD Up To 20 Months
Population: All enrolled participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 Ramucirumab | Percentage of Participants (Pts) With Complete Response (CR), Partial Response (PR) and Minor Response (MR) (Objective Response Rate [ORR]) | 0 percentage of participants |
| Group 2 Olaratumab | Percentage of Participants (Pts) With Complete Response (CR), Partial Response (PR) and Minor Response (MR) (Objective Response Rate [ORR]) | 2.5 percentage of participants |
Secondary
Percentage of Participants With Anti-Olaratumab Antibodies (ADA)
Percentage of Participants with Treatment Emergent (TE) anti-olaratumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20.
Time frame: Start of Treatment to 30-day Post Infusion Follow Up (Up to 6 Months)
Population: All enrolled participant who had any amount of olaratumab and evaluable anti-olaratumab antibody data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 Ramucirumab | Percentage of Participants With Anti-Olaratumab Antibodies (ADA) | 0 percentage of participants |
Secondary
Percentage of Participants With Anti-Ramucirumab Antibodies (ADA)
Percentage of Participants with Treatment Emergent (TE) anti-ramucirumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20.
Time frame: Start of Treatment to 30-day Post Infusion Follow Up (Up to 6 Months)
Population: All enrolled participants who had any amount of ramucirumab and evaluable anti-ramucirumab antibodies.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 Ramucirumab | Percentage of Participants With Anti-Ramucirumab Antibodies (ADA) | 3.1 percentage of participants |
Secondary
Pharmacodynamics (PD) Profiles
Time frame: Cycle 7, Day 1: Prior to Infusion, 1 hr Post Infusion
Population: Zero participants were analyzed for pharmacodynamic profile as the plasma collection procedure in this study was not fit for this purpose.
Secondary
Pharmacokinetics (PK): Concentration Maximum (Cmax) and Concentration Minimum (Cmin) of Ramucirumab
Time frame: Cycle 7, Day 1: Prior to Infusion,1 hour (hr) Post Infusion
Population: All enrolled participants who received at least one dose of ramucirumab and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Ramucirumab | Pharmacokinetics (PK): Concentration Maximum (Cmax) and Concentration Minimum (Cmin) of Ramucirumab | Cmin (n=5) | 85.0 microgram/milliliter (μg/mL) | Geometric Coefficient of Variation 25 |
| Group 1 Ramucirumab | Pharmacokinetics (PK): Concentration Maximum (Cmax) and Concentration Minimum (Cmin) of Ramucirumab | Cmax (n=6) | 396 microgram/milliliter (μg/mL) | Geometric Coefficient of Variation 30 |
Secondary
PK: Cmax and Cmin of Olaratumab
Time frame: Cycle 3, Day 1: Prior to Infusion, 1 hr Post Infusion
Population: All enrolled participants who received at least one dose of Olaratumab and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Ramucirumab | PK: Cmax and Cmin of Olaratumab | Cmin (n=5) | 145 μg/mL | Geometric Coefficient of Variation 22 |
| Group 1 Ramucirumab | PK: Cmax and Cmin of Olaratumab | Cmax (n=5) | 515 μg/mL | Geometric Coefficient of Variation 23 |