Glioblastoma
Conditions
Keywords
Glioblastoma (GBM), Wilms Tumor 1 (WT1), Cancer Vaccines, Neoplasms, Astrocytoma, Glioma, Brain Cancer, Brain Tumor, Bevacizumab
Brief summary
This is an event driven, adaptive design, a randomized, active-controlled, multicenter, open-label, parallel groups, Phase 3 study of DSP-7888 Dosing Emulsion plus Bevacizumab versus Bevacizumab alone in patients with recurrent or progressive glioblastoma multiforme (GBM) following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy.
Interventions
DSP-7888 Dosing Emulsion will be administered i.d. every 7 ± 1 day for Doses 1 to 5, every 14 ± 3 days for Doses 6 to 15, and every 28 ± 7 days for Doses 16 and above.
DRUGBevacizumab
Bevacizumab will be administered intravenously every 14 ± 3 days at 10 mg/kg.
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients or their legal representatives must be able to provide written informed consent. * Histologically confirmed diagnosis of supratentorial GBM (Grade 4 astrocytoma). * Radiographic evidence of first recurrence or progression of GBM following primary therapy consisting of surgery (biopsy or resection) and chemoradiation; patients may have undergone a second debulking surgery following initial recurrence or progression. Patients whose tumors are O6 methyl guanyl-methyltransferase (MGMT) methylated-promoter negative need not have received chemotherapy in the past to be eligible. * Human leukocyte antigen type HLA-A\*02:01, HLA-A\*02:06, or HLA-A\*24:02. * Age ≥18. * KPS score of ≥60. * Serum creatinine value \<2X the upper limit of normal (ULN) for the reference laboratory. * Alanine aminotransferase/aspartate aminotransferase \<3X the ULN and total bilirubin \<2× the ULN for the reference laboratory. * Men and women of childbearing potential must agree to use a reliable method of contraception (oral contraceptives, implantable hormonal contraceptives, or double barrier method) or agree to completely refrain from heterosexual intercourse for the duration of the study and for 180 days following the last dose of DSP-7888 Dosing Emulsion. * Patients must have recovered from the effect of all prior therapy to Grade 2 or less. * Patients must be at least 28 days from any major surgery, and any surgery incisions or wounds must be completely healed. * Patients must be at least 12 weeks from the completion of prior radiation therapy (RT) in order to discriminate pseudo progression of disease from progression. * Patients must be at least 4 weeks from the completion of prior systemic or intracranial chemotherapy. * Patients must stop Novo-TTF treatment one day prior to study therapy (no washout period is needed). However, any wounds from TTF must be adequately healed per Inclusion Criterion #11.15. For patients who are not receiving therapeutic anticoagulation treatment, an international normalized ratio (INR) and a PTT ≤ 1.5 × the ULN; patients who are receiving anticoagulation treatment should be on a stable dose. * Patient's left ventricular ejection fraction (LVEF) \> 40%. 17. Patient has a resting pulse oximetry of 90% or higher.
Exclusion criteria
Patients with any of the following will be excluded from the study: * Prior therapy with Bev. * Patients with secondary GBM. * Any anti-neoplastic therapy, including RT, for first relapse or recurrence. * Evidence of leptomeningeal spread of tumor or any history, presence, or suspicion of metastatic disease extracranially. * Evidence of impending herniation on imaging. * Has known multifocal disease. Multifocal disease is defined as discrete sites of disease without contiguous T2/FLAIR abnormality that require distinct radiotherapy ports. Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the same radiotherapy port as the main lesion(s) are permitted. * Patients with infections that have required treatment with systemic antibiotics within 7 days of first dose of protocol therapy. * The need for systemic glucocorticoids in doses in excess of 4 mg/day of dexamethasone or in comparable doses with other glucocorticoids. * Treatment with any investigational agents within 5 half-lives of the agent in question or, if the half-life is unknown, within 28 days of enrollment. * Pregnant or lactating females. * Prior history of malignancy within 3 years of enrollment other than basal or squamous cell carcinoma of the skin, cervical intra-epithelial neoplasia, in situ carcinoma of the breast, or prostate cancer treated with surgery or RT with a prostate specific antigen of \<0.01 ng/mL. * Patients with active autoimmune diseases within 2 years of enrollment into the study including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Wegener's granulomatosis, ulcerative colitis, Crohn's disease, myasthenia gravis, Graves' disease, or uveitis except for psoriasis not requiring systemic therapy, vitiligo or alopecia areata, or hypothyroidism; if an autoimmune condition has been clinically silent for 12 months or greater, the patient may be eligible for enrollment. * Patients on immunosuppressive therapies; the use of topical, inhalational, ophthalmologic or intra articular glucocorticoids, or the use of physiologic replacement doses of glucocorticoids are permitted. * Patients with primary immunodeficiency diseases. * Patients with significant bleeding in the preceding 6 months or with known coagulopathies. * History of abdominal fistula, intestinal perforation, or intra-abdominal abscess in the preceding 12 months. * Positive serology for human immunodeficiency virus (HIV) infection, active hepatitis B\*, or untreated hepatitis C; patients who have completed a course of anti-viral treatment for hepatitis C are eligible. o \*In cases of negative results for HepB surface antigen with positive HepB core antibody, HBV DNA testing is required. * Patient has a medical history of frequent ventricular ectopy, e.g., non-sustained ventricular tachycardia (VT). * Significant cardiovascular disease, including New York Hospital Association Class III or IV congestive heart failure, myocardial infarction within 6 months of enrollment, unstable angina, poorly controlled cardiac arrhythmias, or stroke within the preceding 6 months. * Any other uncontrolled inter current medical condition, including systemic fungal, bacterial, or viral infection; uncontrolled hypertension; diabetes mellitus; or chronic obstructive pulmonary disease requiring 2 or more hospitalizations in the preceding 12 months. * Any psychiatric condition, substance abuse disorder, or social situation that would interfere with a patient's cooperation with the requirements of the study. * Known sensitivity to Bev or any of the components of DSP-7888 Dosing Emulsion. * Patient has a QTcF (QT corrected based on Fridericia's equation) interval \> 480 msec (CTCAE = Grade 2) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening. (Patients with bundle branch block and a prolonged QTc interval should be reviewed by the Medical Monitor for potential inclusion.) * Patient has dyspnea at rest (CTCAE ≥ Grade 3) or has required supplemental oxygen within 2 weeks of study enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Dose-limiting Toxicity | Dose-limiting toxicity will be evaluated and applied from Day 1 through Day 29 | The number of participants with dose-limiting toxicity (DLT) who were enrolled into Part 1 - the safety set. |
| Overall Survival (OS) of Patients With Recurrent or Progressive Glioblastoma Multiforme (GBM) Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone | 4 weeks after the patient has been off study treatment, every 3 months thereafter until death, the study closes, up to 24 months. | The effect of DSP-7888 Dosing Emulsion plus BEV versus BEV alone on the OS of patients with recurrent or progressive GBM following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Rate in Patients With Recurrent or Progressive GBM at 6 Months | The time from the date of first treatment to the date of first documentation of disease progression or death due to any cause at 6 months | The effect of DSP-7888 dosing emulsion plus Bevacizumab (BEV) versus BEV alone on the Progression Free Survival (PFS) rate in patients with recurrent or progressive GBM following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy. PFS is defined as the interval between randomization date and progression or death from any cause as determined by the central radiology body. The percentage of patients who achieved PFS at 6 months are summarized. |
| The Effect of DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone on the Response Rate of Patients With Recurrent or Progressive GBM | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months | Assessment of the objective response rate (ORR) of DSP-7888 dosing emulsion plus BEV versus BEV alone in patients with recurrent or progressive GBM. The response rate is defined as the percentage of patients exhibiting a response (complete response \[CR\] plus partial response \[PR\]) based on the Modified Response Assessment in Neuro-Oncology (RANO) criteria as determined by the central radiology body. |
| Overall Survival (OS) of Patients With Recurrent or Progressive Glioblastoma Multiforme (GBM) Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone at 12 Months | 12 months | The effect of DSP-7888 dosing emulsion plus BEV versus BEV alone on the OS of patients with recurrent or progressive GBM following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy. |
| Number of Participants With Adverse Events and Serious Adverse Events | The time from the date of first treatment, while the patient is on treatment, and for 30 days after stopping therapy, an average of 4 months | Assessment of safety of DSP7888 dosing emulsion plus Bevacizumab (BEV) versus BEV alone in patients with recurrent or progressive GBM |
| Duration of Response in Patients With Recurrent or Progressive GBM Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone | From the date of first treatment up to 24 months | The effect of DSP-7888 dosing emulsion plus BEV versus BEV alone on the duration of response of patients with recurrent or progressive GBM. The duration of response is defined as the interval between first documented oncological response and progression of disease or death from any cause. |
| Progression Free Survival (PFS) of Patients With Recurrent or Progressive GBM | The time from the date of first treatment to the date of first documentation of disease progression or death due to any cause, up to 24 months | The effect of DSP-7888 dosing emulsion plus Bevacizumab (BEV) versus BEV alone on the Progression Free Survival (PFS) of patients with recurrent or progressive GBM following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy. PFS is defined as the interval between randomization and progression or death from any cause any cause as determined by the central radiology body. |
Countries
Canada, Japan, South Korea, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab Drug: DSP-7888 Dosing Emulsion DSP-7888 Dosing Emulsion will be administered i.d. every 7 ± 1 day for Doses 1 to 5, every 14 ± 3 days for Doses 6 to 15, and every 28 ± 7 days for Doses 16 and above.
Other Name: adegramotide and nelatimotide
Drug: Bevacizumab Bevacizumab will be administered intravenously every 14 ± 3 days at 10 mg/kg. Other Name: Avastin | 4 |
| Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab DSP-7888 Dosing Emulsion: DSP-7888 Dosing Emulsion will be administered i.d. every 7 ± 1 day for Doses 1 to 5, every 14 ± 3 days for Doses 6 to 15, and every 28 ± 7 days for Doses 16 and above.
Bevacizumab: Bevacizumab will be administered intravenously every 14 ± 3 days at 10 mg/kg. | 109 |
| Part 2 - Arm 2: Bevacizumab Bevacizumab: Bevacizumab will be administered intravenously every 14 ± 3 days at 10 mg/kg. | 108 |
| Total | 221 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Randomized but not treated | 0 | 1 | 18 |
Baseline characteristics
| Characteristic | Part 1 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Part 2 - Arm 2: Bevacizumab | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 33 Participants | 34 Participants | 68 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 76 Participants | 74 Participants | 153 Participants |
| HLA Class I Type Both Positive | 0 Participants | 13 Participants | 8 Participants | 21 Participants |
| HLA Class I Type HLA-A*02 Positive Only | 4 Participants | 67 Participants | 61 Participants | 132 Participants |
| HLA Class I Type HLA-A*24 Positive Only | 0 Participants | 29 Participants | 39 Participants | 68 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 38 Participants | 36 Participants | 74 Participants |
| Race/Ethnicity, Customized Black (including African, Caribbean descent) | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 3 Participants | 63 Participants | 67 Participants | 133 Participants |
| Race/Ethnicity, Customized Native Aboriginal (including First Nations, Metis, Inuit) | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Americans or Alaskan Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 7 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 37 Participants | 45 Participants | 85 Participants |
| Sex: Female, Male Male | 1 Participants | 72 Participants | 63 Participants | 136 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 96 / 109 | 89 / 108 |
| other Total, other adverse events | 4 / 4 | 106 / 108 | 79 / 90 |
| serious Total, serious adverse events | 1 / 4 | 10 / 108 | 6 / 90 |
Outcome results
Primary
Number of Participants Who Experienced a Dose-limiting Toxicity
The number of participants with dose-limiting toxicity (DLT) who were enrolled into Part 1 - the safety set.
Time frame: Dose-limiting toxicity will be evaluated and applied from Day 1 through Day 29
Population: Analysis limited to patients enrolled into Part 1 - the safety set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Number of Participants Who Experienced a Dose-limiting Toxicity | 0 Participants |
Primary
Overall Survival (OS) of Patients With Recurrent or Progressive Glioblastoma Multiforme (GBM) Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone
The effect of DSP-7888 Dosing Emulsion plus BEV versus BEV alone on the OS of patients with recurrent or progressive GBM following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy.
Time frame: 4 weeks after the patient has been off study treatment, every 3 months thereafter until death, the study closes, up to 24 months.
Population: Analysis limited to patients randomized into Part 2 - the intent-to-treat set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Overall Survival (OS) of Patients With Recurrent or Progressive Glioblastoma Multiforme (GBM) Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone | 10.2 months |
| Part 2 - Arm 2: Bevacizumab | Overall Survival (OS) of Patients With Recurrent or Progressive Glioblastoma Multiforme (GBM) Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone | 9.4 months |
Secondary
Duration of Response in Patients With Recurrent or Progressive GBM Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone
The effect of DSP-7888 dosing emulsion plus BEV versus BEV alone on the duration of response of patients with recurrent or progressive GBM. The duration of response is defined as the interval between first documented oncological response and progression of disease or death from any cause.
Time frame: From the date of first treatment up to 24 months
Population: Analysis limited to patients randomized into Part 2 - the intent-to-treat set. NE signifies Not Estimable in the results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Duration of Response in Patients With Recurrent or Progressive GBM Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone | 4.81 months | Standard Deviation 7.119 |
| Part 2 - Arm 2: Bevacizumab | Duration of Response in Patients With Recurrent or Progressive GBM Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone | 3.69 months | Standard Deviation 4.017 |
Secondary
Number of Participants With Adverse Events and Serious Adverse Events
Assessment of safety of DSP7888 dosing emulsion plus Bevacizumab (BEV) versus BEV alone in patients with recurrent or progressive GBM
Time frame: The time from the date of first treatment, while the patient is on treatment, and for 30 days after stopping therapy, an average of 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Number of Participants With Adverse Events and Serious Adverse Events | 4 Participants |
| Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Number of Participants With Adverse Events and Serious Adverse Events | 106 Participants |
| Part 2 - Arm 2: Bevacizumab | Number of Participants With Adverse Events and Serious Adverse Events | 79 Participants |
Secondary
Overall Survival (OS) of Patients With Recurrent or Progressive Glioblastoma Multiforme (GBM) Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone at 12 Months
The effect of DSP-7888 dosing emulsion plus BEV versus BEV alone on the OS of patients with recurrent or progressive GBM following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy.
Time frame: 12 months
Population: Analysis limited to patients randomized into Part 2 - the intent-to-treat set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Overall Survival (OS) of Patients With Recurrent or Progressive Glioblastoma Multiforme (GBM) Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone at 12 Months | 37.9 percentage of participants |
| Part 2 - Arm 2: Bevacizumab | Overall Survival (OS) of Patients With Recurrent or Progressive Glioblastoma Multiforme (GBM) Treated With DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone at 12 Months | 31.6 percentage of participants |
Secondary
Progression Free Survival (PFS) of Patients With Recurrent or Progressive GBM
The effect of DSP-7888 dosing emulsion plus Bevacizumab (BEV) versus BEV alone on the Progression Free Survival (PFS) of patients with recurrent or progressive GBM following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy. PFS is defined as the interval between randomization and progression or death from any cause any cause as determined by the central radiology body.
Time frame: The time from the date of first treatment to the date of first documentation of disease progression or death due to any cause, up to 24 months
Population: Analysis limited to patients randomized into Part 2 - the intent-to-treat set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Progression Free Survival (PFS) of Patients With Recurrent or Progressive GBM | 5.3 months |
| Part 2 - Arm 2: Bevacizumab | Progression Free Survival (PFS) of Patients With Recurrent or Progressive GBM | 3.8 months |
Secondary
Progression Free Survival (PFS) Rate in Patients With Recurrent or Progressive GBM at 6 Months
The effect of DSP-7888 dosing emulsion plus Bevacizumab (BEV) versus BEV alone on the Progression Free Survival (PFS) rate in patients with recurrent or progressive GBM following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy. PFS is defined as the interval between randomization date and progression or death from any cause as determined by the central radiology body. The percentage of patients who achieved PFS at 6 months are summarized.
Time frame: The time from the date of first treatment to the date of first documentation of disease progression or death due to any cause at 6 months
Population: Analysis limited to patients randomized into Part 2 - the intent-to-treat set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | Progression Free Survival (PFS) Rate in Patients With Recurrent or Progressive GBM at 6 Months | 36.3 percentage of participants |
| Part 2 - Arm 2: Bevacizumab | Progression Free Survival (PFS) Rate in Patients With Recurrent or Progressive GBM at 6 Months | 35.4 percentage of participants |
Secondary
The Effect of DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone on the Response Rate of Patients With Recurrent or Progressive GBM
Assessment of the objective response rate (ORR) of DSP-7888 dosing emulsion plus BEV versus BEV alone in patients with recurrent or progressive GBM. The response rate is defined as the percentage of patients exhibiting a response (complete response \[CR\] plus partial response \[PR\]) based on the Modified Response Assessment in Neuro-Oncology (RANO) criteria as determined by the central radiology body.
Time frame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months
Population: Analysis limited to patients randomized into Part 2 - the intent-to-treat set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Arm 1: DSP-7888 Dosing Emulsion Plus Bevacizumab | The Effect of DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone on the Response Rate of Patients With Recurrent or Progressive GBM | 21.1 percentage of participants |
| Part 2 - Arm 2: Bevacizumab | The Effect of DSP-7888 Dosing Emulsion Plus Bevacizumab (BEV) Versus BEV Alone on the Response Rate of Patients With Recurrent or Progressive GBM | 13.0 percentage of participants |