Glioblastoma Multiforme, Glioma, Gliosarcoma, Malignant Brain Tumor
Conditions
Keywords
glioblastoma multiforme, glioma, gliosarcoma, malignant brain tumor
Brief summary
In this study, investigators will conduct a phase I/II trial in recurrent (temozolomide resistant) glioma patients. The overall goal of this study is to provide a foundation for future studies with indoximod tested in newly diagnosed glioblastoma patients with radiation and temozolomide, or in combination with vaccine therapies.
Detailed description
The aim of this study is to identify the safety profile and the recommended dose for phase 2 study of the combination of indoximod (portion 1, phase 1b study). Investigators will then evaluate the tolerability and the preliminary activity in patients with recurrent GBM in three different situations: * Combination of indoximod and temozolomide (bevacizumab-naive patients) * Combination of indoximod and temozolomide in patients currently receiving or having received and failed bevacizumab. * Combination of indoximod and temozolomide with stereotactic radiation. Ancillary studies will be conducted to assess the correlation between intra-tumoral IDO expression or serum biomarkers (immune monitoring) and treatment efficacy. If the current study shows an acceptable safety profile and suggests preliminary evidence of activity, this will provide the justification for subsequent randomized phase 2 studies in refractory glioblastoma multiforme (GBM).
Interventions
Sponsors
NewLink Genetics Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven intracranial glioblastoma multiforme (WHO grade IV glioma) or gliosarcoma. In addition, the Phase 1b cohort will include patients with progressive WHO grade III glioma. * Patients will be eligible if the original histology was lower grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made. * Unequivocal radiographic evidence for tumor progression by MRI. It is understood that some patients may be resected prior to enrolling onto protocol * Patients must have completed a course of radiation therapy and at least 2 adjuvant cycles of temozolomide for the phase 2 component. * Patients enrolling onto Cohort 2b who have been taken off bevacizumab must have had at least a 28 day washout from any previous administration of bevacizumab. It is preferred that patients who fail bevacizumab prior to trial entry remain on bevacizumab in the trial. * Prior temozolomide is not required for the phase 1 component; prior radiation is required for the phase 1 arm. * Patients must be on a steroid dose less than or equal to 2 mg of dexamethasone daily (or equivalent), and this dose must not have increased for at least 14 days prior to obtaining the enrollment. * ECOG performance status ≤1 or Karnofsky ≥70%. * Age between 16 * Must be 28 days from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions: * Must be 14 days from administration of non-cytotoxic agents (e.g., bevacizumab (except COHORT 2b), interferon, tamoxifen, thalidomide, cis-retinoic acid, tyrosine kinase inhibitor, etc.).
Exclusion criteria
* Prior invasive malignancy that is not low-grade glioma, high-grade glioma, glioblastoma, or gliosarcoma (except non-melanomatous skin cancer or carcinoma in situ of the cervix) unless the patient has been disease free and off therapy for that disease for a minimum of 3 years. * Patients on the phase 2 portion of the study may not have more than 2 prior regimens for recurrent disease for glioblastoma/gliosarcoma. Patients on the phase 1 portion of the study may not have had more than 3 prior regimens. * Systemic corticosteroid therapy \> 2 mg of dexamethasone daily (or equivalent) at study enrollment. * Active or history of autoimmune disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Regimen-Limiting Toxicities (RLTs) in Phase 1 Subjects | 3 months | Number of RLTs observed in each dose level. |
| Phase 2: Number of Phase 1 Participants With Efficacy Outcomes | 6 months | Six-month progression-free survival. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate for Phase 2 Participants | 18 months | Subjects with a complete response or partial response by RANO assessment. Overall Response Rate was only assessed in phase 2 subjects on this trial. |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 18 Months | Number of subjects with at least 1 treatment emergent adverse event. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Dose Level 1 Phase 1 Cohort 1 patients will receive Indoximod given at 600 mg BID by mouth Temozolomide will also be given by mouth at 150 mg/m\^2 x 5 days | 3 |
| Phase 1 Dose Level 2 Phase 1 Cohort 1 patients will receive Indoximod given at 1000 mg BID by mouth Temozolomide will also be given by mouth at 150 mg/m\^2 x 5 days | 3 |
| Phase 1 Dose Level 3 Phase 1 Cohort 1 patients will receive Indoximod given at 1200 mg BID by mouth Temozolomide will also be given by mouth at 150 mg/m\^2 x 5 days | 6 |
| Phase 2 Cohort 2a Bevacizumab naïve phase II patients who will receive indoximod with temozolomide. Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. | 80 |
| Phase 2 Cohort 2b Phase II patients who will receive indoximod with temozolomide and bevacizumab who have previously been treated with bevacizumab.
Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. Bevacizumab will be dosed at 10mg/kg. | 28 |
| Phase 2 Cohort 2c Phase II patients who will receive indoximod with temozolomide and stereotactic radiosurgery. Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. Single fraction SRS dose will be 16 or 20 Gy depending on target volume. The total 5-fraction SRT dose will be 27.5 Gy. | 40 |
| Total | 160 |
Baseline characteristics
| Characteristic | Phase 1 Dose Level 1 | Phase 1 Dose Level 2 | Phase 1 Dose Level 3 | Phase 2 Cohort 2a | Phase 2 Cohort 2b | Phase 2 Cohort 2c | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 1 Participants | 8 Participants | 3 Participants | 3 Participants | 15 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 19 Participants | 8 Participants | 6 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 5 Participants | 53 Participants | 17 Participants | 31 Participants | 112 Participants |
| Age, Continuous | 42.7 years STANDARD_DEVIATION 4.04 | 52.3 years STANDARD_DEVIATION 12.66 | 48.0 years STANDARD_DEVIATION 11.14 | 56.0 years STANDARD_DEVIATION 13.69 | 54.0 years STANDARD_DEVIATION 14.64 | 56.8 years STANDARD_DEVIATION 12.2 | 55.2 years STANDARD_DEVIATION 13.36 |
| ECOG Performance Status Scale ECOG = 0 | 0 Participants | 0 Participants | 3 Participants | 38 Participants | 7 Participants | 22 Participants | 70 Participants |
| ECOG Performance Status Scale ECOG = 1 | 3 Participants | 2 Participants | 3 Participants | 37 Participants | 20 Participants | 17 Participants | 82 Participants |
| ECOG Performance Status Scale Missing | 0 Participants | 1 Participants | 0 Participants | 5 Participants | 1 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 8 Participants | 1 Participants | 1 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 5 Participants | 68 Participants | 27 Participants | 39 Participants | 145 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 5 Participants |
| Mean BMI | 31.807 kg/m2 STANDARD_DEVIATION 11.9796 | 31.967 kg/m2 STANDARD_DEVIATION 5.1495 | 27.260 kg/m2 STANDARD_DEVIATION 7.894 | 27.904 kg/m2 STANDARD_DEVIATION 5.1508 | 26.633 kg/m2 STANDARD_DEVIATION 3.5701 | 28.037 kg/m2 STANDARD_DEVIATION 6.0775 | 27.84 kg/m2 STANDARD_DEVIATION 5.42 |
| Mean Height | 176.667 Centimeters STANDARD_DEVIATION 12.6623 | 179.133 Centimeters STANDARD_DEVIATION 5.5185 | 171.720 Centimeters STANDARD_DEVIATION 8.8797 | 172.505 Centimeters STANDARD_DEVIATION 9.8244 | 168.710 Centimeters STANDARD_DEVIATION 9.3381 | 173.659 Centimeters STANDARD_DEVIATION 10.1278 | 172.302 Centimeters STANDARD_DEVIATION 9.839 |
| Mean Weight | 96.467 Kilograms STANDARD_DEVIATION 22.7315 | 103.117 Kilograms STANDARD_DEVIATION 22.9877 | 81.083 Kilograms STANDARD_DEVIATION 25.046 | 83.342 Kilograms STANDARD_DEVIATION 17.5121 | 75.882 Kilograms STANDARD_DEVIATION 11.5149 | 84.649 Kilograms STANDARD_DEVIATION 19.2743 | 82.895 Kilograms STANDARD_DEVIATION 17.881 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 5 Participants | 76 Participants | 27 Participants | 38 Participants | 149 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 3 Participants | 28 Participants | 18 Participants | 17 Participants | 68 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 3 Participants | 52 Participants | 10 Participants | 23 Participants | 92 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 6 / 6 | 67 / 77 | 28 / 28 | 34 / 39 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 6 / 6 | 77 / 77 | 28 / 28 | 39 / 39 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 1 / 6 | 21 / 77 | 10 / 28 | 17 / 39 |
Outcome results
Primary
Frequency of Regimen-Limiting Toxicities (RLTs) in Phase 1 Subjects
Number of RLTs observed in each dose level.
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Dose Level 1 | Frequency of Regimen-Limiting Toxicities (RLTs) in Phase 1 Subjects | 0 Participants |
| Phase 1 Dose Level 2 | Frequency of Regimen-Limiting Toxicities (RLTs) in Phase 1 Subjects | 0 Participants |
| Phase 1 Dose Level 3 | Frequency of Regimen-Limiting Toxicities (RLTs) in Phase 1 Subjects | 0 Participants |
Primary
Phase 2: Number of Phase 1 Participants With Efficacy Outcomes
Six-month progression-free survival.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Dose Level 1 | Phase 2: Number of Phase 1 Participants With Efficacy Outcomes | 18.6 Percent |
| Phase 1 Dose Level 2 | Phase 2: Number of Phase 1 Participants With Efficacy Outcomes | 3.9 Percent |
| Phase 1 Dose Level 3 | Phase 2: Number of Phase 1 Participants With Efficacy Outcomes | 22.9 Percent |
Secondary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Number of subjects with at least 1 treatment emergent adverse event.
Time frame: 18 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Dose Level 1 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 3 Participants |
| Phase 1 Dose Level 2 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 3 Participants |
| Phase 1 Dose Level 3 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 6 Participants |
| Phase 2 Cohort 2a | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 72 Participants |
| Phase 2 Cohort 2b | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 27 Participants |
| Phase 2 Cohort 2c | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 39 Participants |
Secondary
Overall Response Rate for Phase 2 Participants
Subjects with a complete response or partial response by RANO assessment. Overall Response Rate was only assessed in phase 2 subjects on this trial.
Time frame: 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Dose Level 1 | Overall Response Rate for Phase 2 Participants | 5.2 Percent |
| Phase 1 Dose Level 2 | Overall Response Rate for Phase 2 Participants | 0 Percent |
| Phase 1 Dose Level 3 | Overall Response Rate for Phase 2 Participants | 7.7 Percent |