Relapsed/Recurrent GBM (Phase 2), Solid Tumors (Phase 1)
Conditions
Keywords
Phase 1, Phase 2, Glioblastoma Multiforme, Glioblastoma, GBM, Brain Tumor, Brain Cancer, Tumor, Solid Tumor, Tumour, Lomustine, CCNU, CXCR4, Phase 1 Clinical Trial, Phase 2 Clinical Trial
Brief summary
This is a multicenter, open-label, Phase 1/2, dose-escalation and dose expansion study of a CXCR4 inhibitor, USL311, alone and in combination with lomustine in subjects with advanced solid tumors (Phase 1) and subjects with relapsed/recurrent GBM (Phase 2). The study is designed to explore the safety, tolerability, pharmacokinetics, and preliminary efficacy of USL311 alone and in combination with lomustine.
Interventions
DRUGUSL311
Administered once weekly in a 21-day cycle
DRUGLomustine
Administered once every 6 weeks in a 42-day cycle
Sponsors
Proximagen, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All Subjects: 1. Provide signed and dated informed consent prior to study-specific screening procedures 2. ≥ 18 years old 3. Karnofsky performance status (KPS) ≥ 70 4. Must have adequate bone marrow and renal/hepatic function within protocol specified limits 5. Disease-free period of \> 2 years from any other previous malignancies, excluding curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Subjects with prostate cancer Stage 1 that do not require treatment may also be included 6. Women and men must use protocol approved methods of contraception 7. Must be able and willing to comply with the study visit schedule and study procedures 8. Must be able to take oral medications 9. Must have available archived tumor tissue and willing and able to provide consent for study access to such tissue 10. For subjects with a history of seizures, must be adequately controlled on a stable regimen of anti-epileptic drugs For Phase 1 Subjects Only: 11. Histologically or cytologically documented diagnosis of solid tumor for which no standard therapy is recognized or have failed or intolerant to the standard-of-care treatment 12. Inoperable metastatic or locally advanced, unresectable disease 13. Subjects may have either evaluable or measurable disease 14. Subjects with treated (surgically excised or irradiated) and stable brain metastases are eligible as long as the subject has adequately recovered from treatment and the treatment was ≥ 28 days prior to initiation of study drug(s) and baseline brain computed tomography (CT) with contrast or magnetic resonance imaging (MRI) ≤ 14 days of initiation of study drug is negative for new brain metastases For Phase 2 Subjects Only: 15. Histologically confirmed diagnosis of GBM 16. Subjects must have documented recurrence after first-line treatment 17. Prior first-line treatment must have included radiation and temozolomide 18. Subject is suitable for re-resection, per Investigator discretion, as a component of their clinical care 19. No more than one prior resection (Note: biopsy does not count as prior resection)
Exclusion criteria
All Subjects 1. Subjects who have had recent systemic anticancer therapies, interventional device treatment and/or radiotherapy either within 14 days prior to first dose of study drug(s) or have not recovered (to grade ≤ 1) from all clinically significant toxicities related to prior therapies 2. Subjects who have had any major surgery (not including re-resection surgery required in Phase 2) within 28 days prior to first dose of study drug(s), or minor surgery within 14 days prior to first day of study drug(s) 3. Subjects taking any strong cytochrome P450 3A4 inducers within 14 days prior to the first dose of study drug(s) 4. Subjects taking any strong cytochrome P450 3A4 inhibitors within 14 days prior to the first dose of study drug(s) 5. Subjects taking any agents with moderate to high risk to prolong QT corrected (QTc) interval or to cause Torsades de Pointes within 14 days prior to the first dose of study drug(s) 6. Subjects who have been treated with an investigational agent or investigational interventional device within 21 days prior to the first dose of study drug(s) 7. Subject is growth factor dependent or transfusion dependent, or has received growth factor support or transfusion support within 14 days prior to the first dose of study drug(s) 8. History of significant cardiac disease 9. Status epilepticus within 1 year prior to the first dose of study drug(s) 10. Pregnant or breastfeeding 11. Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation For Phase 1 Subjects Only: 12. Lymphoma as primary cancer For Phase 2 Subjects Only: 13. Unable or unwilling to consent to the provision of resected tissue after surgery 14. Prior treatment with plerixafor or another CXCR4 inhibitor 15. Prior treatment with bevacizumab 16. Prior treatment with lomustine and/or carmustine For All Cohorts Receiving Oral USL311: 17. Any active medical condition or previous major abdominal surgery or procedure that might, in the investigator's opinion, have a significant effect on USL311 absorption
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Maximum Tolerated Dose (MTD) | Assessed weekly during treatment period. Median duration of exposure was 5.14 (range 2.1-17.3) weeks. | The MTD was defined as the highest safe dose (mg/m\^2) administered where safe is defined by having at least a 50% probability that the dose limiting toxicity (DLT) rate is less than 33%, as determined by a modified continuous reassessment model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Weekly during treatment or every 12 weeks during follow-up | Percentage of subjects alive five years after start of treatment. |
| Median Progression Free Survival (PFS) | Every 6 weeks during treatment | Time after initiation of treatment before disease progression |
| Objective Response Rate (ORR%) | Every 6 weeks | Percentage of patients whose disease decreased (Partial response) and/or disappears (Complete response) after initiation of treatment |
| Percentage Progression Free Survival (PFS) at 6 Months (PFS-6m) | Once every 6 weeks during treatment | Percentage of subjects who were without progression at 6 months as assessed radiographically with response to treatment determined by Response Evaluation Criteria in Solid Tumors (RECIST) or Response Assessment in Neuro-Oncology (RANO) criteria. |
| Time to Peak Concentration (Tmax) | Day 1 | Time to peak concentration of USL311 in plasma |
| Area Under the Concentration Versus Time Curve (AUC) | Day 1 | Area under the curve versus time from time 0 to infinity for USL311 concentration in plasma |
| Peak Concentration (Cmax) | Day 1 | Peak USL311 concentration (Cmax) in plasma |
Countries
Spain, United States
Participant flow
Pre-assignment details
Enrolled subjects participated in only one part (parts 1, 2, 3 or 4) of the study. Due to early termination of the study, no subjects were enrolled in parts 2, 3 or 4.
Participants by arm
| Arm | Count |
|---|---|
| Part 1a, Cohort 1 USL311, intravenous, once per week, 60 mg/m˄2, in 21-day cycles | 3 |
| Part 1a, Cohort 2 USL311, intravenous, once per week, 120 mg/m˄2, in 21-day cycles | 4 |
| Part 1a, Cohort 3, USL311, intravenous, once per week, 180 mg/m˄2, in 21-day cycles | 3 |
| Part 1a, Cohort 4, USL311, intravenous, once per week, 250 mg/m˄2, in 21-day cycles | 3 |
| Part 1b, Cohort 1 USL311, oral, daily, 40 mg, in 21-day cycles | 6 |
| Part 1b, Cohort 2 USL311, oral, daily, 80 mg, in 21-day cycles | 3 |
| Part 1b, Cohort 3 USL311, oral, daily, 160 mg, in 21-day cycles | 4 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Post-treatment Follow-up | Death | 1 | 2 | 1 | 1 | 1 | 1 | 0 |
| Post-treatment Follow-up | Initiation of subsequent treatment | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Post-treatment Follow-up | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Post-treatment Follow-up | Site terminated by sponsor | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Post-treatment Follow-up | Study terminated by the sponsor | 0 | 0 | 0 | 0 | 2 | 2 | 1 |
| Post-treatment Follow-up | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Progressive disease | 3 | 2 | 3 | 3 | 4 | 2 | 2 |
| Treatment Period | Study terminated | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Treatment Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1a, Cohort 1 | Part 1a, Cohort 2 | Part 1a, Cohort 3, | Part 1a, Cohort 4, | Part 1b, Cohort 1 | Part 1b, Cohort 2 | Part 1b, Cohort 3 | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 17 Participants |
| Age, Continuous | 46.7 years STANDARD_DEVIATION 24.83 | 53.5 years STANDARD_DEVIATION 16.2 | 57.7 years STANDARD_DEVIATION 17.79 | 60.3 years STANDARD_DEVIATION 10.97 | 62.5 years STANDARD_DEVIATION 14.6 | 72.0 years STANDARD_DEVIATION 9.17 | 57.3 years STANDARD_DEVIATION 6.95 | 58.8 years STANDARD_DEVIATION 14.77 |
| Body surface area | 1.767 m^2 STANDARD_DEVIATION 0.0503 | 2.018 m^2 STANDARD_DEVIATION 0.3363 | 2.000 m^2 STANDARD_DEVIATION 0.2307 | 1.787 m^2 STANDARD_DEVIATION 0.1704 | 1.910 m^2 STANDARD_DEVIATION 0.3864 | 1.820 m^2 STANDARD_DEVIATION 0.0624 | 2.088 m^2 STANDARD_DEVIATION 0.1893 | 1.923 m^2 STANDARD_DEVIATION 0.2603 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 5 Participants | 2 Participants | 4 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 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 | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 0 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 | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 2 Participants | 2 Participants | 6 Participants | 3 Participants | 3 Participants | 23 Participants |
| Region of Enrollment Spain | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 3 participants | 4 participants | 2 participants | 3 participants | 6 participants | 3 participants | 4 participants | 25 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 3 Participants | 2 Participants | 1 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 3 Participants | 0 Participants | 3 Participants | 1 Participants | 3 Participants | 14 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 | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 4 | 1 / 3 | 1 / 3 | 1 / 6 | 1 / 3 | 0 / 4 |
| other Total, other adverse events | 3 / 3 | 3 / 4 | 1 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 2 / 4 |
| serious Total, serious adverse events | 2 / 3 | 2 / 4 | 0 / 3 | 1 / 3 | 3 / 6 | 1 / 3 | 0 / 4 |
Outcome results
Primary
Phase 1: Maximum Tolerated Dose (MTD)
The MTD was defined as the highest safe dose (mg) administered where safe is defined by having at least a 50% probability that the dose limiting toxicity (DLT) rate is less than 33%, as determined by a modified continuous reassessment model.
Time frame: Assessed weekly during treatment period. Median duration of exposure was 6.00 (range 0.3-30.0) weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a, Dose-escalation, All Oral Cohorts | Phase 1: Maximum Tolerated Dose (MTD) | NA mg |
Primary
Phase 1: Maximum Tolerated Dose (MTD)
The MTD was defined as the highest safe dose (mg/m\^2) administered where safe is defined by having at least a 50% probability that the dose limiting toxicity (DLT) rate is less than 33%, as determined by a modified continuous reassessment model.
Time frame: Assessed weekly during treatment period. Median duration of exposure was 5.14 (range 2.1-17.3) weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a, Dose-escalation, All Oral Cohorts | Phase 1: Maximum Tolerated Dose (MTD) | NA mg/m^2 |
Secondary
Area Under the Concentration Versus Time Curve (AUC)
Area under the curve versus time from time 0 to infinity for USL311 concentration in plasma
Time frame: Day 1
Population: Subjects who received scheduled dose and had sufficient PK samples for determination of parameters
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a, Dose-escalation, All Oral Cohorts | Area Under the Concentration Versus Time Curve (AUC) | 181 ng*h/mL | Geometric Coefficient of Variation 101 |
| Part 1a, Cohort 2 | Area Under the Concentration Versus Time Curve (AUC) | 437 ng*h/mL | Geometric Coefficient of Variation 16.7 |
| Part 1a, Cohort 3a | Area Under the Concentration Versus Time Curve (AUC) | 711 ng*h/mL | — |
| Part 1a, Cohort 3b | Area Under the Concentration Versus Time Curve (AUC) | 1193 ng*h/mL | Geometric Coefficient of Variation 48.3 |
| Part 1a, Cohort 4 | Area Under the Concentration Versus Time Curve (AUC) | 1059 ng*h/mL | Geometric Coefficient of Variation 15.3 |
| Part 1b, Cohort 1 | Area Under the Concentration Versus Time Curve (AUC) | 5.95 ng*h/mL | Geometric Coefficient of Variation 54.1 |
| Part 1b, Cohort 2 | Area Under the Concentration Versus Time Curve (AUC) | 16.4 ng*h/mL | Geometric Coefficient of Variation 51 |
| Part 1b, Cohort 3 | Area Under the Concentration Versus Time Curve (AUC) | 30.4 ng*h/mL | Geometric Coefficient of Variation 56.3 |
Secondary
Median Progression Free Survival (PFS)
Time after initiation of treatment before disease progression
Time frame: Every 6 weeks during treatment
Population: Due to early termination of study in Phase 1, efficacy outcomes, including median PFS, were not analyzed for subjects in Part 1a or Part 1b. Therefore no subjects were included in this analysis population.
Secondary
Objective Response Rate (ORR%)
Percentage of patients whose disease decreased (Partial response) and/or disappears (Complete response) after initiation of treatment
Time frame: Every 6 weeks
Population: Number of participants changed to 0 and explanation modified to Due to early termination of study in Phase 1, efficacy outcomes, including ORR% were not analyzed for subjects in Part 1a or Part 1b. Therefore no subjects were included in this analysis population.
Secondary
Overall Survival (OS)
Percentage of subjects alive five years after start of treatment.
Time frame: Weekly during treatment or every 12 weeks during follow-up
Population: Due to early termination of study in Phase 1, efficacy outcomes, including OS, were not analyzed for subjects in Part 1a or Part 1b. Therefore no subjects were included in this analysis population.
Secondary
Peak Concentration (Cmax)
Peak USL311 concentration (Cmax) in plasma
Time frame: Day 1
Population: Subjects who received scheduled dose and had sufficient PK samples for determination of parameters
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a, Dose-escalation, All Oral Cohorts | Peak Concentration (Cmax) | 48.2 ng/mL | Geometric Coefficient of Variation 41.1 |
| Part 1a, Cohort 2 | Peak Concentration (Cmax) | 69.1 ng/mL | Geometric Coefficient of Variation 66.9 |
| Part 1a, Cohort 3a | Peak Concentration (Cmax) | 200 ng/mL | — |
| Part 1a, Cohort 3b | Peak Concentration (Cmax) | 168 ng/mL | Geometric Coefficient of Variation 94 |
| Part 1a, Cohort 4 | Peak Concentration (Cmax) | 107 ng/mL | Geometric Coefficient of Variation 37.2 |
| Part 1b, Cohort 1 | Peak Concentration (Cmax) | 2.06 ng/mL | Geometric Coefficient of Variation 84.6 |
| Part 1b, Cohort 2 | Peak Concentration (Cmax) | 4.74 ng/mL | Geometric Coefficient of Variation 32.4 |
| Part 1b, Cohort 3 | Peak Concentration (Cmax) | 6.68 ng/mL | Geometric Coefficient of Variation 58.5 |
Secondary
Percentage Progression Free Survival (PFS) at 6 Months (PFS-6m)
Percentage of subjects who were without progression at 6 months as assessed radiographically with response to treatment determined by Response Evaluation Criteria in Solid Tumors (RECIST) or Response Assessment in Neuro-Oncology (RANO) criteria.
Time frame: Once every 6 weeks during treatment
Population: Due to early termination of study in Phase 1, efficacy outcomes, including PFS-6m, were not analyzed for subjects in Part 1a or Part 1b. Therefore no subjects were included in this analysis population.
Secondary
Time to Peak Concentration (Tmax)
Time to peak concentration of USL311 in plasma
Time frame: Day 1
Population: Subjects who received scheduled dose and had sufficient PK samples for determination of parameters
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a, Dose-escalation, All Oral Cohorts | Time to Peak Concentration (Tmax) | 1.05 Hours |
| Part 1a, Cohort 2 | Time to Peak Concentration (Tmax) | 1.04 Hours |
| Part 1a, Cohort 3a | Time to Peak Concentration (Tmax) | 0.53 Hours |
| Part 1a, Cohort 3b | Time to Peak Concentration (Tmax) | 2.28 Hours |
| Part 1a, Cohort 4 | Time to Peak Concentration (Tmax) | 2.55 Hours |
| Part 1b, Cohort 1 | Time to Peak Concentration (Tmax) | 0.63 Hours |
| Part 1b, Cohort 2 | Time to Peak Concentration (Tmax) | 0.67 Hours |
| Part 1b, Cohort 3 | Time to Peak Concentration (Tmax) | 0.565 Hours |