Phase 1/2 Study of USL311 +/- Lomustine in Advanced Solid Tumors or Relapsed/Recurrent Glioblastoma Multiforme (GBM)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2 Dose-escalation of USL311 as Single Agent and in Combination With Lomustine (CCNU) in Subjects With Advanced Solid Tumors, With Subsequent Single Agent and Combination Phase 2 Cohorts for Subjects With Relapsed/Recurrent Glioblastoma Multiforme (GBM)

Conditions
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Solid Tumors (Phase 1), Relapsed/Recurrent GBM (Phase 2)

Intervention / Treatment
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* Drug: USL311
* Drug: USL311
* Drug: USL311
* Drug: Lomustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Subjects: Provide signed and dated informed consent prior to study-specific screening procedures ≥ 18 years old Karnofsky performance status (KPS) ≥ 70 Must have adequate bone marrow and renal/hepatic function within protocol specified limits 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 Women and men must use protocol approved methods of contraception Must be able and willing to comply with the study visit schedule and study procedures Must be able to take oral medications Must have available archived tumor tissue and willing and able to provide consent for study access to such tissue For subjects with a history of seizures, must be adequately controlled on a stable regimen of anti-epileptic drugs For Phase 1 Subjects Only: 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 Inoperable metastatic or locally advanced, unresectable disease Subjects may have either evaluable or measurable disease 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: Histologically confirmed diagnosis of GBM Subjects must have documented recurrence after first-line treatment Prior first-line treatment must have included radiation and temozolomide Subject is suitable for re-resection, per Investigator discretion, as a component of their clinical care No more than one prior resection (Note: biopsy does not count as prior resection) Exclusion Criteria: All Subjects 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 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) Subjects taking any strong cytochrome P450 3A4 inducers within 14 days prior to the first dose of study drug(s) Subjects taking any strong cytochrome P450 3A4 inhibitors within 14 days prior to the first dose of study drug(s) 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) 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) 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) History of significant cardiac disease Status epilepticus within 1 year prior to the first dose of study drug(s) Pregnant or breastfeeding Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation For Phase 1 Subjects Only: Lymphoma as primary cancer For Phase 2 Subjects Only: Unable or unwilling to consent to the provision of resected tissue after surgery Prior treatment with plerixafor or another CXCR4 inhibitor Prior treatment with bevacizumab Prior treatment with lomustine and/or carmustine For All Cohorts Receiving Oral USL311: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-Escalation USL311, Solid Tumor, Part 1a<br>USL311, intravenous, once per week, starting at 60 mg/m˄2 | Drug: USL311<br>* Administered once weekly in a 21-day cycle<br>|
| Experimental: Dose-Escalation USL311, Solid Tumor, Part 1b<br>USL311, oral, daily, starting at 40 mg | Drug: USL311<br>* Administered once daily in a 21-day cycle<br>|
| Experimental: Dose-Escalation USL311 with Lomustine, Solid Tumor, Part 2<br>USL311, oral, daily, starting at dose as determined in Part 1b, in combination with lomustine 90 mg/m˄2, oral, once every 6 weeks | Drug: USL311<br>* Administered once daily in a 42-day cycle<br>Drug: Lomustine<br>* Administered once every 6 weeks in a 42-day cycle<br>|
| Experimental: Dose-Expansion, USL311, GBM, Part 3<br>USL311, oral, daily, starting at dose determined in Part 1b | Drug: USL311<br>* Administered once daily in a 21-day cycle<br>|
| Experimental: Dose-Expansion, USL311 with Lomustine, GBM, Part 4<br>USL311, oral, daily, in combination with lomustine, oral, once every 6 weeks, at dose(s) as determined in part 2 | Drug: USL311<br>* Administered once daily in a 42-day cycle<br>Drug: Lomustine<br>* Administered once every 6 weeks in a 42-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Assessed weekly during treatment period. Median duration of exposure was 5.14 (range 2.1-17.3) weeks. | 
| 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. | Assessed weekly during treatment period. Median duration of exposure was 6.00 (range 0.3-30.0) weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Once every 6 weeks during treatment | 
| Overall Survival (OS) | Percentage of subjects alive five years after start of treatment. | Weekly during treatment or every 12 weeks during follow-up | 
| Median Progression Free Survival (PFS) | Time after initiation of treatment before disease progression | Every 6 weeks during treatment | 
| Objective Response Rate (ORR%) | Percentage of patients whose disease decreased (Partial response) and/or disappears (Complete response) after initiation of treatment | Every 6 weeks | 
| Peak Concentration (Cmax) | Peak USL311 concentration (Cmax) in plasma | Day 1 | 
| Time to Peak Concentration (Tmax) | Time to peak concentration of USL311 in plasma | Day 1 | 
| Area Under the Concentration Versus Time Curve (AUC) | Area under the curve versus time from time 0 to infinity for USL311 concentration in plasma | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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