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

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)

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.

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