Clinical trial NCT02765165: Phase 1/2 Study of USL311 +/- Lomustine in Advanced Solid Tumors or Relapsed/Recurrent Glioblastoma Multiforme (GBM)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Solid Tumors (Phase 1)
Relapsed/Recurrent GBM (Phase 2)
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
Lead sponsor: Proximagen, LLC
Sponsor class: INDUSTRY
First posted: 2016-05-06
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Phase 1: Maximum Tolerated Dose (MTD)
timeFrame: Assessed weekly during treatment period. Median duration of exposure was 5.14 (range 2.1-17.3) weeks.
measure: Phase 1: Maximum Tolerated Dose (MTD)
timeFrame: Assessed weekly during treatment period. Median duration of exposure was 6.00 (range 0.3-30.0) weeks.
Secondary outcomes:
measure: Percentage Progression Free Survival (PFS) at 6 Months (PFS-6m)
timeFrame: Once every 6 weeks during treatment
measure: Overall Survival (OS)
timeFrame: Weekly during treatment or every 12 weeks during follow-up
measure: Median Progression Free Survival (PFS)
timeFrame: Every 6 weeks during treatment
measure: Objective Response Rate (ORR%)
timeFrame: Every 6 weeks
measure: Peak Concentration (Cmax)
timeFrame: Day 1
measure: Time to Peak Concentration (Tmax)
timeFrame: Day 1
measure: Area Under the Concentration Versus Time Curve (AUC)
timeFrame: Day 1
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Oklahoma City
country: United States
facility: University of Oklahoma Stephenson Cancer Center
state: Oklahoma
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics (START)
state: Texas
city: San Antonio
country: United States
facility: UT Health San Antonio Cancer Center
state: Texas
city: Madrid
country: Spain
facility: South Texas Accelerated Research Therapeutics (START) - FJD
Study officials:
affiliation: Proximagen, LLC
name: Tze-Chiang Meng, MD
role: STUDY_DIRECTOR
References: