Advanced Solid Tumors/Relapsed/Recurrent Glioblastoma Multiforme (GBM) MedDRA version: 19.0 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 19.0 Level: PT Classification code 10018337 Term: Glioblastoma multiforme System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: USL311
Product Code: USL311
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: USL311
CAS Number: 1373268-67-7
Current Sponsor code: USL311
Other descriptive
Sponsors
Upsher-Smith Laboratories, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Criteria for both Phase 1 dose-escalation and Phase 2 dose-expansion: 1. Provide signed and dated informed consent prior to study-specific screening procedures 2. =18 years old 3. Karnofsky performance score (KPS) = 70 4. Must have adequate bone marrow and renal/hepatic function at the Screening Visit, defined as: a. Absolute neutrophil count = 1,500/mm3 without granulocyte colony-stimulating factor (G-CSF) support within 7 days preceding the lab assessment b. Platelet count = 100,000/mm3 , without transfusion within 7 days preceding the lab assessment c. Hemoglobin = 9 g/dL, without transfusion support within 7 days preceding the lab assessment d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) = 3 times upper limit of normal (ULN) e. Total serum bilirubin = 1.5 times ULN, except in subjects with known Gilbert’s Syndrome = 3 times ULN f. Serum creatinine = 1.5 times ULN with an estimated creatinine clearance of = 60 mL/min (calculated by the Cockcroft-Gault equation), or creatinine clearance corrected for BSA= 60 mL/min/1.73 m2 g. Activated partial thromboplastin time/ partial thromboplastin time (aPTT/PTT) and prothrombin time (PT) = 1.5 times ULN h. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels within the normal rangeor above the ULN if considered not clinically significant. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels below lower limit of normal must be corrected to within the normal range by supplementation prior to starting study drug(s). 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 of childbearing potential (WOCBP) must have two negative pregnancy tests, the first during Screening and the second within 24 hours prior of first administration of study drug(s) and must agree to use highly effective physician-approved contraception (see Appendix 2) from Screening to 90 days following the last study drug administration. Male subjects must be surgically sterile or must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration (a barrier method of contraception must be employed by all subjects [male and female], when having sexual intercourse, regardless of other methods). a. Females are considered not of childbearing potential if they meet any of the following criteria: • Postmenopausal with > 1 year since last menses and: - If younger than 65 years old, with a follicle-stimulating hormone (FSH) > 40 mIU/mL - If = 65 years old and not on hormone replacement therapy (HRT), with a FSH > 30 mIU/mL - If = 65 years old and on HRT, the FSH requirement in not applicable. Postmenopausal females on HRT will be allowed if the treatment is stable for at least 6 months prior to dosing of study drug(s) • Written medical documentation of being sterilized (e.g. hysterectomy, double oophorectomy, bilateral salpingectomy) Note: Tubal ligation is not considered a form of permanent sterilization 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.
Exclusion criteria
Exclusion criteria: Criteria for both Phase 1 dose-escalation and Phase 2 dose-expansion: 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 dose of study drug(s) 3. For 14 days prior to first dose of study drugs(s) treatment, administration of any strong cytochrome P450 3A4 (CYP3A4) inducers including, but not limited to, the following: carbamazepine, ethotoin, mephenytoin, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St. John’s Wort 4. For 14 days prior to first dose of study drug(s) treatment, administration of any strong cytochrome P450 3A4 (CYP3A4) inhibitors including, but not limited to, the following: amprenavir, ataznavir, boceprevir, clarithromycin, conivaptan, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole 5. For 14 days prior to first dose of study drug(s) treatment, administration of any agent with moderate-to-high risk to prolong the QTc interval or to cause Torsades de Pointes (see Appendix 3) 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. Subjects 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. Significant cardiac diseases includes the following: a. Second/third degree heart block b. Significant ischemic heart disease (e.g. myocardial infarction, unstable angina, Grade 3 or 4 [Canadian Cardiovascular Society] angina, hospitalization for ischemic heart disease) within 2 years of first dose of study drug(s) c. Family history of long QT syndrome; mean Fridericia corrected QT interval (QTcF) > 450 msec on at least two separate ECGs prior to study start d. Poorly controlled hypertension per Investigator opinion e. Congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea) 9. Episode of 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 Criteria for Phase 1 only, dose-escalation in advanced solid tumors 12. Subjects with lymphoma as primary cancer Criteria for Phase 2 only, dose-expansion in relapsed/recurrent GBM: 13. Subjects 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1 dose-escalation: • Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of USL311 as a single agent in subjects with advanced solid tumors for which no SoC treatment is recognized or who have failed or are intolerant to the SoC treatment (Part 1). • Determine the MTD and RP2D of USL311 in combination with lomustine in subjects with advanced solid tumors for which no SoC treatment is recognized or who have failed or are intolerant to the SoC treatment (Part 2). Phase 2 dose-expansion: • Determine the percentage PFS-6m of USL311 as a single agent in subjects with relapsed/recurrent GBM who previously received SoC treatment in the first-line setting and who are candidates for re-resection (Part 3). • Determine the percentage PFS-6m of USL311 in combination with lomustine in subjects with relapsed/recurrent GBM who previously received SOC treatment in the first-line setting and who are candidates for re-resection (Part 4).;Secondary Objective: Parts 1 and 2 (Phase 1 Dose-Escalation in Subjects with Advanced Solid Tumors): • Assess the safety and tolerability of USL311 as a single agent and in combination with lomustine • Determine preliminary efficacy parameters of USL311 as a single agent and in combination with lomustine • Determine the pharmacokinetic (PK) profile of USL311 in plasma and whole blood and of lomustine in plasma (prior to and with concomitant USL311 administration) • Evaluate the drug interaction potential between USL311 and lomustine Parts 3 and 4 (Phase 2 Dose-Expansion in Subjects with Relapsed/Recurrent GBM): • Assess the safety and tolerability of USL311 as a single agent and in combination with lomustine • Assess ORR%, PFS, DCR and OS of USL311 as single agent and in combination with lomustine • Determine the PK profile of USL311 and of lomustine;Primary end point(s): Efficacy endpoint PFS-6m will be determined in all subjects with solid tumors utilizing Response Evaluation Criteria in Solid Tumor | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Pharmakokinetic endpoints (protocol section 8.5) and exploratory assessments (protocol section 8.7);Timepoint(s) of evaluation of this end point: As per protocol section: schedule of vistis and assessments | — |
Countries
Spain, United States
Contacts
Public ContactLindy L. Bancke
Upsher-Smith Laboratories, Inc.
Outcome results
None listed