Diffuse Large B Cell Lymphoma, Kaposi Sarcoma
Conditions
Keywords
Lymphoma, B-cell Lymphomas, Diffuse Large B-cell Lymphoma, Lymphosarcoma, Kaposi's Sarcoma-associated Herpesvirus, KHSV, Human Immunodeficiency Virus, HIV, Epstein-Barr Virus, EBV, Kaposi sarcoma
Brief summary
This is a sequential Phase I and IIa study to identify the maximum tolerated dose and to evaluate safety, tolerability, toxicity, pharmacokinetics and pharmacodynamics of the oral sphingosine kinase inhibitor ABC294640 specifically in patients with diffuse large B-cell lymphoma (DLBCL), including virus-associated (e.g., KSHV- or EBV-associated) DLBCL or Kaposi Sarcoma (KS) after failure of or intolerance to initial standard therapy.
Detailed description
Sphingosine Kinase (SK) is an innovative target for anti-cancer therapy due to its critical role in lipid metabolism which drives cancer cell growth. We have found that the SK inhibitor ABC294640 (which is formulated for clinical use as an oral agent) significantly inhibits and reverses progression of virus-associated DLBCL in pre-clinical animal models \[Qin et a., 2014\]. In addition, we have found that ABC294640 selectively induces death for virus-infected endothelial cells in a laboratory model relevant to KS, with selective sparing of uninfected cells \[Dai et al., 2014; Dai et al., 2015\]. Both DLBCL and KS disproportionately impact patients with immune-deficiencies, including HIV infection, for whom standard chemotherapeutic approaches are less effective and incur greater side effects. Therefore, this trial which utilizes a well-tolerated, oral agent to inhibit SK for DLBCL and KS patients may provide a unique approach to treatment.
Interventions
DRUGABC294640
Sponsors
Louisiana State University Health Sciences Center in New Orleans
Apogee Biotechnology Corporation
RedHill Biopharma Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pathologically confirmed DLBCL or KS. In the case of patients with DLBCL, the disease must be radiographically refractory to standard therapy, or relapsed following standard therapy (one or more tumors measurable on PET-CT scan). In the case of patients with KS, the disease must be either radiographically or clinically refractory (persistent skin lesions) to standard therapy or relapsed following standard therapy (one or more tumors measurable on CT scan or through direct measurement of skin tumors). Please see caveats for antineoplastic therapies in
Exclusion criteria
below. 2. For patients with DLBCL, the patient is not a candidate for hematopoietic stem cell transplantation (as determined by medical oncologists at participating institutions) or has failed stem cell transplantation. 3. Tumor progression after receiving standard/approved chemotherapy, or lack of candidacy for standard therapy. 4. One or more tumors measurable on PET-CT scan (DLBCL), CT scan (KS), or by clinical exam of skin (KS). 5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3. 6. Life expectancy of at least 3 months. 7. Age ≥ 18 years. 8. Signed, written IRB-approved informed consent. 9. A negative pregnancy test (if female). 10. Acceptable liver function: * Bilirubin ≤ 3 times upper limit of normal (CTCAE Grade 2 baseline) * AST (SGOT), ALT (SGPT) ≤ 3 x ULN (CTCAE Grade 1 baseline) * Serum creatinine ≤ 1.5 X ULN (CTCAE Grade 1 baseline) 11. Acceptable hematologic status: * Absolute neutrophil count ≥ 1000 cells/mm3 * Platelet count ≥ 75,000 (plt/mm3) (CTCAE Grade 1 baseline) * Hemoglobin ≥ 8 g/dL 12. Urinalysis: No clinically significant abnormalities. 13. PT and PTT ≤ 1.5 X ULN after correction of nutritional deficiencies that may contribute to prolonged PT/PTT. 14. For men and women of child-producing potential, willingness to use of effective contraceptive methods during the study. If female (or female partner of male subject), is either not of childbearing potential (defined as postmenopausal for ≥ 1 year or surgically sterile \[bilateral tubal ligation, bilateral oophorectomy or hysterectomy\]) or practicing one of the following medically acceptable methods of birth control and agrees to continue with the regimen throughout the duration of the study: * Oral, implantable or injectable contraceptives for 3 consecutive months before the Baseline/Randomization Visit. * Total abstinence from sexual intercourse (≥ 1 complete menstrual cycle before the Baseline/Randomization Visit). * Intrauterine device (IUD). * Double barrier method (condoms, sponge, diaphragm or vaginal ring with spermicidal jellies or cream).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Determine Maximum tolerated dose (MTD) of ABC294640 in patients with refractory/relapsed DLBCL or KS and determine tolerability at MTD. | Patients will be followed until a dose limiting toxicity (DLT) is experienced, if present, expected within the first 8 weeks |
| Evaluate safety of ABC294640 in patients with refractory/relapsed DLBCL or KS | If present, expected within 8 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Measure plasma levels of ABC294640 (pharmacokinetics) in patients with DLBCL or KS | Days 1 and 28, 1,2, 4, 8 and 24 hours post drug administration |
| Measure plasma levels of sphingosine-1-phosphate in response to ABC294640 in patients with DLBCL or KS | Days 1,8,15 and 28 in Cycle 1, Days 14 and 28 for all subsequent cycles and at the end of treatment study |
| Measure levels of circulating CD4+ T cell count, KSHV/EBV viral loads, and HIV viral load (if applicable) in response to ABC294640 in patients with DLBCL or KS | Days 1, 8, 15 and 22 for cycles 1-3 and Days 1, 8, 15, 22 and 28 for Cycle 4 |
| Evaluate antitumor activity of ABC294640 in virus-associated DLBCL or KS patients by objective radiographic assessment using PET (DLBCL) or CT (KS) criteria, or measurement of clinically evident skin lesions (KS) | Within 14 Days of Treatment Day 1 and then on Day 28 of Cycles 2, 4, 6, 8, etc., stopping if tumor progression is observed |
Countries
United States
Outcome results
None listed