ABC294640 (Opaganib) in Refractory / Relapsed Multiple Myeloma

• Status: Terminated
• Trial end date: 2019-05-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a Phase Ib/II safety and efficacy trial of single agent ABC294640, an inhibitor of sphingosine kinase 2 and dihydroceramide desaturase, in refractory or relapsed multiple myeloma (MM). Cohorts of patients with refractory or relapsed MM who have previously been treated with proteasome inhibitors and immunomodulatory agents will receive increasing doses of oral ABC294640. The starting dosage for ABC294640 will be 250 mg bis in die (BID) which is known to be safely tolerated as a single agent, and the ABC294640 dose will be escalated to two additional dose cohorts of 500 and 750 mg BID using Bayesian model average continual reassessment method (BMA-CRM) for dose finding. It is expected that 18 patients will be used to determine the maximum tolerated dose (MTD) for ABC294640 in refractory or relapsed MM. Up to 56 additional patients will be treated on the phase II portion of the study at the MTD or maximum dose used in phase I, with interim stopping rules for futility.

Pharmacokinetic (PK) and pharmacodynamic (PD) assessments of ABC294640 will be conducted on Day 1 of Cycle 1. Bone marrow biopsy will be obtained prior to the initiation of ABC294640, at the end of cycle #3 and at the end of cycle #6. In addition to serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) and serum free light chain measurement, correlative studies will be performed to measure sphingosine kinase 2 (SK2) activity, sphingosine metabolites, and additional biomarkers in CD138+ myeloma cells.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: RedHill Biopharma Limited
• Collaborators: Apogee Biotechnology Corporation; Duke University; National Cancer Institute (NCI)
• Treatments: Proteasome Inhibitors

Criteria

Inclusion Criteria:

1. Patient must have a diagnosis of symptomatic multiple myeloma, relapsed or refractory after previous treatment with a proteasome inhibitor (bortezomib or carfilzomib) and an immunomodulatory agent (thalidomide, lenalidomide or pomalidomide).

2. Have measurable disease as defined by at least one of the following:

• Serum monoclonal (M) protein ≥1.0 g/dl by protein electrophoresis

• >200 mg of M protein in the urine on 24 hour electrophoresis

• Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio

• Monoclonal bone marrow plasmacytosis ≥30%

3. Voluntary signed and dated institutional review board (IRB) approved informed consent form in accordance with regulatory and institutional guidelines.

4. Time interval from last systemic chemotherapy (not including low dose dexamethasone) more than 2 weeks prior to initiation of ABC294640. Patients receiving high dose dexamethasone defined as 40mg dexamethasone a day for 4 days will need 2 weeks washout prior to initiation of ABC294640

5. 18 years of age or older.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

7. Acceptable liver function:

• Bilirubin ≤ 1.5 times upper limit of normal (CTCAE Grade 1 baseline)

• AST (aminotransferase) (SGOT), ALT (alanine aminotransferase) (SGPT) ≤ 5 x ULN (CTCAE Grade 2 baseline)

• Serum creatinine ≤1.5 XULN (1.5 times the upper limit of normal) (CTCAE Grade 1 baseline)

8. Acceptable hematologic status (with or without transfusion support):

• Absolute neutrophil count ≥1000 cells/mm3,

• Platelet count ≥50,000 (plt/mm3),

• Hemoglobin ≥9 g/dL.

9. Urinalysis: No clinically significant abnormalities.

10. PT (partial thromboplastin) and PTT (partial thromboplastin time) ≤ 1.5 X ULN after correction of nutritional deficiencies that may contribute to prolonged PT/PTT.

11. As determined by the treating investigator, the patient must have well-controlled blood pressure, defined as systolic blood pressure <150mmHg (Millimeter of Mercury)and/or diastolic blood pressure <100 mmHg for the majority of measurements.

12. A negative pregnancy test (if female of child bearing potential).

13. For men and women of child-producing potential, willingness to use effective contraceptive methods during the study.

Exclusion Criteria:

1. Pregnant or nursing women.

2. Patients who are currently participating in any other clinical trial of an investigational product.

3. Major surgery within 30 days prior to start of treatment

4. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to start of treatment

5. Known human immunodeficiency virus infection

6. Active hepatitis B or C infection with abnormal liver functions (i.e., LFTs (liver function test) > 2 x upper normal limits)

7. Unstable angina or myocardial infarction within 4 months prior to start of treatment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker

8. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to start of treatment

9. Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder

10. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to initiation of ABC294640

11. Any other clinically significant medical or psychiatric disease or condition, or social situation that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent