ABC294640 (Opaganib) in Refractory / Relapsed Multiple Myeloma (ABC-103)

• ClinicalTrials.gov Identifier: NCT02757326
• Recruitment Status: Terminated
• First Posted: May 2, 2016
• Results First Posted: June 18, 2021
• Last Update Posted: June 18, 2021
• Sponsor: RedHill Biopharma Limited
• Collaborators: Apogee Biotechnology Corporation; Duke University; National Cancer Institute (NCI)
• Information provided by (Responsible Party): RedHill Biopharma Limited

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: Opaganib	Phase 1; Phase 2

Detailed Description:

Objectives for Phase 1b:

Primary Objectives • To assess safety and determine the maximum tolerated dose (MTD) of single agent ABC294640 in patients with refractory or relapsed multiple myeloma (MM) who have been previously treated with proteasome inhibitors and immunomodulatory agents.

Secondary Objectives

• To assess the antitumor activity of single agent ABC294640 in patients with refractory or relapsed MM after 3 cycles of treatment.
• To determine the pharmacokinetics of ABC294640 following administration of the drug.
• To describe the effects of ABC294640 on plasma levels of sphingosine 1-phosphate and IL-6 (interleukin - 6) in patients with refractory or relapsed MM.
• To assess pharmacodynamic markers (SK2 mRNA (messenger ribonucleic acid) level or activity, sphingolipid metabolites, c-Myc, Mcl-1 and pS6) in bone marrow CD138+ myeloma cells.

Objectives for Phase 2:

Primary Objectives

• Assess overall treatment response rate and overall survival in patients with relapsed or refractory MM treated with single-agent ABC294640.

Secondary Objectives

• To assess the treatment response of ABC294640 in patients with refractory or relapsed MM after 3 cycles of treatment.
• To determine if pharmacodynamic markers (SK2 mRNA or activity, sphingolipid metabolites, c-Myc, Mcl-1 and pS6) in bone marrow CD138+ myeloma cells predict tumor response to the treatment with ABC294640.

The projected ABC294640 doses for the escalation phase are: 250, 500, and 750 mg BID orally continuously as determined in the single agent trial for ABC294640. The dose will be given under fasting conditions (at least 1 hour before or 2 hours after eating). Each cycle of treatment is 28 days.

Patients will be monitored for safety and pharmacodynamics effects weekly in Cycle 1, biweekly for Cycles 2-4, and monthly for subsequent cycles.

Myeloma treatment response will be assessed as follows:

• Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) and serum free light chains before each cycle.
• Skeletal survey at screening, then every year or at the end of study if the study ends before the anniversary.
• Bone marrow biopsy and aspirates at the last day of cycle #3 and cycle #6 (± 7 days).

For the phase II portion of the study, patients will be treated with single agent ABC294640 at the MTD determined from the phase Ib study (or highest dose used, if MTD is not reached) until disease progression or intolerable toxicity occurs.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/II Safety and Efficacy Study of ABC294640 in Patients With Refractory or Relapsed Multiple Myeloma Who Have Previously Been Treated With Proteasome Inhibitors and Immunomodulatory Drugs
• Actual Study Start Date: December 13, 2016
• Actual Primary Completion Date: May 2019
• Actual Study Completion Date: May 2019

Arms and Interventions

Arm

Intervention/treatment

Experimental: Phase Ib/II; For Phase Ib, the planned ABC294640 (Opaganib) doses for the escalation phase are: 250, 500, and 750 mg BID given continuously. The dose will be given under fasting conditions (at least 1 hour before or 2 hours after eating). One cycle is 28 days of treatment. For phase II study, the patients will be treated with single agent ABC294640 at the MTD determined from the phase IB study (or at the highest dose used, if MTD is not reached) until disease progression or intolerable toxicity occurs in an individual patient.

Drug: Opaganib; Opaganib, [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (N-(Pyridin-4-ylmethyl)pyridine-4-carboxamide) amide, hydrochloride salt] is an orally available inhibitor of the enzyme SK2.; Other Name: ABC294640

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose [ Time Frame: 6 months ]
   Evaluation of three doses of opaganib - 250 mg bid, 500 mg bid and 750 mg bid to determine the maximum tolerated dose (MTD) based upon the dose limiting toxicity (DLT) using a Bayesian model averaging continual reassessment method and is the dose at which the estimated probability of toxicity is closest to the target probability 0.33 among all doses.

Secondary Outcome Measures :

1. To Assess the Antitumor Activity of Single Agent Opaganib in Patients With Refractory or Relapsed Multiple Myeloma After 3 Cycles of Treatment. [ Time Frame: After 3 cycles (12 weeks) of treatment ]
   Stable disease, partial response, complete response or disease progression.
2. Number of Patients With Dose Limiting Toxicity [ Time Frame: 12 months ]

   For the phase 1b portion of the trial, a dose-limiting toxicity (DLT) was defined as an adverse event at least possibly related to the study medication:

   Non-hematologic DLT is defined as any Grade 3 or greater ADR (adverse drug reaction), except symptomatic AEs such as nausea, vomiting, and diarrhea which could be reduced to less than Grade 3 within 72 hours with standard supportive measures (i.e., antiemetics and antidiarrheals).

   Hematologic DLT is defined as

   • Grade 4 neutropenia or thrombocytopenia that lasts more than 7 days after the last dose of study drug
   • or greater than or equal to Grade 3 thrombocytopenia in the presence of greater than or equal to Grade 3 hemorrhage of any organ/site
   • or any Grade 5 hematologic toxicity
3. Maximum Concentration (Cmax) of ABC294640 [ Time Frame: 8 hours ]
   To determine the Cmax of ABC294640 following administration of the drug.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27705

Sponsors and Collaborators

RedHill Biopharma Limited

Apogee Biotechnology Corporation

Duke University

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Yubin Kang, MD; Duke University

  Study Documents (Full-Text)

Documents provided by RedHill Biopharma Limited:

Study Protocol  [PDF] March 22, 2019

Statistical Analysis Plan  [PDF] September 10, 2019

Informed Consent Form  [PDF] June 7, 2018

More Information

Publications:

Venkata JK, An N, Stuart R, Costa LJ, Cai H, Coker W, Song JH, Gibbs K, Matson T, Garrett-Mayer E, Wan Z, Ogretmen B, Smith C, Kang Y. Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood. 2014 Sep 18;124(12):1915-25.

• Responsible Party: RedHill Biopharma Limited
• ClinicalTrials.gov Identifier: NCT02757326
• Other Study ID Numbers: Pro00062304; 1R44CA199767-01 ( U.S. NIH Grant/Contract )
• First Posted: May 2, 2016
• Results First Posted: June 18, 2021
• Last Update Posted: June 18, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by RedHill Biopharma Limited:

sphingosine kinase 2 inhibitor; sphingosine kinase 2; SK2 inhibitor; SK2

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases