ABC294640 (Opaganib) in Refractory / Relapsed Multiple Myeloma

NCT02757326 | Terminated Phase 1 Results DMC

• 2 other identifiers: Pro000623041R44CA199767-01
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Myeloma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose

  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.

  6 months

Secondary Outcomes (3)

• To Assess the Antitumor Activity of Single Agent Opaganib in Patients With Refractory or Relapsed Multiple Myeloma After 3 Cycles of Treatment.

  After 3 cycles (12 weeks) of treatment

• Number of Patients With Dose Limiting Toxicity

  12 months

• Maximum Concentration (Cmax) of ABC294640

  8 hours

Study Arms (1)

Phase Ib/II

EXPERIMENTAL

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

Interventions

Opaganib DRUG

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.

Also known as: ABC294640

Phase Ib/II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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%
• Voluntary signed and dated institutional review board (IRB) approved informed consent form in accordance with regulatory and institutional guidelines.
• 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
• years of age or older.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• 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)
• Acceptable hematologic status (with or without transfusion support):

You may not qualify if:

• Pregnant or nursing women.
• Patients who are currently participating in any other clinical trial of an investigational product.
• Major surgery within 30 days prior to start of treatment
• Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to start of treatment
• Known human immunodeficiency virus infection
• Active hepatitis B or C infection with abnormal liver functions (i.e., LFTs (liver function test) \> 2 x upper normal limits)
• 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
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to start of treatment
• 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
• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to initiation of ABC294640
• 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

Sponsors & Collaborators

• RedHill Biopharma Limited: lead
• Apogee Biotechnology Corporation: collaborator
• Duke University: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Related Publications (2)

• 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. doi: 10.1182/blood-2014-03-559385.

  PMID: 25122609 BACKGROUND

• Kang Y, Sundaramoorthy P, Gasparetto C, Feinberg D, Fan S, Long G, Sellars E, Garrett A, Tuchman SA, Reeves BN, Li Z, Liu B, Ogretmen B, Maines L, Ben-Yair VK, Smith C, Plasse T. Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma. Ann Hematol. 2023 Feb;102(2):369-383. doi: 10.1007/s00277-022-05056-7. Epub 2022 Dec 3.

  PMID: 36460794 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Yubin Kang, M.D., Principal Investigator
• Organization: Duke University Medical Center, Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy

yubin.kang@duke.edu

(919) 668-2331

Study Officials

• Yubin Kang, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2016
• First Posted: May 2, 2016
• Study Start: December 13, 2016
• Primary Completion: May 1, 2019
• Study Completion: May 1, 2019
• Last Updated: June 18, 2021
• Results First Posted: June 18, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)