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Immunomodulating Agents

Proteasome Inhibitors

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.

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.

Opaganib

Yubin Kang, MD

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.

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.

ABC294640 (Opaganib) in Refractory / Relapsed Multiple Myeloma

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

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.

Stable disease, partial response, complete response or disease progression.

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

To determine the Cmax of ABC294640 following administration of the drug.

Apogee Biotechnology Corporation

Duke University

National Cancer Institute (NCI)

RedHill Biopharma Limited

Treatment emergent adverse events (TEAE) were any event not present before exposure to study medication or any event already present that worsens in either intensity or frequency following exposure to study drug.

For Phase 1b, ABC294640 was dosed at 250 BID given continuously. The dose was given under fasting conditions (at least 1 hour before or 2 hours after eating). One cycle is 28 days of treatment.

250 mg Phase 1b

For Phase 1b, ABC294640 was dosed at 500 BID given continuously. The dose was given under fasting conditions (at least 1 hour before or 2 hours after eating). One cycle is 28 days of treatment.

500 mg Phase 1b

For Phase 1b, ABC294640 was dosed at 750 BID given continuously. The dose was given under fasting conditions (at least 1 hour before or 2 hours after eating). One cycle is 28 days of treatment.

750 mg Phase 1b

Phase 1b - 250 mg BID

For Phase 1b, ABC294640 was dosed at 500 BID given continuously. The dose was given under fasting conditions (at least 1 hour before or 2 hours after eating). One cycle is 28 days of treatment

Phase 1b - 500 mg BID

For Phase 1b, ABC294640 was dosed at 750 mg BID given continuously. The dose was given under fasting conditions (at least 1 hour before or 2 hours after eating). One cycle is 28 days of treatment

Phase 1b - 750 mg BID

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Lower ECOG grades correlate with a better clinical status:

Grade 0- Fully active, able to carry on all pre-disease performance without restriction

1. - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature
2. -Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about \>50% of waking hours
3. -Capable of only limited self-care, confined to a bed or chair \>50% of waking hours
4. - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5. - Dead

Baseline ECOG (Eastern Cooperative Oncology Group)Status

Patients with Refractory or Relapsed Multiple Myeloma Who have Previously Been Treated with Proteasome Inhibitors and Immunomodulatory Agents were treated with three doses of ABC294640.

Yubin Kang, M.D., Principal Investigator

Unblinded Phase 1b dose-finding study with dose escalation of study drug ABC294640. Once a subject was determined to be eligible for the study, the subject was enrolled in the dose escalation Phase 1b study testing ABC294640 at 250, 500 and 750 mg twice a day. A cycle of treatment was defined as 28 days and doses were given initially under fasting conditions. Subsequent to a food effect study, treatment was given after a light to moderate meal.

Maximum Tolerated Dose

ABC294640 250 mg BID

ABC294640 500 mg BID

ABC294640 750 mg BID

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

All participants receiving any amount of study drug

Number of Patients With Dose Limiting Toxicity

Samples for PK were drawn on Day 1 of Cycle 1 immediately before dosing and at 1, 2, 4, and 8 hours after dosing.

Maximum Concentration (Cmax) of ABC294640

Unblinded Phase 1b dose-finding study with dose escalation of study drug ABC294640 (Opaganib). Once a subject was determined to be eligible for the study, the subject was enrolled in the dose escalation Phase 1b study testing ABC294640 at 250 mg twice a day (bis in die). A cycle of treatment was defined as 28 days and doses were given initially under fasting conditions. Subsequent to a food effect study, treatment was given after a light to moderate meal.

250 mg

Unblinded Phase 1b dose-finding study with dose escalation of study drug ABC294640. Once a subject was determined to be eligible for the study, the subject was enrolled in the dose escalation Phase 1b study testing ABC294640 at 500 mg twice a day). A cycle of treatment was defined as 28 days and doses were given initially under fasting conditions. Subsequent to a food effect study, treatment was given after a light to moderate meal.

500 mg

Unblinded Phase 1b dose-finding study with dose escalation of study drug ABC294640. Once a subject was determined to be eligible for the study, the subject was enrolled in the dose escalation Phase 1b study testing ABC294640 doses at 750 mg twice a day ). A cycle of treatment was defined as 28 days and doses were given initially under fasting conditions. Subsequent to a food effect study, treatment was given after a light to moderate meal.

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