A Clinical Study to Assess the Safety and Activity of SRT501 Alone or in Combination With Bortezomib in Patients With Multiple Myeloma

Study Overview
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Brief Summary
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The primary purpose of this study is to determine the safety and tolerability of SRT501 (5.0 g) with or without concurrent bortezomib administration, when administered once daily in 21 day cycles, in male and female subjects with Multiple Myeloma. The purpose is also to define objective response (ORR, CR, PR, MR, SD) and time to progression (TTP) of SRT501 with or without concurrent bortezomib administered concurrently in male and female subjects with Multiple Myeloma. In addition, 15 subjects will participate in a sub-study to assess the pharmacokinetics of SRT501.

Detailed Description
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This is an, open-label, phase II study of SRT501, alone or in combination with bortezomib, in subjects with measurable Multiple Myeloma. Sixty-one (61) evaluable subjects, who fulfill the inclusion/exclusion criteria, will be enrolled in this study. Pharmacokinetic (PK) samples will be collected from a subset of 15 subjects to determine SRT501 plasma concentrations in this patient population. Subjects will sign the informed consent form prior to any study related procedures. If eligible, subjects will receive 5.0 g of SRT501 to be administered for 20 consecutive days in a 21 day cycle for a maximum of 12 cycles. SRT501 will be administered as an oral suspension product at the same time each morning (approximately 15-30 minutes following consumption of breakfast) on all dosing days. Safety assessments will be performed continuously throughout the cycle and these will be reviewed for all subjects at Day 21 of each cycle prior to subjects proceeding to the next cycle. SRT501 will not be administered on Day 21 of each cycle. Subjects will be assessed for efficacy and response of SRT501 at the end of every 2 cycles (6 weeks) of treatment. When necessary, a bone marrow biopsy and CT (or appropriate radiographic imaging) of the chest and abdomen/pelvis will be performed to confirm response. After the first two cycles of SRT501 treatment and review of the efficacy and response analysis, any subject who exhibits stable disease or better with SRT501 monotherapy may continue on SRT501 monotherapy (5.0 g/day) for an additional two cycles. If, after the first two cycles of SRT501 monotherapy, a subject exhibits PD, then that subject will receive bortezomib (1.3 mg/ m2 on Day 1, Day 4, Day 8, and Day 11 in a 21 day cycle) in conjunction with SRT501 (5.0 g/day). Bortezomib will be administered prior to SRT501 administration. If after two additional cycles of SRT501 monotherapy (4 cycles total), the subject exhibits a MR or better, they will remain on SRT501 (5.0 g/day) treatment until they are judged to have SD or PD. At the time the subject is judged to have SD or PD after receiving at least four cycles of SRT501 (5.0 g/day) monotherapy, then they may also receive bortezomib (1.3 mg/m2 on Day 1, Day 4, Day 8, and Day 11 in a 21 day cycle) in conjunction with daily SRT501 dosing. If at any point while a subject is receiving SRT501 and bortezomib the subject is assessed to have PD, then they will be removed from the study and will be required to undergo End of Study assessments/follow-up approximately 28 days (+/- 7 days) following the last dose of SRT501 or SRT501 and bortezomib.

Official Title
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A Phase II, Open-Label, Clinical Study to Assess the Safety and Activity of SRT501 Alone or in Combination With Bortezomib in Patients With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: 5.0g SRT501
* Drug: Bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be male or female ≥ 18 years at the time of signing Informed Consent. Subject was previously diagnosed with Multiple Myeloma and has failed at least one prior treatment regimen for the disease. Subject must have measurable disease. Subjects must have relapsed or relapsed/refractory disease as defined in Appendix 4. Subject must have a life expectancy of greater than 6 months. Subject has an ECOG Performance status of 0 to 2 (Appendix 2). Subject has no prior history of HIV-1, HIV-2, Hepatitis B or C infection. Subject has a normal 12 lead ECG or an ECG with an abnormality considered to be clinically insignificant. Subject has the ability to communicate with the investigative site staff in a manner sufficient to carry out all protocol procedures as described. Subject must be able to adhere to the study visit schedule and other protocol requirements. Subject must understand and voluntarily sign an informed consent document. All subjects of reproductive potential must agree prior to study entry to use adequate contraception (hormonal or double barrier method of birth control; abstinence) for the duration of the study dosing and at least 12 weeks after completion of study drug. Adequate end organ function, defined as the following: Total bilirubin < 2 x ULN, unless attributable to Gilbert's disease ALT (SGPT) and AST (SGOT) < 2.5 x ULN Creatinine < 2.0 x ULN ANC > 0.5 x 10^9/L Platelets > 20,000 cells/mm3 Exclusion Criteria: Intolerance to resveratrol, SRT501 or bortezomib or significant allergy to either compound, boron or mannitol or significant prior toxicity with either agent that would preclude the safe use of that agent. Prior therapy with either compound is permitted. Subjects with other active malignancy, with the exception of basal cell or squamous cell carcinoma of the skin. An uncontrolled intercurrent illness including, but not limited to, recent (≤ 6 months), ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, acute diffuse infiltrative pulmonary or pericardial disease, or psychiatric illness/social situations that would limit compliance with study requirements. Subject with a history of or current gastro-intestinal diseases influencing drug absorption, with the exception of an appendectomy. Women who are breast-feeding, pregnant, expect to become pregnant during the course of the study, or are sexually active in a heterosexual relationship and are not using a medically acceptable double barrier method birth control. Confirmation that the subject is not pregnant must be established by a negative serum beta-hCG pregnancy test result obtained during the Screening period. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Women relying solely on oral contraceptives for birth control are excluded. Subjects who have had chemotherapy or radiotherapy within 4 weeks prior to signing Informed Consent or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Subjects who are on any concurrent medications that may exhibit anti-neoplastic therapy, with the exception of < 10 mg of prednisone or equivalent as indicated for other medical conditions, or up to 100 mg of hydrocortisone as premedication for administration of certain medications or blood products. Subjects currently taking any investigational therapies and/or dietary supplements containing resveratrol. Subjects with peripheral neuropathy of Grade 2 or greater. Subjects with uncontrolled bleeding. Subjects with evidence of mucosal or internal bleeding and/or platelet refractory (i.e., unable to maintain a platelet count ≥ 20,000 cells/mm3). Subjects with a hemoglobin < 8.0 g/dL. Transfusions and/or EPO treatment are permitted in subjects who are potentially excluded by this criteria. Any condition, including laboratory abnormalities, that in the opinion of the Investigator, would preclude treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>5.0 g SRT501 will be administered for 20 consecutive days in a 21 day cycle for a maximum of 12 cycles. SRT501 will be administered at the same time each morning (approximately 15-30 minutes after breakfast) on all dosing days. No SRT501 administration will occur on Day 21 of each cycle. After the first two cycles of SRT501, any subject who exhibits stable disease or better with SRT501 monotherapy (5.0 g/day) will continue for an additional two cycles. If, after the first two cycles, a subject exhibits PD, that subject will receive bortezomib (1.3 mg/m2 on Day 1, Day 4, Day 8, and Day 11 in a 21 day cycle) in conjunction with SRT501. Bortezomib will be administered prior to breakfast and SRT501 administration. If after two additional cycles of SRT501 monotherapy (4 cycles total), the subject exhibits a MR or better, they they will remain on SRT501 therapy. If PD or SD are exibited, they are to undergo bortezomib regiment listed above. | Drug: 5.0g SRT501<br>* 5.0g SRT501 will be supplied in clinical kits as a powder which will be reconstituted with vehicle and water into a liquid suspension. SRT501 will be administered orally as a liquid suspension for 20 consecutive days in each 21 day cycle.<br>Drug: Bortezomib<br>* Bortezomib (1.3 mg/m2) will be given as an intravenous solution in a 3-5 second push on Day 1, 4, 8 and 11 in every 21 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, or is an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury. | Approximately up to 12 cycles of 3 weeks each | 
| Number of Participants With Overall Response Rate | Overall response rate, defines proportion of participants with Complete response (CR), Partial response (PR) or Minimal response (MR) as best response for all cycles. In atleast 2 determinations for minimum of 6 week (Wks) for every criteria listed. CR defined as disappearance of original monoclonal (MC) paraprotein (PP) in blood and urine on immunofixation determinations (IFD); < 5 % plasma cells in bone marrow; no increase in size or number of lytic bone lesions (LBLs); disappearance of soft tissue plasmacytomas (STP). PR defined as >= 50% reduction (RE) in level of serum MC PP for 2 IFDs; if present RE in 24 hour urinary light chain excretion (ULCE) by >= 90% RE or <200 mg; >= 50% RE in STP for; no increase in size or number of LBLs. MR criteria defined were >= 25% to <=49% RE serum MC PP; if present 50 to 89% RE in 24 hour LCE exceeding 200 mg/24 hour; 25% to 49% RE in size of STP; no increase in size or number of LBLs. | Approximately up to 12 cycles of 3 weeks | 
| Number of Participants With Partial Response (PR) as Best Response (BR) | PR includes some, but not all, criteria for CR providing the remaining criteria are satisfied: ≥50% reduction in the level of serum monoclonal paraprotein for at least 2 immunofixation determinations for a minimum of 6 weeks, If present, reduction in 24 hr urinary light chain excretion by either ≥90% or to <200 mg for at least 2 determinations for a minimum of 6 weeks, ≥50% reduction in the size of soft tissue plasmacytomas (by clinical or radiographic examination) for a minimum of 6 weeks, No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response). | Up to 12 cycles of 3 weeks each | 
| Number of Participants With Minor Response (MR) as Best Response (BR) | MR includes some, but not all, criteria for PR providing the remaining criteria satisfied: ≥25% to ≤ 49% reduction in the level of serum monoclonal paraprotein for at least 2 immunofixation determinations for a minimum of 6 weeks, If present, a 50 to 89% reduction in 24 hr light chain excretion, which still exceeds 200 mg/24 hr, for at least 2 determinations for a minimum of 6 weeks, 25-49% reduction in the size of plasmacytomas (by clinical or radiographic examination) for a minimum of 6 weeks, No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response). | Up to 12 cycles of 3 weeks each | 
| Number of Participants With Partial Response (PR) as Last Observed Response (LOR) | PR includes some, but not all, criteria for CR providing the remaining criteria are satisfied: ≥50% reduction in the level of serum monoclonal paraprotein for at least 2 immunofixation determinations for a minimum of 6 weeks, If present, reduction in 24 hr urinary light chain excretion by either ≥90% or to <200 mg for at least 2 determinations for a minimum of 6 weeks, ≥50% reduction in the size of soft tissue plasmacytomas (by clinical or radiographic examination) for a minimum of 6 weeks, No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response). | Up to 12 cycles of 3 weeks each | 
| Number of Participants With Stable Disease (SD) as Best Response (BR) | Stable disease included not meeting the criteria for MR or PD. | Up to 12 cycles of 3 weeks each | 
| Number of Participants With Stable Disease (SD) as Last Observed Response (LOR) | Stable disease included not meeting the criteria for MR or PD. | Up to 12 cycles of 3 weeks each | 
| Number of Participants With Progressive Disease (PD) PD as Best Response (BR) | PD includes one or more of the following criteria: >25% increase in the level of serum monoclonal paraprotein, which must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation, >25% increase in 24 hr urinary light chain excretion, which must also be an absolute increase of at least 200 mg/24 hr and confirmed on a repeat investigation, >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10%., Definite increase in the size of existing lytic bone lesions or soft tissue plasmacytomas, Development of new bone lesions or soft tissue plasmacytomas (not including compression fracture), Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). | Up to 12 cycles of 3 weeks each | 
| Number of Participants With Progressive Disease (PD) PD as Last Observed Response (LOR) | PD includes one or more of the following criteria: >25% increase in the level of serum monoclonal paraprotein, which must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation, >25% increase in 24 hr urinary light chain excretion, which must also be an absolute increase of at least 200 mg/24 hr and confirmed on a repeat investigation, >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10%., Definite increase in the size of existing lytic bone lesions or soft tissue plasmacytomas, Development of new bone lesions or soft tissue plasmacytomas (not including compression fracture), Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). | Up to 12 cycles of 3 weeks each | 
| Time to Disease Progression | Time to disease progression was defined as the time from first dose until objective tumor progression. Participants who did not experience tumor progression were censored at their last known date in the study. It was estimated using Kaplan-Meier methodology. Participants who did not experience tumor progression were censored at their last known date in the study. The first quartile for time to disease progression was evaluated when 25th percentile of participants of mITT population reported disease progression. Similarly, median and 75th percentile of participants of MITT population was planned to be reported. If, less than 75th percentile of participants reported disease progression at the end of the study period, then the observation was censored for the purpose of this analysis and in such case the data was planned to be reported as not evaluable (NA). | From Day 1 till disease progression (approximately 12 cycles of 3 weeks each) | 
| Change From Baseline in Hematology: White Blood Cell (WBC) Count, Neutrophils, Lymphocytes, Platelets | Blood samples collected to evaluate the hematology parameters were WBC count, neutrophils, lymphocytes and platelets. Change from Baseline was defined as the value of Baseline minus from the End of study visit. Baseline was defined as Day 1. | Baseline (Day 1) and End of Study assessments/follow-up approximately 28 days (+/- 7 days) following the last dose of SRT501 or SRT501 and bortezomib (approximately 280 days) | 
| Change From Baseline in Hematology: Hematocrit | Blood samples were collected to evaluate the hematology parameter hematocrit. Change from Baseline was defined as the value of baseline minus from the End of study visit. Baseline was defined as Day 1. | Baseline (Day 1) and End of Study assessments/follow-up approximately 28 days (+/- 7 days) following the last dose of SRT501 or SRT501 and bortezomib (approximately 280 days) | 
| Change From Baseline in Hematology: Hemoglobin | Blood samples were collected to evaluate the hematology parameter hemoglobin. Change from Baseline was defined as the value of Baseline minus from the End of study visit. Baseline was defined as Day 1. | Baseline (Day 1) and End of Study assessments/follow-up approximately 28 days (+/- 7 days) following the last dose of SRT501 or SRT501 and bortezomib (approximately 280 days) | 
| Change From Baseline in Hematology: Red Blood Cell (RBC) | Blood samples were collected to evaluate the hematology parameter RBC. Change from Baseline was defined as the value of Baseline minus from the End of study visit. Baseline was defined as Day 1. | Baseline (Day 1) and End of Study assessments/follow-up approximately 28 days (+/- 7 days) following the last dose of SRT501 or SRT501 and bortezomib (approximately 280 days) | 
| Change From in Baseline Biochemistry: Serum Creatinine, Total Bilirubin | Blood samples were collected to evaluate hematology parameters serum creatinine and total bilirubin. Change from Baseline was defined as the value of baseline minus from the End of study visit. Baseline was defined as Day 1. | Baseline (Day 1) and End of Study assessments/follow-up approximately 28 days (+/- 7 days) following the last dose of SRT501 or SRT501 and bortezomib (approximately 280 days) | 
| Change From Baseline in Biochemistry -Urea, Bicarbonate | Blood samples were collected to evaluate the biochemistry parameter urea and bicarbonate. Change from Baseline was defined as the value of Baseline minus from the End of study visit. Baseline was defined as Day 1. | Baseline (Day 1) and End of Study assessments/follow-up approximately 28 days (+/- 7 days) following the last dose of SRT501 or SRT501 and bortezomib (approximately 280 days) | 
| Change From Baseline in Biochemistry: Prothrombin Time (PT)/ International Normalized Ratio (INR) | Blood samples were collected to evaluate the biochemistry parameter PT/INR. Change from Baseline was defined as the value of Baseline minus from the End of study visit. Baseline was defined as Day 1. | Baseline (Day 1) and End of Study assessments/follow-up approximately 28 days (+/- 7 days) following the last dose of SRT501 or SRT501 and bortezomib (approximately 280 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of SRT501 at Indicated Time Points | Pharmacokinetic sampling on Day1/2 and Day 20/21 of Cycle 1 for participants ready to participate was planned. The sampling was planned to be collected at timepoints on Cycle 1 Day 1 at pre-dose, 30 minute, 1 hour, 2 hour, 4 hour, 6 hour and 24 hour post-dose and the same timepoints on Day 2 and Day 20 post- dose. It was to be collected in participants who fasted atleast for an hour. Due to early termination of the study, the data for Pharmacokinetic analysis was not collected. | Cycle 1 Day 1, Cycle 1 Day 2 and Cycle 1 Day 20 at pre-dose, 30 minute, 1 hour, 2 hour, 4 hour, 6 hour and 24 hour post-dose. Day 2 and Day 20, samples collected post-dose. Each cycle duration was 21 days. |