A Clinical Study to Assess the Safety and Activity of SRT... | NCT00920556

Status Module

Name	Class
GlaxoSmithKline	INDUSTRY

Description Module

Detailed Description

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Treatment	Experimental	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 Drug: Bortezomib

Interventions

Name	Type	Description	Arm Group Labels	Other Names
5.0g SRT501	Drug	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.

Outcomes Module

Primary Outcomes

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).

Secondary Outcomes

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.

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Vejle		7100	Denmark
GSK Investigational Site

PubMed Identifier	Type	Citation	Retractions
23205612	Derived	Popat R, Plesner T, Davies F, Cook G, Cook M, Elliott P, Jacobson E, Gumbleton T, Oakervee H, Cavenagh J. A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br J Haematol. 2013 Mar;160(5):714-7. doi: 10.1111/bjh.12154. Epub 2012 Dec 4. No abstract available.

Label	URL
Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.	View source

ID	Type	URL	Comment
113222	Clinical Study Report	View IPD

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Overall Study	Eligible participants were administered 5 gram (g) of SRT501, as oral suspension every morning approximately 15-30 minutes after breakfast), for 20 days in 21-day cycle, for max period of 12 cycles (Not administered on Day 21 of each cycle). Post first two cycles, participant who exhibited stable disease (SD) or better, with SRT501 monotherapy, continued for additional two cycles. If, after first 2 cycles, participant exhibited PD, then received bortezomib (1.3 milligram(mg)/meter square (m^2)on Day 1, Day 4, Day 8, and Day 11 in a 21 day cycle) along with SRT501. Bortezomib was administered intravenous suspension, prior to breakfast and SRT501 administration. If after 2 additional cycles of SRT501 monotherapy (4 cycles total), participant exhibited SD or better, they remained on SRT501 therapy, until judged to have PD. If PD,participants underwent bortezomib regiment as above. At any point of (SRT501+Bortezoimb),participant was assessed with PD, was discontinued

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Safety Population was defined as all the participants who received any amount of SRT501 or bortezomib.

Posted

Count of Participants

Participants

Approximately up to 12 cycles of 3 weeks each

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Units	Counts
Participants	OG00024 OG0019

Title

Denominators

Categories

Any AE

Title	Measurements
	OG00024 OG0019

Any SAE

Title	Measurements
	OG000

Primary

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.

Modified Intent to Treat (mITT), had participants who completed first (2) cycles of SRT501 monotherapy. Participants dropped were not counted; those withdrew after 2nd cycle were considered evaluable regardless of discontinuation reason; alongwith participants discontinued for missing clinical trial material after 2 cycle, were considered.

Posted

Count of Participants

Participants

Approximately up to 12 cycles of 3 weeks

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.

Primary

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).

mITT Population.

Posted

Count of Participants

Participants

Up to 12 cycles of 3 weeks each

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

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).

mITT Population.

Posted

Count of Participants

Participants

Up to 12 cycles of 3 weeks each

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

Number of Participants With Partial Response (PR) as Last Observed Response (LOR)

mITT

Posted

Count of Participants

Participants

Up to 12 cycles of 3 weeks each

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

Number of Participants With Stable Disease (SD) as Best Response (BR)

Stable disease included not meeting the criteria for MR or PD.

mITT Population

Posted

Count of Participants

Participants

Up to 12 cycles of 3 weeks each

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Units	Counts

Primary

Number of Participants With Stable Disease (SD) as Last Observed Response (LOR)

Stable disease included not meeting the criteria for MR or PD.

mITT Population.

Posted

Count of Participants

Participants

Up to 12 cycles of 3 weeks each

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Units	Counts

Primary

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).

mITT Population.

Posted

Count of Participants

Participants

Up to 12 cycles of 3 weeks each

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib

Primary

Number of Participants With Progressive Disease (PD) PD as Last Observed Response (LOR)

mITT Population.

Posted

Count of Participants

Participants

Up to 12 cycles of 3 weeks each

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib

Primary

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).

mITT Population. Only those participants available at the specified timepoints were analyzed.

Posted

Median

Inter-Quartile Range

Months

From Day 1 till disease progression (approximately 12 cycles of 3 weeks each)

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001

Primary

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.

Safety Population. Only those participants available at the specified timepoints were analyzed.

Posted

Mean

Standard Deviation

10^9 cells per liter (L)

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)

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

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.

Safety population. Only those participants available at the specified time-points were analyzed.

Posted

Mean

Standard Deviation

Proportion of red blood cells in blood

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)

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

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.

Safety population. Only those participants available at the specified timepoints were analyzed.

Posted

Mean

Standard Deviation

Gram per litre

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)

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

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.

Safety population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

10^12 cells per liter

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)

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

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.

Safety Population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Micromole per liter

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)

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

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.

Safety population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

millimole per liter

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)

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, orally every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care. SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Primary

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.

Safety Population. Only those participants available at the particular timepoints were analyzed

Posted

Mean

Standard Deviation

Ratio of PT/INR

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)

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. SRT501 was not administered on Day 21 of each cycle.
OG001	SRT501 + Bortezomib	The eligible participants in this arm received an intravenous solution of Bortezomib at 1.3 mg/m^2 in conjunction with SRT501 (5.0 g/day) daily dosing. Bortezomib was administered prior to breakfast and SRT501 administration, on Day 1, 4, 8 and 11 in every 21 day cycle. It was given as per the local institution's guidelines and standards of care.SRT501 + Bortezomib, is a subset of arm SRT501 monotherapy.

Secondary

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.

Subjects who receive study drug and have adequate pharmacokinetic data available will be included in the pharmacokinetics population, with data summarized by dose group. Data not collected due to early termination of the study.

Posted

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.

ID	Title	Description
OG000	SRT501 Monotherapy	The eligible participants in this arm received 5 g of SRT501, oral suspension every morning at the same time approximately 15-30 minutes following consumption of breakfast) on all dosing days, for 20 consecutive days in a 21-day cycle for a maximum period of 12 cycles. There was no time between the cycles i.e Day 1 of a cycle was started on the day following Day 21 of the previous cycle. No administration of SRT501, will occur on Day 21 of each cycle.
OG001	SRT501 + Bortezomib

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anemia	Blood and lymphatic system disorders	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk
Sinus Bradycardia	Cardiac disorders	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk
Nausea	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk
Vomiting	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk
Disease progression	General disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Pyrexia	General disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Pneumonia	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Neutropenic sepsis	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk
Urinary tract infection	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk
Viral infection	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk
Renal failure acute	Renal and urinary disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
Renal failure	Renal and urinary disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Renal impairment	Renal and urinary disorders	MedDRA 13.1	Systematic Assessment	EG0001 affected24 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG00019 affected24 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG00018 affected24 at risk
Vomiting	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG00012 affected24 at risk
Constipation	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0007 affected24 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0005 affected24 at risk
Fatigue	General disorders	MedDRA 13.1	Systematic Assessment	EG00011 affected24 at risk
PYREXIA	General disorders	MedDRA 13.1	Systematic Assessment	EG0004 affected24 at risk
OEDEMA PERIPHERAL	General disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
CHILLS	General disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
DISEASE PROGRESSION	General disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
HEADACHE	Nervous system disorders	MedDRA 13.1	Systematic Assessment	EG0009 affected24 at risk
NEUROPATHY PERIPHERAL	Nervous system disorders	MedDRA 13.1	Systematic Assessment	EG0006 affected24 at risk
DIZZINESS	Nervous system disorders	MedDRA 13.1	Systematic Assessment	EG0005 affected24 at risk
DYSGEUSIA	Nervous system disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
LETHARGY	Nervous system disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
PAIN IN EXTREMITY	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0009 affected24 at risk
ARTHRALGIA	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0006 affected24 at risk
BACK PAIN	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0006 affected24 at risk
MUSCLE SPASMS	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0004 affected24 at risk
MUSCULOSKELETAL CHEST PAIN	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
MUSCULOSKELETAL PAIN	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
BONE PAIN	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
JOINT SWELLING	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
MUSCULAR WEAKNESS	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
NECK PAIN	Musculoskeletal and connective tissue disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
COUGH	Respiratory, thoracic and mediastinal disorders	MedDRA 13.1	Systematic Assessment	EG0006 affected24 at risk
PHARYNGOLARYNGEAL PAIN	Respiratory, thoracic and mediastinal disorders	MedDRA 13.1	Systematic Assessment	EG0005 affected24 at risk
DYSPNOEA	Respiratory, thoracic and mediastinal disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
EPISTAXIS	Respiratory, thoracic and mediastinal disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
PLEURAL EFFUSION	Respiratory, thoracic and mediastinal disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
PRODUCTIVE COUGH	Respiratory, thoracic and mediastinal disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
RHINORRHOEA	Respiratory, thoracic and mediastinal disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
ANOREXIA	Metabolism and nutrition disorders	MedDRA 13.1	Systematic Assessment	EG0007 affected24 at risk
HYPOKALAEMIA	Metabolism and nutrition disorders	MedDRA 13.1	Systematic Assessment	EG0004 affected24 at risk
DECREASED APPETITE	Metabolism and nutrition disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
LOWER RESPIRATORY TRACT INFECTION	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
NASOPHARYNGITIS	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
ORAL CANDIDIASIS	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
PNEUMONIA	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
RHINITIS	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
URINARY TRACT INFECTION	Infections and infestations	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
ANAEMIA	Blood and lymphatic system disorders	MedDRA 13.1	Systematic Assessment	EG0008 affected24 at risk
NEUTROPENIA	Blood and lymphatic system disorders	MedDRA 13.1	Systematic Assessment	EG0006 affected24 at risk
THROMBOCYTOPENIA	Blood and lymphatic system disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
DEPRESSION	Psychiatric disorders	MedDRA 13.1	Systematic Assessment	EG0004 affected24 at risk
CONFUSIONAL STATE	Psychiatric disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
ANXIETY	Psychiatric disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
RASH	Skin and subcutaneous tissue disorders	MedDRA 13.1	Systematic Assessment	EG0008 affected24 at risk
PRURITUS	Skin and subcutaneous tissue disorders	MedDRA 13.1	Systematic Assessment	EG0004 affected24 at risk
WEIGHT DECREASED	Investigations	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
BLOOD CREATININE INCREASED	Investigations	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
RENAL FAILURE ACUTE	Renal and urinary disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
RENAL IMPAIRMENT	Renal and urinary disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
HYPERTENSION	Vascular disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
TACHYCARDIA	Cardiac disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0004 affected24 at risk
Oral pain	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0003 affected24 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Ascites	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Eructation	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk
Hypoaesthesia oral	Gastrointestinal disorders	MedDRA 13.1	Systematic Assessment	EG0002 affected24 at risk

ID	Term
D054219	Neoplasms, Plasma Cell
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D020141	Hemostatic Disorders
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D010265	Paraproteinemias
D001796	Blood Protein Disorders
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D006474	Hemorrhagic Disorders
D008232	Lymphoproliferative Disorders
D007160	Immunoproliferative Disorders
D007154	Immune System Diseases

ID	Term
D000081225	Stilbestrols
D013267	Stilbenes
D001597	Benzylidene Compounds
D001555	Benzene Derivatives
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals
D059808	Polyphenols
D010636	Phenols
D001897	Boronic Acids
D000148	Acids, Noncarboxylic
D000143	Acids
D007287	Inorganic Chemicals
D001896	Boron Compounds
D011719	Pyrazines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds