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

NCT00920556 | Terminated Phase 2 Results

• 1 other identifier: 113222
• Study Type: interventional
• Target: 24
• Locations: 2 countries
• Sites: 5

Brief Summary

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.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (17)

• 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 Outcomes (1)

• Plasma Concentrations of SRT501 at Indicated Time Points

  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.

Study Arms (1)

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

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.

Treatment

Bortezomib DRUG

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.

Treatment

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sirtris, a GSK Company: lead
• GlaxoSmithKline: collaborator

Study Sites (5)

GSK Investigational Site

Vejle, 7100, Denmark

Location

GSK Investigational Site

Sutton, Surrey, SM2 5NG, United Kingdom

Location

GSK Investigational Site

Birmingham, B15 2TH, United Kingdom

Location

GSK Investigational Site

Leeds, LS9 7TF, United Kingdom

Location

GSK Investigational Site

London, EC1A 7BE, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 23205612 DERIVED

Related Links

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

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Resveratrol; Bortezomib

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

Intervention Hierarchy (Ancestors)

Stilbestrols; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polyphenols; Phenols; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

The study of Multiple Myeloma, was terminated early due to minimal efficacy signal observed.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2009
• First Posted: June 15, 2009
• Study Start: March 30, 2009
• Primary Completion: November 4, 2010
• Study Completion: November 4, 2010
• Last Updated: February 27, 2019
• Results First Posted: February 27, 2019

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will share

Locations

GB (4); DK (1)