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

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

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.

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.

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.