A Trial of ASP7487 (OSI-906) in Combination With Bortezomib for the Treatment of Relapsed Multiple Myeloma

This is a multi-center, open-label, non-randomized study. Patients will receive ASP7487 (OSI-906) in combination with bortezomib and dexamethasone. Phase 1 involves dose escalation of the combination, whereas Phase 2 involves the expansion of ASP7487 (OSI-906) combined with bortezomib and dexamethasone at the MTD to establish the ORR. This trial will accrue patients with relapsed or relapsed/refractory MM - a disease state for which bortezomib is approved to treat by the FDA and Health Canada. The combination of ASP7487 (OSI-906) with bortezomib is supported by pre-clinical work in MM in which the combination with an IGF1-R inhibitor enhances anti-tumor activity of bortezomib.

The Phase 1 portion of the study will determine the MTD and DLTs of bortezomib administered on days 1, 4, 8 and 11 of a 21-day cycle combined with ASP7487 (OSI-906) dosed twice daily orally continuously. The combination of ASP7487 (OSI-906) with bortezomib has not previously been tested. The active agent bortezomib will be used during Cycle 1 - 8 at the recommended treatment dose of 1.3 mg/m2 days 1, 4, 8 and 11 and Cycles 9+ on days 1, 8, 15 and 22 of a 5-week cycle and ASP7487 (OSI-906) will be dose escalated form 75 mg to 150mg utilizing 3+3 design

Eligibility Criteria:
Inclusion Criteria

1. Males or females, age 18 years or older.
2. Relapsed or relapse/refractory MM with at least 1 prior line of therapy for phase 1 and 1 to 5 prior lines of therapy for phase 2.
3. Patients with measurable disease defined as at least one of the following

   1. Serum M-protein ≥ 0.5 g/dl (≥ 5 g/l)
   2. Urine M-protein ≥ 200 mg/24 h
   3. Serum free light chains (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) and an abnormal serum free light chain ratio (\< 0.26 or \> 1.65)
   4. Biopsy proven plasmacytoma. Prior biopsy is acceptable.
   5. If the serum protein electrophoresis is unreliable for routine M-protein measurement, quantitative immunoglobulin levels on nephrolometry or turbidometry will be followed.
4. ECOG ≤ 2 OR Karnofsky ≥ 60%.
5. Predose mean QTc≤ 450 msec or QTcF ≤ 450 msec.
6. Negative pregnancy test for Females of childbearing potential.
7. Voluntary, written informed consent.
8. Ability to understand the purpose and risks of the study.
9. Must be able to take and retain oral medications.
10. Inclusion Clinical Laboratories Criteria

    1. Absolute neutrophil count (ANC) \> 1,000 cells/dL (1.0 x 109/L)
    2. Platelet count \> 50,000 cells/dL (50 x 109/L)
    3. Hemoglobin ≥ 8.0 g/dL (4.96 mmol/L)
    4. Serum AST or ALT ≤ 1.2 x ULN
    5. Total bilirubin within normal limits
    6. Creatinine clearance ≥ 30 mL/min
    7. Serum creatinine ≤ 1.5 x ULN
    8. Serum calcium (ionized or corrected for albumin) ≥ 2.0 mmol/L (8.0 mg/dL or 1.0 mmol/L ionized calcium) to ≤ 1.2 x ULN.
    9. Serum potassium, and magnesium within normal limits
    10. HgbA1c of ≤ 7%
    11. Troponin I or T within normal limits
    12. BNP or NT-proBNP within normal limits
    13. Fasting glucose of ≤126 mg/dL (7.0 mmol/L).
11. Resolution of prior treatment associated toxicities to ≤ grade 1

Exclusion Criteria

1. Bortezomib refractory patients are not permitted on the Phase 2 part of the study.
2. Diagnosed or treated for another malignancy within 3 years of enrollment, except completely resected basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
3. Patient has received other investigational drugs or chemotherapy within 21 days or approved anti-myeloma therapy within 14 days.
4. History (within the last 6 months) of significant cardiovascular disease.
5. Mean QTcF interval \> 450 msec at screening.
6. Prior autologous, peripheral stem cell transplant within 12 weeks of the first dose of study drug.
7. Daily requirement for corticosteroids (except for inhalation corticosteroids).
8. Patients with evidence of mucosal or internal bleeding and/or platelet transfusion refractory (i.e., unable to maintain a platelet count ≥ 50,000 cells/dL).
9. Known active infection requiring parenteral or oral anti-infective treatment.
10. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation.
11. Use of any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient.
12. Patient has hypersensitivity to any of the components of study drugs.
13. Known HIV or active hepatitis B or C viral infection.
14. Diabetes mellitus currently requiring insulin or insulinotropic therapy or prior history of steroid induced diabetes.
15. History of cerebrovascular accident (CVA) within 6 months prior to registration or that is not stable.
16. Prior therapy with an IGF-1R inhibitor.
17. Use of drugs that have a risk of causing QT interval prolongation and/or have a known risk of causing Torsades de Pointes (TdP) before 14 days or the recommended 5 half-life.
18. Use of strong/moderate CYP1A2 inhibitors.
19. Gastro-intestinal abnormalities that could affect the absorption of study drug.
20. Peripheral neuropathy ≥ grade 2.
21. Significant liver disease or metastatic disease to the liver
22. History of amyloid, plasma cell leukemia or CNS involvement.
23. Radiation therapy or major surgical procedure within 4 weeks of the first dose.