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

Inclusion Criteria:

1. Males or females, age 18 years or older.
2. A diagnosis of MM and documentation of relapsed or relapse/refractory status following at least 1 prior therapy and a maximum of 4 prior regimens.

3. Patients with measurable disease defined as at least one of the following these baseline laboratory studies for determining eligibility must be obtained within 21 days prior to enrollment):

   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 (should be measured within 28 days of first study drug administration). 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. Patient has an Eastern Cooperative Oncology Group (ECOG) ≤ 2 OR Karnofsky

   • 60% performance status (PS) (Appendix 13-2).
5. Predose mean QTc ≤ 450 msec or mean QTc Fridericia's Correction (QTcF)on Day 1(cycle 1 or cycle 0 if applicable) must be ≤ 450 msec.
6. Females of childbearing potential (FCBP): a female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months). Pregnancy status in women of childbearing potential must be confirmed by serum β-hCG at screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. FCBP must use acceptable forms of birth control or agree to abstain from heterosexual intercourse while participating in the study and for 90 days following the last dose of study drug. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy while participating in the study and for 90 days following the last dose of study drug.
7. Voluntary, written informed consent before performance of any study-related procedure not part of routine medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).
9. Must be able to take and retain oral medications.

10. Inclusion Clinical Laboratories Criteria The following laboratory results must be met within 7 (+3 days if necessary for holiday/scheduling conflicts) days of first study drug administration:

    1. Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 10^9/L) (Growth factors cannot be used within 14 days of first study drug administration);
    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 within normal limits;
    5. Total bilirubin within normal limits;
    6. Creatinine clearance ≥ 30 mL/min (Cockcroft-Gault calculation);
    7. Serum creatinine ≤1.5 x ULN (correction with hydration and re-testing is permitted)(values ≥ 1.5 X ULN may be acceptable if improved to < 1.5 x ULN, with hydration and/or attributable to progressing MM);
    8. Serum calcium (ionized or corrected for albumin) ≥ 2.0 mmol/L (8.0 mg/dL or 1.0 mmol/L ionized calcium) to ULN. Treatment of hypercalcemia or hypocalcemia is allowed and patient may enroll if serum calcium returns to > 2.0 mmols/L to ULN with standard treatment
    9. Serum potassium and magnesium within normal limits (correction with supplementation is permitted);
    10. HgbA1c of ≤ 7%;
    11. Fasting glucose of ≤126 mg/dL (7.0 mmol/L). A diagnosis of Type II diabetes mellitus is permitted if > 4 weeks since diagnosis and well controlled. Concurrent non-insulinotropic antihyperglycemic therapy is permitted if the dose has been stable for 8 weeks.

11. Resolution of prior toxicities associated with a prior treatment to

    • grade 1.

Exclusion Criteria:

1. Patients refractory or intolerant to bortezomib are not permitted (Refractory = non-responsive/progressed on therapy or within 60 days of bortezomib) on phase 2 part of the study only.
2. Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of 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 including steroid therapy within 14 days prior to first study drug administration.
4. History (within the last 6 months) of significant cardiovascular disease unless the disease is well-controlled. Significant cardiac disease includes but is not limited to second/third degree heart block; clinically significant ischemic heart disease; superior vena cava (SVC) syndrome; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (≥ grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded;
5. Mean QTc interval ≥ 450 msec or 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. Examples of such conditions include any pre-existing kidney disease (acute or chronic, unless renal insufficiency is felt to be secondary to MM), hypertension, active seizure disorder or pulmonary diseases that 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 washout period elapses (as indicated in Appendix 13-6), which ever is longer prior to Cycle 1 Day 1 dosing;. Drugs that have a known risk of causing TdP can be found on (www.azcert.org/medical- pros/drug-lists/bycategory.cfm);
18. Use of strong/moderate CYP1A2 inhibitors such as ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded (see appendix 13-9)
19. Gastrointestinal abnormalities, including bowel obstruction, inability to take oral medication, requirement for intravenous (IV) alimentation, active peptic ulcer or prior surgical procedures or bowel resection or other poorly controlled gastrointestinal disorders that could affect the absorption of study drug (eg, Crohn's disease or ulcerative colitis);
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. Prior radiation therapy or major surgical procedure within 4 weeks of the first dose of study treatment (this does not include limited course of radiation used for management of bone pain).