Multiple Myeloma
Conditions
Keywords
Relapsed or relapse/refractory Multiple Myeloma
Brief summary
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.
Detailed description
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
Interventions
DRUGASP7487, Velcade, Dexamethasone
ASP7487- Oral (75, 100, 150 mg)BID Bortezomib- 1.3 mg/m2 IV on days 1, 4, 8, 15 of each 21 day cycle up to cycle 8 and days 1, 5, 15, 22 of each 35 day cycle beyond cycle 9 Dexamethasone- 20 mg on the day of Bortezomib administration
Sponsors
Multiple Myeloma Research Consortium
Astellas Pharma Inc
University Health Network, Toronto
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of the Combination of ASP7487 (OSI-906) With Velcade and Dexamethasone | 45 months | * Phase 1: To determine the maximum tolerated dose (MTD) of ASP7487 (OSI-906) administered in combination with the recommended dose and schedule of bortezomib and dexamethasone; * Phase 2: To evaluate the antitumor activity of ASP7487 (OSI-906) in combination with bortezomib and dexamethasone at the MTD established from the Phase 1 component. |
Countries
Canada, United States
Participant flow
Recruitment details
Subject enrollment under this IND was stopped prematurely due to the drug manufacturer's decision to terminate the development of the study drug, Linsitinib (letter dated 1 November 2015). Therefore, the study did not proceed to Phase II portion of the study protocol. The available study drug supply at the study sites expired on 31 May 2016.
Participants by arm
| Arm | Count |
|---|---|
| ASP7487, Velcade, Dexamethasone ASP7487 administered orally 75, 100 and 150 mg) BID continuously for each cycle. Bortezomib administered at 1.3 mg/m2 twice weekly for the first 8 21 day cycles and once weekly beyond cycle 9 for 35 day cycles. Dexamethasone is administered on bortezomib administration days at 20 mg
ASP7487, Velcade, Dexamethasone: ASP7487- Oral (75, 100, 150 mg)BID Bortezomib- 1.3 mg/m2 IV on days 1, 4, 8, 15 of each 21 day cycle up to cycle 8 and days 1, 5, 15, 22 of each 35 day cycle beyond cycle 9 Dexamethasone- 20 mg on the day of Bortezomib administration | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Available drug expired on 31 May 16 | 3 |
Baseline characteristics
| Characteristic | ASP7487, Velcade, Dexamethasone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment Canada | 18 Participants |
| Region of Enrollment United States | 1 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 19 |
| other Total, other adverse events | 19 / 19 |
| serious Total, serious adverse events | 8 / 19 |
Outcome results
Primary
Maximum Tolerated Dose of the Combination of ASP7487 (OSI-906) With Velcade and Dexamethasone
* Phase 1: To determine the maximum tolerated dose (MTD) of ASP7487 (OSI-906) administered in combination with the recommended dose and schedule of bortezomib and dexamethasone; * Phase 2: To evaluate the antitumor activity of ASP7487 (OSI-906) in combination with bortezomib and dexamethasone at the MTD established from the Phase 1 component.
Time frame: 45 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ASP7487, Velcade, Dexamethasone | Maximum Tolerated Dose of the Combination of ASP7487 (OSI-906) With Velcade and Dexamethasone | Linsitinib starting dose in milligrams | 75 milligrams |
| ASP7487, Velcade, Dexamethasone | Maximum Tolerated Dose of the Combination of ASP7487 (OSI-906) With Velcade and Dexamethasone | Linsitinib maximum dose in milligrams | 150 milligrams |