A Trial of ASP7487 (OSI-906) in Combination With Bortezomib for the Treatment of Relapsed Multiple Myeloma
This study is currently recruiting participants.
Verified December 2013 by University Health Network, Toronto
Multiple Myeloma Research Consortium
Astellas Pharma Inc
Information provided by (Responsible Party):
University Health Network, Toronto
First received: August 1, 2012
Last updated: December 18, 2013
Last verified: December 2013
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.
Drug: ASP7487, Velcade, Dexamethasone
||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||A Phase 1/2 Trial of ASP7487 OSI-906)in Combination With Bortezomib and Dexamethasone for the Treatment of Relapsed or Relapsed/Refractory Multiple Myeloma
Primary Outcome Measures:
- Maximum Tolerated Dose of the combination of ASP7487 (OSI-906) with Velcade and Dexamethasone [ Time Frame: It is estimated that it will take approximately 3-5 months determine MTD. The efficacy analysis could take upto 2.5 years after the activation date of the study to be completed. ] [ Designated as safety issue: Yes ]
- 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.
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||December 2015 (Final data collection date for primary outcome measure)
Experimental: 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
Drug: 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
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
|Ages Eligible for Study:
||18 Years and older
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- Males or females, age 18 years or older.
- 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.
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):
- Serum M-protein ≥ 0.5 g/dl (≥ 5 g/l)
- Urine M-protein ≥ 200 mg/24 h
- 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)
- Biopsy proven plasmacytoma (should be measured within 28 days of first study drug administration). Prior biopsy is acceptable.
- If the serum protein electrophoresis is unreliable for routine M-protein measurement, quantitative immunoglobulin levels on nephelometry or turbidimetry will be followed.
Patient has an Eastern Cooperative Oncology Group (ECOG) ≤ 2 OR Karnofsky
- 60% performance status (PS) (Appendix 13-2).
- 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.
- 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.
- 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.
- 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).
- Must be able to take and retain oral medications.
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:
- 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);
- Platelet count ≥ 50,000 cells/dL (50 x 109/L);
- Hemoglobin ≥ 8.0 g/dL (4.96 mmol/L);
- Serum AST or ALT within normal limits;
- Total bilirubin within normal limits;
- Creatinine clearance ≥ 30 mL/min (Cockcroft-Gault calculation);
- 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);
- 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
- Serum potassium and magnesium within normal limits (correction with supplementation is permitted);
- HgbA1c of ≤ 7%;
- 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.
Resolution of prior toxicities associated with a prior treatment to
- 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.
- 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.
- 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.
- 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;
- Mean QTc interval ≥ 450 msec or QTcF interval > 450 msec at screening;
- Prior autologous, peripheral stem cell transplant within 12 weeks of the first dose of study drug;
- Daily requirement for corticosteroids (except for inhalation corticosteroids);
- 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);
- Known active infection requiring parenteral or oral anti-infective treatment.
- Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation.
- 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.
- Patient has hypersensitivity to any of the components of study drugs;
- Known HIV or active hepatitis B or C viral infection;
- Diabetes mellitus currently requiring insulin or insulinotropic therapy or prior history of steroid induced diabetes ;
- History of cerebrovascular accident (CVA) within 6 months prior to registration or that is not stable;
- Prior therapy with an IGF-1R inhibitor;
- 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);
- Use of strong/moderate CYP1A2 inhibitors such as ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded (see appendix 13-9)
- 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);
- Peripheral neuropathy ≥ grade 2;
- Significant liver disease or metastatic disease to the liver;
- History of amyloid, plasma cell leukemia or CNS involvement.
- 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).
Please refer to this study by its ClinicalTrials.gov identifier: NCT01672736
|Emory University Winship Cancer Institute
|Atlanta, Georgia, United States, 30322 |
|Contact: Kenisha Barron 404-778-5144 firstname.lastname@example.org |
|Principal Investigator: Jonathan Kaufman, MD |
|University Of Chicago Medical Center
|Chicago, Illinois, United States, 60637 |
|Contact: Kathryn McDonnell, BS 773-702-1835 email@example.com |
|Principal Investigator: Andrzej Jakubowiak, MD |
|Queen Elizabeth II Health Sciences Center
|Halifax, Nova Scotia, Canada, B3H2Y9 |
|Contact: Donna Mann, RN (902) 429-2597 Donna.firstname.lastname@example.org |
|Principal Investigator: Darrell White, MD |
|University Health Network-Princess Margaret Hospital
|Toronto, Ontario, Canada, M5G 2M9 |
|Contact: Engin Gul, HBSc 416 946 4501 ext 2608 email@example.com |
|Principal Investigator: Suzanne Trudel, MD |
|Sir Mortimer B. Davis-Jewish General Hospital
|Montreal, Quebec, Canada, H3T 1E3 |
|Contact: Caroline Lambert, PhD 514-340-8222 ext 4599 firstname.lastname@example.org |
|Principal Investigator: Martin Gyger, MD |
|Montreal, Quebec, Canada, H1T 2M4 |
|Contact: Nathalie Lachapelle, BSN 514-252-3400 ext 4471 email@example.com |
|Principal Investigator: Richard LeBlanc, MD |
University Health Network, Toronto
Multiple Myeloma Research Consortium
Astellas Pharma Inc
||Suzanne Trudel, MD
No publications provided
||University Health Network, Toronto
History of Changes
|Other Study ID Numbers:
|Study First Received:
||August 1, 2012
||December 18, 2013
||United States: Food and Drug Administration
Canada: Health Canada
Keywords provided by University Health Network, Toronto:
Relapsed or relapse/refractory Multiple Myeloma
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on March 06, 2014
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Blood Protein Disorders
Immune System Diseases
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents