Study of Arry-520 and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma
This trial is active, not recruiting.
|Treatments||arry-520, carfilzomib, dexamethasone, filgrastim|
|Sponsor||M.D. Anderson Cancer Center|
|Start date||February 2012|
|End date||February 2018|
|Trial size||75 participants|
|Trial identifier||NCT01372540, 2011-0144, NCI-2011-01120|
This study is divided into study groups, as described below. The goal of Groups 1A and 2A of this clinical research study is to find the highest tolerable dose of the combination of ARRY-520 and carfilzomib that can be given to patients with multiple myeloma or plasma cell leukemia.
The goal of Groups 1B and 2B of this study is to learn if the combination of carfilzomib and ARRY-520 can help to control multiple myeloma or plasma cell leukemia. Researchers would also like to learn if ARRY-520 can help carfilzomib to work in patients who have built up a resistance to carfilzomib or carfilzomib alone has not helped to control the disease.
The safety of the study drugs will be studied in all groups.
|Endpoint classification||safety/efficacy study|
|Intervention model||single group assignment|
Maximum Tolerated Dose (MTD) of ARRY-520 With Carfilzomib in Participants With Relapsed/Refractory Multiple Myeloma
time frame: Evaluated with each 28 day cycle
Overall Response (OR) Rate of ARRY-520 With Carfilzomib in Participants With Relapsed/Refractory Multiple Myeloma
time frame: 2 months
Overall Response (OR) Rate of ARRY-520 With Carfilzomib in Participants With Relapsed/Refractory Multiple Myeloma
time frame: 28 days
Male or female participants at least 18 years old.
Inclusion Criteria: 1. Confirmed relapsed or refractory MM or PCL. Patients should have received at least 1 prior treatment regimen. Prior treatment must have included at least one full cycle of a proteasome inhibitor (e.g., bortezomib) and at least one full cycle of an IMiD (e.g., thalidomide, lenalidomide or pomalidomide). Patients who have had prior ARRY-520 and carfilzomib will be allowed in the dose escalation phase, however prior ARRY-520 and carfilzomib will be excluded in the dose expansion cohort 1 of Part A. There will be 2 cohorts in the dose expansion of part A: Cohort 1 will be patients who are carfilzomib sensitive; Cohort 2 will be patients who are carfilzomib refractory. 2. Continuation of Inclusion Criteria #1: Part B: For Part B dose expansion: Once a MTD has been established in Part A, additional dose escalation will occur with subsequent dose escalation of Carfilzomib. During the dose escalation of Part B, pt must have at least 1 line of prior therapy and no limitations on prior therapy. Patients who had prior clinical benefit/response to ARRY-520 or Carfilzomib with a SD or better may be eligible for dose expansion of Part B. Dose expansion of part B will be patients who are carfilzomib sensitive. 3. Measurable MM disease, defined as one of the following: A monoclonal immunoglobulin (Ig) concentration on serum electrophoresis of >/= 0.5 g/dL for an IgG myeloma, >/= 0.1 g/dL for an IgD myeloma or 0.5 g/dL for an IgA myeloma. Measurable urinary light chain secretion by quantitative analysis of >/= 200 mg/24 hours. Involved serum FLC level >/= 10 mg/dL, provided the serum free light chain (FLC) ratio is abnormal. Patients with oligo- or non-secretory disease must have bone marrow involvement with at least 30% plasmacytosis. 4. Male or female, >/= 18 years of age at time of signing consent. 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2. 6. Adequate hematology laboratory values without transfusion support and without hematological growth factor support within 2 weeks of Screening: Absolute Neutrophil Count (ANC) >/= 1.5 × 10^9/L. Platelets >/= 75 × 10^9/L. If the bone marrow contains >/= 50% plasma cells, a platelet count of >/= 50 × 10^9/L is allowed. 7. LVEF >/= 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available. 8. Adequate liver and renal function: Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) = 2.5 × the upper limit of normal (ULN). Bilirubin < 2.0 mg/dL. Serum creatinine = 2.5 mg/dL or a calculated creatinine clearance of at least 50 mL/min (using the Cockcroft and Gault method). 9. Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, ( those who are post menopausal for less than 1 year) must have negative serum or urine pregnancy test and agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Male patients, even if surgically sterilized (i.e., status postvasectomy), who: Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR Agree to completely abstain from heterosexual intercourse. 10. Understand and voluntarily signed informed consent. Exclusion Criteria: 1. Primary amyloidosis. 2. Treatment with an investigational product or device within 21 days of Cycle 1 Day 1. 3. History of allergic reaction/hypersensitivity to any of the study medications, their analogues or excipients in the various formulations. 4. Cytotoxic therapy or monoclonal antibodies within 21 days prior to Cycle 1 Day 1. 5. Radiotherapy within 21 days prior to Cycle 1 Day 1. However, if the radiation portal covered = 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy. 6. Major surgery within 14 days and minor surgery within 7 days prior to Cycle 1 Day 1. 7. Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to Cycle 1 Day 1. 8. Medical, psychiatric, cognitive or other conditions that compromise the patient's ability to understand the patient information, to give informed consent, to comply with the study protocol or to complete the study or, in the judgment of the Investigator, would make the patient inappropriate for study participation. 9. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) 10. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment 11. Patients who are eligible for autologous transplantation 12. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. 13. Myocardial infarction within four months prior to enrollment 14. Lactating women 15. Patients with known HIV seropositivity 16. Patients with active clinical infections
|Official title||A Phase I Study of Arry-520 and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma|
|Principal investigator||Robert Orlowski, MD, PHD|
|Description||Study Drugs: Carfilzomib, an investigational drug, is designed to keep cancer cells from repairing themselves. If the cancer cells cannot repair themselves, this may cause them to die. ARRY-520, an investigational drug, is designed to prevent cancer cells from reproducing. By preventing the tumor cells from reproducing, ARRY-520 may slow the spread of the cancer cells and may cause them to die. Dexamethasone is a steroid that causes myeloma cancer cells to die. Study Groups: If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 4 groups of 3-6 participants will be enrolled in Group 1A, and up to 28 total participants will be enrolled in Group 1B. There will be between 1 and 5 groups of 3-6 participants in Group 2A and up to 28 participants in Group 2B. Group 1A: If you are enrolled in Group 1A, the dose of ARRY-520 you receive will depend on when you joined this study. The first group of participants will receive the lowest dose levels of ARRY-520 . Each new group will receive a higher dose of ARRY-520 than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of ARRY-520 is found. Group 1B Expansion: If you are enrolled in Group 1B, you will receive ARRY-520 at the highest dose that was tolerated in Group 1A. Everyone in Group 1A and B will receive the same dose of carfilzomib. Group 2A: If you are enrolled in the Group 2A, the dose of carfilzomib you receive will depend on when you joined this study. The first group of participants will receive the lowest dose levels of carfilzomib. Each new group will receive a higher dose of carfilzomib than the group before it, if no intolerable side effects were seen. Sometimes, the new dose level for one drug will be raised, while the dose level for the other drug will be the same as the dose given to the earlier group. This will continue until the highest tolerable dose of carfilzomib is found. Group 2B Expansion: If you are enrolled in Group 2B, you will receive carfilzomib at the highest tolerated dose that was tolerated in Group 2A. You will also receive dexamethasone. Everyone in Group 2A and B will receive the highest tolerated dose of ARRY-520 that was found in Group 1. Group 2B patients may receive ARRY-520 either at the highest tolerated dose from Group 1 or one dose level lower. Study Drug Administration: Each study cycle is 28 days. On Days 1, 2, 8, 9, 15, and 16 of Cycles 1-8, you will receive carfilzomib by vein over about 10-30 minutes. On Days 1, 2, 15, and 16 of Cycles 1-8, you will receive ARRY-520 by vein over 1 hour. After 8 cycles, you may continue receiving carfilzomib on Days 1, 2, 15, and 16. If the doctor thinks it is in your best interest, you may also receive ARRY-520 on Days 1, 2, 15, and 16 or may continue with carfilzomib on Days 1, 2, 8, 9, 15, 16 and ARRY-520. On Day 1, 8, and 15 of each cycle, you will be given dexamethasone by mouth or vein to help prevent side effects. If it is by vein it will be over 10 minutes. You may also receive dexamethasone if you develop chills, rigors, fevers, or shortness of breath when carfilzomib is given. You may also receive filgrastim under the skin. This will begin on Day 3 or 4 and Day 17 or 18 of every cycle, and continue 1 time each day for 5-7 days. You will take an anti-viral drug (such as acyclovir, famciclovir, or valacyclovir) while on this study to help prevent side effects. Your doctor will explain how often you will need to take this anti-viral drug. You must be well hydrated while you are taking carfilzomib: - Starting 2 days before your first dose of carfilzomib, you must drink 6-8 cups (8 ounces each) of water each day. - If the doctor thinks it is needed, you may need to keep drinking 6-8 cups of water each day during Cycle 2 and beyond. - During every Cycle 1 dose, you will also be given fluids by vein for an hour after you receive the drug. Study Visits: At every study visit, you will be asked about side effects you may have had (such as numbness and/or tingling). On Day 1 of every cycle: - You will have a complete physical exam, including measurement of your vital signs, height, and weight. - Your performance status will be recorded. - Blood (about 2 teaspoons) will be drawn for routine tests and to check the status of the disease. The routine blood draw will also include a pregnancy test if you are able to become pregnant. A urine test may also be used rather than the blood test to check for pregnancy. - Blood (about 1 tablespoon) and urine will be collected to check the status of the disease. This urine will be collected over a 24-hour period. You will be given a container for urine collection. On Days 8, 15, and 22 of Cycle 1, blood (about 2 teaspoons) will be drawn for routine tests. On Day 8 and 15 of Cycles 2 and beyond, blood (about 2 teaspoons) will be drawn for routine tests. Length of Study: You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. Your participation on the study will be over once you have completed the end-of-dosing visit. Leftover blood and tissue will be stored in a research tissue bank at MD Anderson for use in future research related to cancer. Before your samples can be used for research, the researchers must get approval from the Institutional Review Board (IRB) of MD Anderson. The IRB is a committee of doctors, researchers, and community members. The IRB is responsible for protecting study participants and making sure all research is safe and ethical. Your samples will be given a code number. No identifying information will be directly linked to your samples. Only the researcher in charge of the bank will have access to the code numbers and be able to link the samples to you. This is to allow medical data related to the samples to be updated as needed. End-of-Dosing Visit: Within 30 days after you stop taking the study drugs, you will have an end-of-dosing visit. At this visit, the following tests and procedures will be performed: - You will have a physical exam. - Blood (about 1-2 teaspoons) and urine will be collected for routine tests. - You will be asked about any drugs you may be taking and any side effects or symptoms (such as numbness and/or tingling) that you may have. - Blood (about 4 tablespoons) and urine will be collected to check the status of the disease. This urine will be collected over a 24-hour period. You will be given a container for urine collection. - If your doctor thinks it is needed, you will have a bone marrow aspiration and/or biopsy to check the status of the disease. - Blood (about 4 teaspoons) will be drawn for genetic biomarker testing. This is an investigational study. ARRY-520 is not FDA approved or commercially available. It is currently being used for research purposes only. Carfilzomib is FDA approved and commercially available for the treatment of certain types of multiple myeloma. Its use in this study is investigational. Up to 76 participants will take part in this study. All will be enrolled at MD Anderson.|
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