Carfilzomib Based Chemotherapy Mobilization for Autologous Stem Cell Transplants in Multiple Myeloma

Study Overview
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Brief Summary
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This phase I study utilizes a 3+3 design with escalating cohorts of Carfilzomib at 20mg/m2, 27mg/m2, 36mg/m2, 45mg/m2, 56mg/m2, and 70mg/m2 to be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone and Granulocyte colony-stimulating factor (G-CSF)

Detailed Description
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This study will be conducted as an open-label Phase I, single-center study in which subjects will receive carfilzomib, in combination cyclophosphamide and dexamethasone, for mobilization of peripheral blood stem cells. Study treatment will be administered in sequential cohorts, with three to six subjects in each cohort. Following induction therapy, eligible patients will complete screening procedures. Treatment will consist of Dexamethasone 40mg IV/PO to be administered as a premedication. Carfilzomib dosed at each respective cohort level to be administered over 30 minutes followed by Cyclophosphamide dosed at 2gm/m2 administered over 1 hour. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing. On day 7 subjects will initiate high dose G-CSF injections at 14mcg/kg daily (with a cap of 1440mcg daily). On day 12 peripheral blood stem cell collection will begin per institutional protocol. After successful peripheral blood stem cell mobilization, patients will proceed to a melphalan based autologous stem cell transplant. Patients will have disease parameters assessed monthly after the transplant.

Official Title
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Phase I Study of Carfilzomib-based Chemotherapy Mobilization for Autologous Stem Cell Transplantation in Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Cyclophosphamide
* Drug: Dexamethasone
* Drug: Granulocyte Colony-Stimulating Factor


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Subject has voluntarily agreed to participate by giving written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Informed Consent must be obtained prior to mobilization. Subject has a confirmed diagnosis of multiple myeloma as specified by the International Myeloma Working Group criteria and must have measurable disease as defined by at least one of the following criteria: Serum monoclonal protein ≥ 0.5 g/dL ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis Serum immunoglobulin free light chain: involved FLC ≥ 10 mg/dL (≥ 100 mg/L) AND abnormal serum immunoglobulin kappa to lambda free light chain ratio Subject is ≥18 years of age at the time of signing the informed consent form. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of < 2. Subjects must have measurable monoclonal protein, free light chains, and/or M-spike in blood or urine. Subjects must have completed any induction therapyand have achieved less than a complete response (CR). Subject has a life expectancy of >12 weeks. Absolute neutrophil count (ANC) ≥1000 cells/mm3 (≥500 for patients with bone marrow biopsy displaying >50% involvement by myeloma) Platelets count ≥ 50,000/mm3 (≥ 30,000 for patients with bone marrow biopsy displaying >50% involvement by myeloma) Hemoglobin > 9.0 g/dL Serum SGOT/AST <3.0 x upper limits of normal (ULN) Serum SGPT/ALT <3.0 x upper limits of normal (ULN) Serum total bilirubin <1.5 x ULN Subject must have a MUGA scan or echo with LVEF >50% within 6 months of enrollment. Females of childbearing potential (FCBP) must have a negative serum pregnancy test should be done within 7 days of treatment initiation and a negative urine pregnancy test within the 24 hours prior to the first study drug administration FCBP and male subjects who are sexually active with FCBP must agree to use 2 highly effective concomitant methods of contraception including a male condom during the study and for 90 days following the last dose of study treatment Male subjects must agree to not donate sperm while taking carfilzomib and for 90 days after the last dose of carfilzomib. EXCLUSION CRITERIA Subject has a history of allergic reactions to compounds containing captisol, or Carfilzomib Subject has a NYHA Class III or IV heart disease and/or a history of active unstable angina, congestive heart disease, severe uncontrolled cardiac arrhythmia, electrocardiographic evidence of acute ischemia, active conduction system abnormalities or myocardial infarction within 6 months prior to enrollment. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant. Uncontrolled hypertension Pulmonary hypertension Subject has a known HIV or hepatitis A, B, or C positivity---ONLY IF ACTIVE Subject has active viral or bacterial infections or any coexisting medical problem that would significantly increase the risks of this treatment program. Subject has concurrent, uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place him/her at unacceptable risk, including, but not limited to, uncontrolled hypertension, uncontrolled diabetes, active uncontrolled infection, and/or acute chronic liver disease (i.e., hepatitis, cirrhosis). Subject has ≥Grade 2 peripheral neuropathy. Subject has been 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. Subject has received radiation therapy within 3 weeks of enrollment Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy. Subject has had prior mobilization or stem cell transplant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This phase I study utilizes a 3+3 design with escalating cohorts of Carfilzomib at 20mg/m2, 27mg/m2, 36mg/m2, 45mg/m2, 56mg/m2, and 70mg/m2 to be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone and G-CSF
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib Mobilization - Dose Level 0<br>Carfilzomib at 20mg/m2 over 10 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing. | Drug: Carfilzomib<br>* Carfilzomib will be administered over 10 minutes for the 20 mg/m2 and 27 mg/m2 dose and over 30 minutes for all higher doses.<br>* Other names: Kyprolis;Drug: Cyclophosphamide<br>* Cyclophosphamide dosed at 2gm/m2 administered over 1 hour.<br>* Other names: Cytoxan;Drug: Dexamethasone<br>* Dexamethasone 40mg IV/PO to be administered as a premedication.<br>* Other names: Decadron;Drug: Granulocyte Colony-Stimulating Factor<br>* On day 7 subjects will initiate high dose G-CSF injections at 14mcg/kg daily (with a cap of 1440mcg daily).<br>* Other names: Neupogen;|
| Experimental: Carfilzomib Mobilization - Dose Level 1<br>Carfilzomib at 27mg/m2 over 10 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing. | Drug: Carfilzomib<br>* Carfilzomib will be administered over 10 minutes for the 20 mg/m2 and 27 mg/m2 dose and over 30 minutes for all higher doses.<br>* Other names: Kyprolis;Drug: Cyclophosphamide<br>* Cyclophosphamide dosed at 2gm/m2 administered over 1 hour.<br>* Other names: Cytoxan;Drug: Dexamethasone<br>* Dexamethasone 40mg IV/PO to be administered as a premedication.<br>* Other names: Decadron;Drug: Granulocyte Colony-Stimulating Factor<br>* On day 7 subjects will initiate high dose G-CSF injections at 14mcg/kg daily (with a cap of 1440mcg daily).<br>* Other names: Neupogen;|
| Experimental: Carfilzomib Mobilization - Dose Level 2<br>Carfilzomib at 36mg/m2 over 30 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing. | Drug: Carfilzomib<br>* Carfilzomib will be administered over 10 minutes for the 20 mg/m2 and 27 mg/m2 dose and over 30 minutes for all higher doses.<br>* Other names: Kyprolis;Drug: Cyclophosphamide<br>* Cyclophosphamide dosed at 2gm/m2 administered over 1 hour.<br>* Other names: Cytoxan;Drug: Dexamethasone<br>* Dexamethasone 40mg IV/PO to be administered as a premedication.<br>* Other names: Decadron;Drug: Granulocyte Colony-Stimulating Factor<br>* On day 7 subjects will initiate high dose G-CSF injections at 14mcg/kg daily (with a cap of 1440mcg daily).<br>* Other names: Neupogen;|
| Experimental: Carfilzomib Mobilization - Dose Level 3<br>Carfilzomib at 45mg/m2 over 30 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing. | Drug: Carfilzomib<br>* Carfilzomib will be administered over 10 minutes for the 20 mg/m2 and 27 mg/m2 dose and over 30 minutes for all higher doses.<br>* Other names: Kyprolis;Drug: Cyclophosphamide<br>* Cyclophosphamide dosed at 2gm/m2 administered over 1 hour.<br>* Other names: Cytoxan;Drug: Dexamethasone<br>* Dexamethasone 40mg IV/PO to be administered as a premedication.<br>* Other names: Decadron;Drug: Granulocyte Colony-Stimulating Factor<br>* On day 7 subjects will initiate high dose G-CSF injections at 14mcg/kg daily (with a cap of 1440mcg daily).<br>* Other names: Neupogen;|
| Experimental: Carfilzomib Mobilization - Dose Level 4<br>Carfilzomib at 56mg/m2 over 30 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing. | Drug: Carfilzomib<br>* Carfilzomib will be administered over 10 minutes for the 20 mg/m2 and 27 mg/m2 dose and over 30 minutes for all higher doses.<br>* Other names: Kyprolis;Drug: Cyclophosphamide<br>* Cyclophosphamide dosed at 2gm/m2 administered over 1 hour.<br>* Other names: Cytoxan;Drug: Dexamethasone<br>* Dexamethasone 40mg IV/PO to be administered as a premedication.<br>* Other names: Decadron;Drug: Granulocyte Colony-Stimulating Factor<br>* On day 7 subjects will initiate high dose G-CSF injections at 14mcg/kg daily (with a cap of 1440mcg daily).<br>* Other names: Neupogen;|
| Experimental: Carfilzomib Mobilization - Dose Level 5<br>Carfilzomib at 70mg/m2 over 30 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing. | Drug: Carfilzomib<br>* Carfilzomib will be administered over 10 minutes for the 20 mg/m2 and 27 mg/m2 dose and over 30 minutes for all higher doses.<br>* Other names: Kyprolis;Drug: Cyclophosphamide<br>* Cyclophosphamide dosed at 2gm/m2 administered over 1 hour.<br>* Other names: Cytoxan;Drug: Dexamethasone<br>* Dexamethasone 40mg IV/PO to be administered as a premedication.<br>* Other names: Decadron;Drug: Granulocyte Colony-Stimulating Factor<br>* On day 7 subjects will initiate high dose G-CSF injections at 14mcg/kg daily (with a cap of 1440mcg daily).<br>* Other names: Neupogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Safety and tolerability will be assessed by clinical review of all relevant parameters including Adverse Events (CTCAE v4.0) | 24 Months | 
| Maximum tolerated dose (MTD) | To determine the maximum tolerated dose (MTD) of carfilzomib in combination with cyclophosphamide, dexamethasone and G-CSF in mobilizing and collecting peripheral blood stem cells | 28 Days |