Busulfan, Melphalan, Escalating Carfilzomib Conditioning Auto Stem Cell Transplantation for Multiple Myeloma (MM)

Study Overview
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Brief Summary
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In this protocol, the investigators hypothesize that the combination of intravenous busulfan and melphalan with carfilzomib will be an effective preparative regimen with acceptable toxicity for participants with multiple myeloma who are candidates for autologous stem cell transplantation. To test this hypothesis, the investigators designed a phase I/II trial combining IV busulfan 130 mg/m2 plus melphalan 140 mg combined with escalating doses of carfilzomib ranging from 20 mg/m2 to 45 mg/m2. These results will be compared with the center's historical controls of participants treated with melphalan, busulfan and bortezomib.

Detailed Description
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Participants enrolled in this study protocol will receive daily intravenous (IV) infusions of carfilzomib for a total of 4 days (Day-9, -8 and Days -2, -1). The first two daily infusions will be given at a fixed dose of 20 mg/m2 and the final two doses will be escalated from the standard dose of 27 mg/m2 to 56 mg/m2 in a Phase I design, based on toxicity. The busulfan will be administered for 2 days over 3 hours from D-7, -6, at 130 mg/m2 . This dose was found to be safe and equivalent to the standard daily dose of 3.2 mg/kg. The 3rd and 4th daily doses of IV Busulfan will be adjusted in order to yield a systemic plasma drug exposure represented by a daily area under the plasma concentration versus time curve (AUC) of approximately 5,000 millimoles-minute per dose (mM-min). These targeted plasma concentration of IV busulfan will be based on pharmacokinetics studies performed during the first day of IV busulfan. Melphalan will be given at a dose of 140 mg/m2 on Day -3. Each cohort will start with a goal of accruing three patients to determine the dose limiting toxicity.

Official Title
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Phase I/II Study Utilizing High Dose Busulfan and Melphalan With Escalating Carfilzomib as Conditioning in Autologous Peripheral Blood Stem Cell Transplantation for Patients With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Busulfan IV
* Drug: Melphalan IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be greater than or equal to 18 years of age. Participants must have been diagnosed with multiple myeloma in a first or subsequent remission and have undergone a successful pre-transplant work up and are otherwise eligible for an autotransplant with a busulfan/melphalan preparative regimen at Loyola University Medical Center. Participants may receive this preparative regimen if in first or subsequent remission. Participants may enter if they have received a prior autologous stem cell transplant and this therapy produced a remission that lasted greater than 18 months before progression of disease. Participants who have undergone prior allogeneic transplantation are excluded. All participants must have responsive disease as defined by a Partial Response or greater to most recent conventional regimen. Participants receiving prior carfilzomib will be eligible for inclusion provided they demonstrated responsive disease to this agent and either had a remission that lasted greater than 6 months after its discontinuance, or if in remission after a carfilzomib containing regimen administered to qualify for transplant. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) less than or equal to 2. Acceptable heart function test. Exclusion Criteria: Participants must not have below normal kidney function. Participants must not have below normal liver function. Participants must not have active bacterial, fungal, or viral infection. Participants must not have severe lung function. Participants must not have Grade 2 or greater peripheral neuropathy. Participants must not have uncontrolled hypertension.

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: Busulfan IV over 3 hours every 24 hours for a total of 4 doses from D-6 to D-3. First two daily infusions will be given at a fixed dose of 3.2 mg/kg over 3 hours from D-6 to D-5. The 3rd and 4th daily doses will be adjusted to an AUC of approximately 5,000 mMol-min per dose. Melphalan 140 mg/ m2 IV over 15-30 minutes for one dose on day -3. Carfilzomib administration will follow a Phase I dose escalation design. Each cohort will start with a goal of accruing three patients to determine the dose limiting toxicities. Once the Maximum Tolerated Dose is established an expansion cohort will be treated to include a total of 10 additional patients.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib IV at dose: 20 mg/m2<br>The participants will receive Carfilzomib IV at dose: 20 mg/m2 on days -9 and -8 over 30 minutes. The participant will receive Busulfan IV over 3 hours every 24 hours for a total of 4 doses from Day -6 to Day -3 and Melphalan IV over 15-30 minutes for one dose on day -3.The participants will receive stem cell infusion on Day 0 and Granulocyte-Colony stimulating factor (G-CSF) given daily until engraftment occurs. | Drug: Carfilzomib<br>* Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.<br>* Other names: Kyprolis;Drug: Busulfan IV<br>* Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Busulfex;Drug: Melphalan IV<br>* Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Alkeran;|
| Experimental: Carfilzomib IV at dose: 27 mg/m2<br>The participants will receive Carfilzomib IV at dose: 27 mg/m2 on days -9 and -8 over 30 minutes. The participant will receive Busulfan IV over 3 hours every 24 hours for a total of 4 doses from Day -6 to Day -3 and Melphalan IV over 15-30 minutes for one dose on day -3.The participants will receive stem cell infusion on Day 0 and G-CSF given daily until engraftment occurs. | Drug: Carfilzomib<br>* Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.<br>* Other names: Kyprolis;Drug: Busulfan IV<br>* Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Busulfex;Drug: Melphalan IV<br>* Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Alkeran;|
| Experimental: Carfilzomib IV at dose: 36 mg/m2<br>The participants will receive Carfilzomib IV at dose: 36 mg/m2 on days -9 and -8 over 30 minutes. The participant will receive Busulfan IV over 3 hours every 24 hours for a total of 4 doses from Day -6 to Day -3 and Melphalan IV over 15-30 minutes for one dose on day -3.The participants will receive stem cell infusion on Day 0 and G-CSF given daily until engraftment occurs. | Drug: Carfilzomib<br>* Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.<br>* Other names: Kyprolis;Drug: Busulfan IV<br>* Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Busulfex;Drug: Melphalan IV<br>* Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Alkeran;|
| Experimental: Carfilzomib IV at dose: 45 mg/m2<br>The participants will receive Carfilzomib IV at dose: 45 mg/m2 on days -9 and -8 over 30 minutes. The participant will receive Busulfan IV over 3 hours every 24 hours for a total of 4 doses from Day -6 to Day -3 and Melphalan IV over 15-30 minutes for one dose on day -3.The participants will receive stem cell infusion on Day 0 and G-CSF given daily until engraftment occurs. | Drug: Carfilzomib<br>* Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.<br>* Other names: Kyprolis;Drug: Busulfan IV<br>* Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Busulfex;Drug: Melphalan IV<br>* Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Alkeran;|
| Experimental: Carfilzomib IV at dose: 56 mg/m2<br>The participants will receive Carfilzomib IV at dose: 56 mg/m2 on days -9 and -8 over 30 minutes. The participant will receive Busulfan IV over 3 hours every 24 hours for a total of 4 doses from Day -6 to Day -3 and Melphalan IV over 15-30 minutes for one dose on day -3.The participants will receive stem cell infusion on Day 0 and G-CSF given daily until engraftment occurs. | Drug: Carfilzomib<br>* Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.<br>* Other names: Kyprolis;Drug: Busulfan IV<br>* Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Busulfex;Drug: Melphalan IV<br>* Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.<br>* Other names: Alkeran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 36 participants evaluated for safety with treatment-related adverse events and grading by using CTCAE v4.0. | To determine the maximal tolerated dose of carfilzomib when added to busulfan and melphalan as a preparative regimen for high dose therapy with autologous hematopoietic transplantation for patients with multiply myeloma. | 3 years | 
| 36 participants evaluated for tolerability with treatment-related adverse events and grading by using CTCAE v4.0. | To determine the maximal tolerated dose of carfilzomib when added to busulfan and melphalan as a preparative regimen for high dose therapy with autologous hematopoietic transplantation for patients with multiply myeloma. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 36 participants evaluated for response to treatment by testing blood for multiple myeloma levels. | To evaluate complete, very good partial, partial and stable disease response rate for both clinical and biologic endpoints. | 100 days | 
| 36 participants evaluated for progression by testing blood for multiple myeloma levels. | Progression Free Survival | 3 years | 
| 36 participants evaluated for overall survival by clinical visit or contact by phone. | Overall Survival | 3 years | 
| 36 participants evaluated for absolute neutrophil count by testing white blood cells levels. | Days to neutrophil engraftment: Absolute neutrophil count > 500/microliter | 100 days | 
| 36 participants evaluated for platelet engraftment by testing platelet count in blood cells. | Days to platelet engraftment: platelet count > 20,000/microliter untransfused | 100 days | 
| 36 participants evaluated by oral exam to assess mucositis events and grading levels by using CTCAE v4.0. | Mucositis: CTCAE v 4.0 grade and severity | 100 days | 
| 36 participants evaluated by the liver to assess Veno-occlusive disease and grading levels by using CTCAE v4.0. | Veno-occlusive disease | 100 days | 
| 36 participants evaluated by a physical exam to assess peripheral neuropathy and grading by using CTCAE v4.0. | Peripheral neuropathy greater than or equal to CTCAE V 4.0 Grade 3 | 3 years | 
| 36 participants evaluated for response to treatment by testing urine for multiple myeloma levels. | To evaluate complete, very good partial, partial no stable disease response rate for both clinical and biologic endpoints | 100 days | 
| 36 participants evaluated for progression by testing urine for multiple myeloma levels. | Progression Free Survival | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Autologous, Stem Cell Transplantation, Bone Marrow Transplant, Carfilzomib