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

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ClinicalTrials.gov Identifier: NCT03795597
Recruitment Status : Recruiting
First Posted : January 8, 2019
Last Update Posted : August 20, 2019
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
Patrick Stiff, Loyola University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Carfilzomib Drug: Busulfan IV Drug: Melphalan IV Phase 1 Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : May 22, 2019
Estimated Primary Completion Date : November 1, 2022
Estimated Study Completion Date : November 1, 2023


Arm Intervention/treatment
Experimental: Carfilzomib IV at dose: 20 mg/m2
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
Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.
Other Name: Kyprolis

Drug: Busulfan IV
Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.
Other Name: Busulfex

Drug: Melphalan IV
Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.
Other Name: Alkeran

Experimental: Carfilzomib IV at dose: 27 mg/m2
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
Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.
Other Name: Kyprolis

Drug: Busulfan IV
Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.
Other Name: Busulfex

Drug: Melphalan IV
Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.
Other Name: Alkeran

Experimental: Carfilzomib IV at dose: 36 mg/m2
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
Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.
Other Name: Kyprolis

Drug: Busulfan IV
Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.
Other Name: Busulfex

Drug: Melphalan IV
Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.
Other Name: Alkeran

Experimental: Carfilzomib IV at dose: 45 mg/m2
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
Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.
Other Name: Kyprolis

Drug: Busulfan IV
Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.
Other Name: Busulfex

Drug: Melphalan IV
Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.
Other Name: Alkeran

Experimental: Carfilzomib IV at dose: 56 mg/m2
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
Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.
Other Name: Kyprolis

Drug: Busulfan IV
Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.
Other Name: Busulfex

Drug: Melphalan IV
Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.
Other Name: Alkeran




Primary Outcome Measures :
  1. 36 participants evaluated for safety with treatment-related adverse events and grading by using CTCAE v4.0. [ Time Frame: 3 years ]
    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.

  2. 36 participants evaluated for tolerability with treatment-related adverse events and grading by using CTCAE v4.0. [ Time Frame: 3 years ]
    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.


Secondary Outcome Measures :
  1. 36 participants evaluated for response to treatment by testing blood for multiple myeloma levels. [ Time Frame: 100 days ]
    To evaluate complete, very good partial, partial and stable disease response rate for both clinical and biologic endpoints.

  2. 36 participants evaluated for progression by testing blood for multiple myeloma levels. [ Time Frame: 3 years ]
    Progression Free Survival

  3. 36 participants evaluated for overall survival by clinical visit or contact by phone. [ Time Frame: 3 years ]
    Overall Survival

  4. 36 participants evaluated for absolute neutrophil count by testing white blood cells levels. [ Time Frame: 100 days ]
    Days to neutrophil engraftment: Absolute neutrophil count > 500/microliter

  5. 36 participants evaluated for platelet engraftment by testing platelet count in blood cells. [ Time Frame: 100 days ]
    Days to platelet engraftment: platelet count > 20,000/microliter untransfused

  6. 36 participants evaluated by oral exam to assess mucositis events and grading levels by using CTCAE v4.0. [ Time Frame: 100 days ]
    Mucositis: CTCAE v 4.0 grade and severity

  7. 36 participants evaluated by the liver to assess Veno-occlusive disease and grading levels by using CTCAE v4.0. [ Time Frame: 100 days ]
    Veno-occlusive disease

  8. 36 participants evaluated by a physical exam to assess peripheral neuropathy and grading by using CTCAE v4.0. [ Time Frame: 3 years ]
    Peripheral neuropathy greater than or equal to CTCAE V 4.0 Grade 3

  9. 36 participants evaluated for response to treatment by testing urine for multiple myeloma levels. [ Time Frame: 100 days ]
    To evaluate complete, very good partial, partial no stable disease response rate for both clinical and biologic endpoints

  10. 36 participants evaluated for progression by testing urine for multiple myeloma levels. [ Time Frame: 3 years ]
    Progression Free Survival



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03795597


Contacts
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Contact: Patrick Stiff, MD 708-327-3148 mailto:pstiff@lumc.edu
Contact: Mary Lee, RN 708-327-2241 mailto:mlee@luc.edu

Locations
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United States, Illinois
Loyola University Medical Center Recruiting
Maywood, Illinois, United States, 60153
Contact: Patrick Stiff, MD    708-327-3148    pstiff@lumc.edu   
Contact: Mary Lee, RN    708-327-2241    mlee@luc.edu   
Sponsors and Collaborators
Loyola University
Amgen
Investigators
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Principal Investigator: Patrick Stiff, MD Loyola University
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Responsible Party: Patrick Stiff, Principal Investigator, Loyola University
ClinicalTrials.gov Identifier: NCT03795597    
Other Study ID Numbers: 209274
First Posted: January 8, 2019    Key Record Dates
Last Update Posted: August 20, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Patrick Stiff, Loyola University:
Multiple Myeloma
Autologous
Stem Cell Transplantation
Bone Marrow Transplant
Carfilzomib
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Melphalan
Busulfan
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs