Clinical Trials /

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

NCT03795597

Description:

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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT03795597

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 209274
  • NCT ID: NCT03795597

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
CarfilzomibKyprolisCarfilzomib IV at dose: 20 mg/m2
Busulfan IVBusulfexCarfilzomib IV at dose: 20 mg/m2
Melphalan IVAlkeranCarfilzomib IV at dose: 20 mg/m2

Purpose

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

      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.

Trial Arms

NameTypeDescriptionInterventions
Carfilzomib IV at dose: 20 mg/m2ExperimentalThe 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.
  • Carfilzomib
  • Busulfan IV
  • Melphalan IV
Carfilzomib IV at dose: 27 mg/m2ExperimentalThe 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.
  • Carfilzomib
  • Busulfan IV
  • Melphalan IV
Carfilzomib IV at dose: 36 mg/m2ExperimentalThe 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.
  • Carfilzomib
  • Busulfan IV
  • Melphalan IV
Carfilzomib IV at dose: 45 mg/m2ExperimentalThe 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.
  • Carfilzomib
  • Busulfan IV
  • Melphalan IV
Carfilzomib IV at dose: 56 mg/m2ExperimentalThe 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.
  • Carfilzomib
  • Busulfan IV
  • Melphalan IV

Eligibility 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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:36 participants evaluated for safety with treatment-related adverse events and grading by using CTCAE v4.0.
Time Frame:3 years
Safety Issue:
Description: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

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Loyola University

Trial Keywords

  • Multiple Myeloma
  • Autologous
  • Stem Cell Transplantation
  • Bone Marrow Transplant
  • Carfilzomib

Last Updated

April 26, 2021