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UARK 2012-02 Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission

Primary Purpose

Multiple Myeloma

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

myPRS

Induction 1 - MEL-10+CFZ-TD-PACE

First Transplant - MEL-80+CFZ-TD-PACE + PBSC (biologic)

Inter-Therapy - MEL-20+CFZ-TD-PACE (75%)

Second Transplant - MEL-80+CFZ-TD-PACE + PBSC (biologic)

Consolidation - CFZ-TD-PACE

Maintenance - CFZ-R(T)-D

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring High-Risk, Carfilzomib

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must have newly diagnosed active MM requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy.
Patients must be either untreated or have not had more than one cycle of systemic MM therapy, excluding bisphosphonates and localized radiation.
Participants must have high-risk disease, as defined by GEP70 risk score of ≥ 0.66
Zubrod ≤ 2, unless solely due to symptoms of MM-related bone disease.
Patients must have a platelet count of ≥ 50,000/μL, unless lower levels are explained by extensive bone marrow plasmacytosis.
Patients must be at least 18 years of age and not older than 75 years of age at the time of registration.
Participants must have preserved renal function as defined by a serum creatinine level of < 3 mg/dL.
Participants must have an ejection fraction by ECHO or MUGA scan ≥ 45%
Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted. If the patient is unable to complete pulmonary function tests due to MM related pain or condition, exception may be granted if the principal investigator documents that the patient is a candidate for high dose therapy.
Patients must have signed an IRB-approved informed consent indicating their understanding of the proposed treatment and understanding that the protocol has been approved by the IRB.

Exclusion Criteria:

Does not have high-risk disease
Poorly controlled hypertension, diabetes mellitus, or other serious medical illness or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
Patients must not have prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has not received treatment for one year prior to enrollment. Other cancers will only be acceptable if the patient's life expectancy exceeds five years.
Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration. Subjects of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

Sites / Locations

University of Arkansas for Medical Sciences

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Total Therapy 5b

Arm Description

Induction, optional bridging, first transplant, optional bridging, inter-therapy, optional bridging, second transplant, optional bridging, consolidation, maintenance

Outcomes

Primary Outcome Measures

The Remission Rate for Participants With High-risk Myeloma

Toward improving the clinical outcomes of research subjects with high-risk MM (HR-MM) in the context of the immediately preceding TT5 trial 2008-02 and TT3 trials 2003-33 and 2006-66, TT5B will attempt to accelerate and sustain, at 2 years from starting therapy, the proportion of subjects in complete remission (AS-CR-2) by reducing host-imposed toxicity and thus facilitating timely completion of highly synergistic 8-drug combination therapy, including the next generation proteasome inhibitor, Carfilzomib (CFZ). This will result in avoiding MM re-growth that, we postulate, ensued in TT3 during recovery phases from severe de-conditioning. Furthermore, we speculate that the incidence of positive minimal residual disease (MRD) will be reduced with the addition of one cycle of consolidation therapy.

Secondary Outcome Measures

Full Information

NCT ID

NCT02128230

First Posted

April 29, 2014

Last Updated

May 28, 2021

Sponsor

University of Arkansas

Collaborators

Amgen

1. Study Identification

Unique Protocol Identification Number

NCT02128230

Brief Title

UARK 2012-02 Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission

Official Title

A Phase II Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission (AS-CR) by Applying Non-Host-Exhausting and Timely Dose-Reduced Mel-80-CFZ-TD-Pace Transplant(s) With Interspersed Mel-20-CFZ-TD-Pace With CFZ-RD and CFZ-D Maintenance

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Terminated

Why Stopped

Low enrollment and Futility as determined by Amgen's Carfilzomib NASCR program.

Study Start Date

June 10, 2014 (Actual)

Primary Completion Date

February 19, 2019 (Actual)

Study Completion Date

February 19, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Arkansas

Collaborators

Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to improve the clinical outcomes of research subjects with high-risk multiple myeloma in the context of the immediately preceding Total therapy 5 trial 2008-02 and Total therapy 3 trials 2003-33 and 2006-66.

Detailed Description

Total therapy 5B will attempt to accelerate and sustain, at 2 years from starting therapy, the proportion of subjects in complete remission by reducing host-imposed toxicity and facilitating timely completion of highly synergistic 8-drug combination therapy, including the next generation proteasome inhibitor, Carfilzomib. This will result in avoiding multiple myeloma re-growth that, we postulate, ensued in Total therapy 3 during recovery phases from severe de-conditioning. It is speculated that the incidence of positive minimal residual disease will be reduced with the addition of one cycle of consolidation therapy. The following approach will be implemented: apply a 4-day fractionated lower dose melphalan (80 mg/m2) together with CFZ-TD-PACE regimen in MEL80-CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE as a hopefully less toxic and more effective transplant regimen interspersed with 1 cycle of non-transplant supported MEL-20-CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE (in lower doses than with transplant) inter-therapy (reduced from two cycles due to prolonged thrombocytopenia) followed by CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE consolidation therapy post transplant #2 CFZ-RD (carfilzomib, lenalidomide and dexamethasone) maintenance for 1 year followed by CFZ-D for an additional year

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Myeloma

Keywords

High-Risk, Carfilzomib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Total Therapy 5b

Arm Type

Experimental

Arm Description

Induction, optional bridging, first transplant, optional bridging, inter-therapy, optional bridging, second transplant, optional bridging, consolidation, maintenance

Intervention Type

Device

Intervention Name(s)

myPRS

Other Intervention Name(s)

Gep70

Intervention Description

Genome expression profiling used to identify high-risk and low-risk multiple myeloma

Intervention Type

Drug

Intervention Name(s)

Induction 1 - MEL-10+CFZ-TD-PACE

Other Intervention Name(s)

Melphalan (Alkeran™), Carfilzomib (Kyprolis®), Thalidomide (Thalomid®), Dexamethasone (Decadron®), Cisplatin (CDDP) (Platinol®), Doxorubicin (Adriamycin®), Cyclophosphamide (Cytoxan®), Etoposide (VP-16) (Vepesid®), Granulocyte colony-stimulating factor (G-CSF), filgrastim (Neupogen®)

Intervention Description

Melphalan (MEL) and Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and Dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), Adriamycin (A), Cyclophosphamide (C) and Etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. After completion of the continuous chemotherapy, Granulocyte colony-stimulating factor (G-CSF), a shot just under the skin to help the bone marrow and blood counts recover more quickly after chemotherapy, will be given. Regimen: CFZ 20 mg/m2 on days 1, 5, & 6; MEL 10mg/m2 on day 3; T 200 mg/d, D 40 mg/d, P 10 mg/m2/d, A 10 mg/m2/d, C 400 mg/m2/d, and E 40 mg/m2/d on days 5-8; G-CSF 10 mcg/kg/day from day 11 through end of Peripheral Blood Stem Cell (PBSC) collection. Optional Bridging with T 50 mg/d and D 20 mg on day 1-4 every 21 days until 1st transplant.

Intervention Type

Drug

Intervention Name(s)

First Transplant - MEL-80+CFZ-TD-PACE + PBSC (biologic)

Other Intervention Name(s)

Autologous Peripheral Blood Stem Cell Transplant, Melphalan (Alkeran™), Carfilzomib (Kyprolis®), Thalidomide (Thalomid®), Dexamethasone (Decadron®), Cisplatin (CDDP) (Platinol®), Doxorubicin (Adriamycin®), Cyclophosphamide (Cytoxan®), Etoposide (VP-16) (Vepesid®)

Intervention Description

Melphalan (MEL) and Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and Dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), Adriamycin (A), Cyclophosphamide (C) and Etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. After completion of the continuous chemotherapy, Granulocyte colony-stimulating factor (G-CSF), a shot just under the skin to help the bone marrow and blood counts recover more quickly after chemotherapy, will be given. Regimen: CFZ 20 mg/m2 on days -5 & -4; MEL 20 mg/m2/d, T 200 mg/d, D 40 mg/d, P 10 mg/m2/d, A 10 mg/m2/d, C 100 mg/m2/d, and E 80 mg/m2/d on days -5 & -2; PBSC transplant on day 0. Optional Bridging with T 50 mg/d and D 20 mg on day 1-4 every 21 days until inter-therapy.

Intervention Type

Drug

Intervention Name(s)

Inter-Therapy - MEL-20+CFZ-TD-PACE (75%)

Other Intervention Name(s)

Intervention Description

Melphalan (MEL) and Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and Dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), Adriamycin (A), Cyclophosphamide (C) and Etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. After completion of the continuous chemotherapy, Granulocyte colony-stimulating factor (G-CSF), a shot just under the skin to help the bone marrow and blood counts recover more quickly after chemotherapy, will be given. Regimen: CFZ 27 mg/m2 on days 1-2; MEL 5 mg/m2/d, T 200 mg/d, D 20 mg/d, P 7.5 mg/m2/d, A 7.5 mg/m2/d, C 75 mg/m2/d, and E 60 mg/m2/d on days 1-4. Optional Bridging with T 50 mg/d and D 20 mg on day 1-4 every 21 days until 2nd transplant.

Intervention Type

Drug

Intervention Name(s)

Second Transplant - MEL-80+CFZ-TD-PACE + PBSC (biologic)

Other Intervention Name(s)

Intervention Description

Melphalan (MEL) and Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and Dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), Adriamycin (A), Cyclophosphamide (C) and Etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. After completion of the continuous chemotherapy, Granulocyte colony-stimulating factor (G-CSF), a shot just under the skin to help the bone marrow and blood counts recover more quickly after chemotherapy, will be given. Regimen: CFZ 20 mg/m2 on days -5 & -4; MEL 20 mg/m2/d, T 200 mg/d, D 40 mg/d, P 10 mg/m2/d, A 10 mg/m2/d, C 100 mg/m2/d, and E 80 mg/m2/d on days -5 & -2; PBSC transplant on day 0. Optional Bridging with T 50mg/d and D 20 mg on day 1-4 every 21 days until consolidation.

Intervention Type

Drug

Intervention Name(s)

Consolidation - CFZ-TD-PACE

Other Intervention Name(s)

Carfilzomib (Kyprolis®), Thalidomide (Thalomid®), Dexamethasone (Decadron®), Cisplatin (CDDP) (Platinol®), Doxorubicin (Adriamycin®), Cyclophosphamide (Cytoxan®), Etoposide (VP-16) (Vepesid®)

Intervention Description

Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), adriamycin (A), cyclophosphamide (C) and etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. Regimen: CFZ 27 mg/m2 on days 1-2; T 200 mg/d, D 40 mg/d, P 7.5 mg/m2/d, A 7.5 mg/m2/d, C 300 mg/m2/d, and E 30 mg/m2/d on days 1-4.

Intervention Type

Drug

Intervention Name(s)

Maintenance - CFZ-R(T)-D

Other Intervention Name(s)

Carfilzomib (Kyprolis®), Lenalidomide (CC-5013) (Revlimid®), Dexamethasone (Decadron®), Thalidomide (Thalomid®)

Intervention Description

Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) and lenalidomide (R) are capsules and dexamethasone (D) is a pill; all will be taken by mouth. Regimen: For Cycles 1-12 CFZ 27 mg/m2/wk and D 12 mg/wk on days 1, 8, 15, & 22; lenalidomide (R) 15 mg/d on days 1-21. For Cycles 13-24 CFZ 27 mg/m2/wk and D 12 mg/wk on days 1, 8, 15, & 22. T may be substituted for R at 100 mg/day at the treating physician's discretion.

Primary Outcome Measure Information:

Title

The Remission Rate for Participants With High-risk Myeloma

Description

Time Frame

from baseline to either death or study completion for each subject (up to approximately 48 months)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients must have newly diagnosed active MM requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy. Patients must be either untreated or have not had more than one cycle of systemic MM therapy, excluding bisphosphonates and localized radiation. Participants must have high-risk disease, as defined by GEP70 risk score of ≥ 0.66 Zubrod ≤ 2, unless solely due to symptoms of MM-related bone disease. Patients must have a platelet count of ≥ 50,000/μL, unless lower levels are explained by extensive bone marrow plasmacytosis. Patients must be at least 18 years of age and not older than 75 years of age at the time of registration. Participants must have preserved renal function as defined by a serum creatinine level of < 3 mg/dL. Participants must have an ejection fraction by ECHO or MUGA scan ≥ 45% Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted. If the patient is unable to complete pulmonary function tests due to MM related pain or condition, exception may be granted if the principal investigator documents that the patient is a candidate for high dose therapy. Patients must have signed an IRB-approved informed consent indicating their understanding of the proposed treatment and understanding that the protocol has been approved by the IRB. Exclusion Criteria: Does not have high-risk disease Poorly controlled hypertension, diabetes mellitus, or other serious medical illness or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol. Patients must not have prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has not received treatment for one year prior to enrollment. Other cancers will only be acceptable if the patient's life expectancy exceeds five years. Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration. Subjects of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Frits Van Rhee, MD, Ph.D

Organizational Affiliation

University of Arkansas

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Arkansas for Medical Sciences

City

Little Rock

State/Province

Arkansas

ZIP/Postal Code

72205

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

33357481

Citation

Pawlyn C. High-risk myeloma: a challenge to define and to determine the optimal treatment. Lancet Haematol. 2021 Jan;8(1):e4-e6. doi: 10.1016/S2352-3026(20)30361-6. Epub 2020 Dec 22. No abstract available.

Results Reference

derived

PubMed Identifier

29567784

Citation

Davies FE, Rosenthal A, Rasche L, Petty NM, McDonald JE, Ntambi JA, Steward DM, Panozzo SB, van Rhee F, Zangari M, Schinke CD, Thanendrarajan S, Walker B, Weinhold N, Barlogie B, Hoering A, Morgan GJ. Treatment to suppression of focal lesions on positron emission tomography-computed tomography is a therapeutic goal in newly diagnosed multiple myeloma. Haematologica. 2018 Jun;103(6):1047-1053. doi: 10.3324/haematol.2017.177139. Epub 2018 Mar 22.

Results Reference

derived

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UARK 2012-02 Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission

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