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

NCT ID: NCT02128230

Last Updated: 2021-06-22

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-06-10
• Study Completion Date: 2019-02-19

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

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Total Therapy 5b

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

Group Type: EXPERIMENTAL

myPRS

Intervention Type: DEVICE

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

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

Intervention Type: DRUG

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.

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

Intervention Type: DRUG

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.

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

Intervention Type: DRUG

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.

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

Intervention Type: DRUG

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.

Consolidation - CFZ-TD-PACE

Intervention Type: DRUG

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.

Maintenance - CFZ-R(T)-D

Intervention Type: DRUG

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.

Interventions

myPRS

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

Intervention Type: DEVICE

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

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

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

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

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

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

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

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

Consolidation - CFZ-TD-PACE

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

Maintenance - CFZ-R(T)-D

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.

Intervention Type: DRUG

Other Intervention Names

Gep70; 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®); 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®); Melphalan (Alkeran™); Carfilzomib (Kyprolis®); Thalidomide (Thalomid®); Dexamethasone (Decadron®); Cisplatin (CDDP) (Platinol®); Doxorubicin (Adriamycin®); Cyclophosphamide (Cytoxan®); Etoposide (VP-16) (Vepesid®); 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®); Carfilzomib (Kyprolis®); Thalidomide (Thalomid®); Dexamethasone (Decadron®); Cisplatin (CDDP) (Platinol®); Doxorubicin (Adriamycin®); Cyclophosphamide (Cytoxan®); Etoposide (VP-16) (Vepesid®); Carfilzomib (Kyprolis®); Lenalidomide (CC-5013) (Revlimid®); Dexamethasone (Decadron®); Thalidomide (Thalomid®)

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: collaborator

University of Arkansas

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Frits Van Rhee, MD, Ph.D

Role: PRINCIPAL_INVESTIGATOR

University of Arkansas

Locations

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33357481 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29567784 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

134668

Identifier Type: -

Identifier Source: org_study_id