Carfilzomib, Cyclophosphamide, Dexamethasone in Multiple Myeloma

Sponsor
PETHEMA Foundation (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03336073
Collaborator
(none)
199
24
2
59.4
8.3
0.1

Study Details

Study Description

Brief Summary

This is a multicenter, open label, phase II randomized controlled study that will evaluate the efficacy of carfilzomib and dexamethasone in combination with cyclophosphamide in R/R MM patients.

For this purpose, R/R MM patients that have received 1-3 prior lines of therapy, and who are not primary refractory or refractory to proteasome inhibitors will be randomized to receive:

  • Experimental arm: carfilzomib at a dose of 70 mg/m2 (20 mg/m2 only in the first infusion) intravenously (iv) on days 1, 8, and 15, dexamethasone by mouth (po) at a dose of 20 mg (10 mg for patients >75 years) days 1, 2, 8, 9, 15 and 16 and cyclophosphamide at a dose of 300 mg/m2 iv on days 1, 8 and 15, in 28 days cycles; or

  • Control arm: the same treatment but without cyclophosphamide.

Once the first 12 cycles are administered, treatment will be administered on days 1 and 15 of each cycle and the visit and doses on day 8 will be omitted in both study arms.

Patients older than 75 years will receive in both arms carfilzomib at a dose of 56 mg/m2 (20 mg/m2 only in the first infusion) during the cycles 1 and 2. If tolerability is acceptable, the dose could be increased up to 70 mg/m2 since the cycle 3.

Treatment will be continued until progression, unacceptable toxicity or investigator or patient decision.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Treatment will consist of 28-days cycles with:
  • Arm 1 (experimental arm):

  • Carfilzomib administered iv at a dose of 70 mg/m2 (20 mg/m2 only in the first infusion) iv on days 1, 8 and 15.

  • Dexamethasone at a dose of 20 mg po (10 mg for patients >75 years) days 1, 2, 8, 9, 15 and 16.

  • Cyclophosphamide at a dose of 300 mg/m2 iv on days 1, 8 and 15

  • Arm 2 (control arm):

  • Carfilzomib administered iv at a dose of 70 mg/m2 (20 mg/m2 only in the first infusion) iv on days 1, 8, and 15.

  • Dexamethasone at a dose of 20 mg po (10 mg for patients >75 years) days 1, 2, 8, 9, 15 and 16.

Once the first 12 cycles are administered, treatment will be administered on days 1 and 15 of each cycle and the visit and doses on day 8 will be omitted in both study arms.

Patients older than 75 years will receive in both arms carfilzomib at a dose of 56 mg/m2 (20 mg/m2 only in the first infusion) during the cycles 1 and 2. If tolerability is acceptable, the dose could be increased up to 70 mg/m2 since the cycle 3.

Treatments will be administered until progressive disease (PD) or unacceptable toxicity. Carfilzomib and cyclophosphamide will be provided by the sponsor. Dexamethasone may be utilized per a site's standard practice and will not be provided by the sponsor.

Study Design

Study Type:
Interventional
Actual Enrollment :
199 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Carfilzomib and Dexamethasone in Combination With Cyclophosphamide vs. Carfilzomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma: a Phase II Randomized Controlled Trial
Actual Study Start Date :
Dec 18, 2017
Anticipated Primary Completion Date :
Dec 1, 2022
Anticipated Study Completion Date :
Dec 1, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: carfilzomib, dexamethasone and cyclophosphamide

carfilzomib at a dose of 70 mg/m2 (20 mg/m2 only in the first infusion) intravenously (iv) on days 1, 8, and 15, dexamethasone by mouth (po) at a dose of 20 mg (10 mg for patients >75 years) days 1, 2, 8, 9, 15 and 16 and cyclophosphamide at a dose of 300 mg/m2 iv on days 1, 8 and 15, in 28 days cycles

Drug: Carfilzomib
carfilzomib at a dose of 70 mg/m2 (20 mg/m2 only in the first infusion) intravenously (iv) on days 1, 8, and 15

Drug: Dexamethasone
dexamethasone oral at a dose of 20 mg (10 mg for patients >75 years) days 1, 2, 8, 9, 15 and 16

Drug: cyclophosphamide
cyclophosphamide at a dose of 300 mg/m2 iv on days 1, 8 and 15

Active Comparator: carfilzomib and dexamethasone

carfilzomib at a dose of 70 mg/m2 (20 mg/m2 only in the first infusion) intravenously (iv) on days 1, 8, and 15, dexamethasone by mouth (po) at a dose of 20 mg (10 mg for patients >75 years) days 1, 2, 8, 9, 15 and 16 , in 28 days cycles

Drug: Carfilzomib
carfilzomib at a dose of 70 mg/m2 (20 mg/m2 only in the first infusion) intravenously (iv) on days 1, 8, and 15

Drug: Dexamethasone
dexamethasone oral at a dose of 20 mg (10 mg for patients >75 years) days 1, 2, 8, 9, 15 and 16

Outcome Measures

Primary Outcome Measures

  1. Progression free survival (PFS) [36 months]

    PFS is defined as the number of months from randomization to the disease progression or death due to any cause, whichever occurs first. The disease outcome determined will be the primary data source for the final PFS analysis.

Secondary Outcome Measures

  1. Safety of carfilzomib, dexamethasone and cyclophosphamide in number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [2 years]

    the safety as determined by the incidence of clinical and laboratory toxicities

  2. Efficacy of carfilzomib, dexamethasone and cyclophosphamide in number and rate of responses obtained [2 years]

    Evaluate the efficacy of carfilzomib and dexamethasone in combination with cyclophosphamide in terms of rate of response in multiple myeloma (MM) patients.

  3. Time-to progression (TTP) [36 months]

    Duration from randomization to disease progression, with deaths due to causes other than progression censored.

  4. Overall Survival (OS) [36 months]

    Duration from the date of randomization until the date of death. The patients lost to follow-up will be censored at the date of the last visit.

  5. Efficacy of carfilzomib, dexamethasone and cyclophosphamide in rate of achievement of immunophenotypic CR [2 years]

    Evaluate the efficacy of carfilzomib and dexamethasone in combination with cyclophosphamide in terms of achievement of immunophenotypic CR in multiple myeloma (MM) patients.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  1. Age ≥18 years.

  2. Performance status (ECOG) <2.

  3. Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.

  4. Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

  5. Patients previously diagnosed with MM according to the IMWG criteria (Lancet Oncology

  1. that after previous treatment with 1-3 regimens require therapy due to a relapse/progression of the disease.
  1. Patients must have measurable disease, defined as follows:
  • Serum monoclonal protein ≥ 0.5 g/L, or

  • Urine light-chain excretion of ≥ 0.2g /24 hours, or

  • Abnormal ratio of serum free light chains (FLCs) plus involved FLC level ≥100 mg/L.

Exclusion Criteria:
  1. Primary refractory patients defined as not having achieved at least a PR with a prior therapy.

  2. Refractoriness to prior proteasome inhibitor therapies, defined as not having achieved at least MR or having progressed under treatment or in the first 60 days after the last dose of the proteasome inhibitor.

  3. Biochemical and haematological abnormalities as specified below:

  • Hemoglobin < 8.0 g/dL.

  • Platelet count <75x109/L without previous platelet transfusions in the last 7 days. If bone marrow infiltration is greater than 50%, a platelet count of ≥50x109/L is required.

  • Absolute neutrophil count (ANC) < 0.75 x109/L without G-CSF support in the last 7 days.

  • Aspartate transaminase (AST): > 2.5 times the upper limit of normal.

  • Alanine transaminase (ALT): > 2.5 times the upper limit of normal.

  • Calculated or measured creatinine clearance: <30 mL/min (calculated from the Cockcroft and Gault formula, specified in Appendix C).

  1. Left ventricle ejection fraction < 50%.

  2. Absence of recovery from any significant non-haematological toxicity derived from previous treatments. The presence of alopecia and NCI-CTC grade < 2 symptomatic peripheral neuropathy is allowed.

  3. Pregnant or breastfeeding women; men and women of reproductive potential who are not using effective contraceptive methods (double barrier method, intrauterine device, and oral contraception).

  4. Previous history of any other neoplastic disease in the last five years (except basal cell carcinoma, skin epithelioma or carcinoma in situ of any site).

  5. Other relevant diseases or adverse clinical conditions:

  • Congestive heart failure or angina pectoris, myocardial infarction within 12 months before inclusion in the study.

  • Uncontrolled arterial hypertension or cardiac arrhythmias (i.e. requiring a change in medication within the last 3 months or a hospital admission within the past 6 months).

  • History of significant neurological or psychiatric disorders.

  • Active infection

  • Significant non-neoplastic liver disease (e.g. cirrhosis, active chronic hepatitis).

  1. Patient is known to be human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive or to suffer active hepatitis C infection

  2. The patient has received concomitant anti-myeloma therapy within 14 days prior to Day 1 of Cycle 1.

  3. Limit to the patient's ability to comply with the treatment or follow-up protocol.

  4. Uncontrolled endocrine diseases (e.g. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months).

Contacts and Locations

Locations

Site City State Country Postal Code
1 Hospital Universitario de Canarias Tenerife Islas Canarias Spain
2 H.Universitari Germans Trias I Pujol de Badalona Barcelona Spain
3 Hospital Clínic i Provincial de Barcelona Barcelona Spain
4 Hospital de la Santa Creu i Sant Pau Barcelona Spain
5 Ico L'Hospitalet Barcelona Spain
6 Complejo Hospitalario de Cáceres Cáceres Spain
7 Hospital de Cabueñes Gijón Spain
8 Centro Hospitalario Universitario de Granada Granada Spain
9 Hospital de León León Spain
10 H. 12 de Octubre Madrid Spain
11 H. Ramón y Cajal Madrid Spain
12 Hospital Sanchinarro Madrid Spain
13 Hospital Universitario Morales Meseguer Murcia Spain
14 Hospital Virgn de la Arrixaca Murcia Spain
15 Hospital Costa del Sol Málaga Spain
16 Hospital Central de Asturias Oviedo Spain
17 Hospital de Son Llàtzer Palma De Mallorca Spain
18 Clinica Universitaria de Navarra Pamplona Spain
19 Hospital Clínico Universitario de Salamanca Salamanca Spain 37007
20 Hospital Universitario de Santiago Santiago De Compostela Spain
21 Hospital de Segovia Segovia Spain
22 Complejo Hospitalario Regional Virgen Del Rocío Sevilla Spain
23 Hospital de Toledo Toledo Spain
24 Hospital Lozano Blesa Zaragoza Spain

Sponsors and Collaborators

  • PETHEMA Foundation

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
PETHEMA Foundation
ClinicalTrials.gov Identifier:
NCT03336073
Other Study ID Numbers:
  • GEM-KyCyDex
First Posted:
Nov 8, 2017
Last Update Posted:
Apr 6, 2021
Last Verified:
Apr 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of Apr 6, 2021