Clinical trial NCT01346787: Carfilzomib, Cyclophosphamide and Dexamethasone In Newly Diagnosed Multiple Myeloma Patients
Official title: A MULTICENTER, OPEN LABEL PHASE II STUDY OF CARFILZOMIB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE IN NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: carfilzomib
dexamethasone
cyclophosphamide
multiple myeloma
newly diagnosed
Lead sponsor: European Myeloma Network B.V.
Sponsor class: NETWORK
Collaborators: name: Fondazione EMN Italy Onlus
First posted: 2011-05-03
Enrollment: 58
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether the association of Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) as induction treatment is safe and provides benefits in patients with newly diagnosed Multiple Myeloma (MM).

Detailed description: This protocol is a phase II multicenter, international, non-comparative, open label study designed to jointly assess the safety and the efficacy of the association Carfilzomib with Cyclophosphamide and Dexamethasone (CCd) as induction treatment and Carfilzomib alone as maintenance in newly diagnosed MM patients.

Patients will be evaluated at scheduled visits in up to 4 study periods: pre-treatment, treatment, maintenance and long-term follow-up.

The pre-treatment period includes screening visits, performed at study entry. After providing written informed consent to participate in the study, patients will be evaluated for study eligibility. The screening period includes the availability of inclusion criteria described above.

The treatment period includes administration of Carfilzomib, Cyclophosphamide and Dexamethasone for 9 4-week courses. In order to assess the toxicity of treatment, patients will attend the study centre visits at each scheduled Carfilzomib administration. The response will be assessed after each 4-week cycle.

The maintenance period includes carfilzomib alone on days 1, 2, 15, 16 at 36mg/m2. For patients who show evidence of progression during maintenance phase, the frequency of Carfilzomib can be increased to days 1, 2, 8, 9, 15, 16 at the discretion of the investigator. It will be initiated at the end of the 9th course and will be stopped at progression or intolerance. The median expected duration of the maintenance treatment is approximately 2 years.

The Long Term Follow Up periods will start after development of confirmed Progression Disease, all patients are to be followed for survival during the Long Term Follow Up period every 3 months via telephone or office visit.

Approximately 15 Italian centers and foreign centers will participate to the protocol.

Patients with symptomatic newly diagnosed MM whose age is ≥ 65 years or who are ineligible for autologous stem cell transplantation. Up to 53 patients will be enrolled from different centers.

The duration of the treatment is approximately 9 months. This length of time is required to complete 9 courses of CCd. At the end of the first stage (19 patients), the trial will be temporarily stopped until all 19 patients complete the toxicity and efficacy evaluation (3 cycle): if there are more than 7 responses and less than 8 toxicities, a further group of 34 patients (total=53) will be enrolled. Otherwise, the trial will be definitively stopped or the DSMC will recommend testing other doses of the drugs.

The maintenance period in both phases will start at the end of the 9th course and will be stopped at progression or intolerance. The median expected duration of the maintenance treatment is approximately 2 years. The duration of follow-up from relapse will be approximately 2 years. The occurrence of PD will determine the duration of TTP of each patient. The occurrence of death will determine the duration of overall survival. The first analysis to evaluate safety and efficacy is planned when the 19 patients enrolled in the first stage of the study have completed the third cycle of induction treatment.

The trial will be stopped if there are \< 6 responses, or \> 9 toxicities or the Data Safety Monitoring Committee recommends testing other doses of the drugs; Otherwise, a further group of 34 patients (total=53) will be enrolled. The final conclusion will be negative if there are ≤ 23/53 responses, or ≥ 20/53 drug-related toxicities.

Eligibility criteria: Inclusion Criteria:

* Patient is of a legally consenting age as defined by local regulations.
* Patient is age ≥ 65 year of age or who are ineligible for autologous stem cell transplantation.
* Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
* 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.
* Female patient is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
* Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) for the duration of the study.
* Patient is a newly diagnosed MM patient.
* Patient has measurable disease, defined as follows: any quantifiable serum monoclonal protein value (generally, but not necessarily, ≥ 0.5 g/dL of M-protein) and, where applicable, urine light-chain excretion of \>200 mg/24 hours. For patients with oligo or non-secretory MM, it is required that they have measurable plasmacytoma \> 2 cm as determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan) or an abnormal free light chain ratio (n.v.: 0.26-1.65). We anticipate that less than 10% of patients admitted to this study will be oligo- or non-secretory MM with free light chains only in order to maximize interpretation of benefit results.
* - Patient has a Karnofsky performance status ≥60%.
* Patient has a life-expectancy \>3 months.
* Patient has the following laboratory values within 14 days before Baseline (day

  1 of the Cycle 1, before study drug administration):
* Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone marrow is \> 50%) within 14 days prior to drug administration).
* Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors.
* Corrected serum calcium ≤14 mg/dL (3.5 mmol/L)
* Alanine transaminase (ALT): ≤ 3 x the ULN.
* Total bilirubin: ≤ 2 x the ULN.
* Calculated or measured creatinine clearance: ≥ 15 mL/minute

Exclusion Criteria:

* - Patients with non-secretory MM, unless serum free light chains are present and the ratio is abnormal.
* Pregnant or lactating females
* Patient has active infectious hepatitis type B or C or HIV.
* Patients with myocardial infarction or unstable angina ≤ 4 months or other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
* Peripheral neuropathy \> CTCAE grade 2 and ≥ grade 2 painful peripheral neuropathy (with the difference being in the exclusion of patients with Grade 2 painful PN).
* Known history of allergy to Capsidol (a cyclodextrin derivative used to solubilize carfilzomib)
* Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
* Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to baseline;
* Patient has any other clinically significant illness that would, in the investigator's opinion, increase the patient's risk for toxicity.
* Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix or breast, or localized prostate cancer of Gleason score \<7 with a stable PSA)

Primary outcomes:
measure: Toxicity: Assessment of adverse events will be performed at the end of third cycle according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0)
timeFrame: 4 years
measure: Efficacy will be assessed by considering partial response (PR) following the proposed regimen. Assessment of Partial Response rate will be performed at the end of third cycle according to the criteria of the International Myeloma Working Group.
timeFrame: 4 years
Secondary outcomes:
measure: Response rate
timeFrame: 4 years
measure: Duration of Progression Free Survival
timeFrame: 4 years
measure: Time to progression (TTP)
timeFrame: 4 years
measure: Duration of Response (DOR)
timeFrame: 4 years
measure: Duration of Overall Survival
timeFrame: 4 years
measure: Time to next therapy
timeFrame: 4 years
measure: Progressio Free Survival
timeFrame: 4 years
measure: β2-microglobulin as prognostic factors
timeFrame: 4 years
measure: peripheral neuropathy
timeFrame: 4 years
measure: Progression Free Survival
timeFrame: 4 years
measure: C reactive protein as prognostic factors
timeFrame: 4 years
measure: cytogenetics as prognostic factors
timeFrame: 4 years
measure: microRNA
timeFrame: 4 years
measure: gene expression profile
timeFrame: 4 years
measure: Overall Survival
timeFrame: 4 years
Other outcomes:
Locations:
city: Rionero In Vulture
country: Italy
facility: IRCCS CROB UOC di Ematologia e trapianto cellule staminali Ospedale Oncologico Regionale
state: PZ
city: Ancona
country: Italy
facility: azienda ospedaliero-universitaria umberto I Clinica di Ematologia
city: Bologna
country: Italy
facility: Policlinico S. Orsola Istituto di Ematologia e Oncologia Medica
city: Catania
country: Italy
facility: Ospedale Ferrarotto_Reparto di Ematologia
city: Firenze
country: Italy
facility: Az.Osp. Di Careggi_Dh ematologia
city: Milano
country: Italy
facility: Istituto Nazionale per lo Studio e la Cura dei Tumori_UO Ematologia_Trapianto di Midollo Osseo Allogenico
city: Novara
country: Italy
facility: Divisione di Ematologia Dipartimento di Medicina Clinica e Sperimentale Università Amedeo Avogadro
city: Roma
country: Italy
facility: Cattedra di ematologia Università La Sapienza
city: Roma
country: Italy
facility: Divisione di Ematologia Ospedale S. Eugenio
city: Terni
country: Italy
facility: S.C.di Oncoematologia, Azienda Ospedaliera S. Maria di Terni
city: Torino
country: Italy
facility: SC Ematologia - A.O.U. Città della Salute e della Scienza di Torino
city: Torino
country: Italy
facility: SSD CLINICAL TRIAL IN ONCOEMATOLOGIA E MIELOMA MULTIPLO - A.O.U. Città della Salute e della Scienza di Torino
city: Rotterdam
country: Netherlands
facility: Erasmus MC
Study officials:
References:
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citation: Montefusco V, Gay F, Spada S, De Paoli L, Di Raimondo F, Ribolla R, Musolino C, Patriarca F, Musto P, Galieni P, Ballanti S, Nozzoli C, Cascavilla N, Ben-Yehuda D, Nagler A, Hajek R, Offidani M, Liberati AM, Sonneveld P, Cavo M, Corradini P, Boccadoro M. Outcome of paraosseous extra-medullary disease in newly diagnosed multiple myeloma patients treated with new drugs. Haematologica. 2020 Jan;105(1):193-200. doi: 10.3324/haematol.2019.219139. Epub 2019 Jun 20.
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citation: Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, Offidani M, McCarthy P, Evangelista A, Lonial S, Zweegman S, Musto P, Terpos E, Belch A, Hajek R, Ludwig H, Stewart AK, Moreau P, Anderson K, Einsele H, Durie BG, Dimopoulos MA, Landgren O, San Miguel JF, Richardson P, Sonneveld P, Rajkumar SV. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015 Mar 26;125(13):2068-74. doi: 10.1182/blood-2014-12-615187. Epub 2015 Jan 27.
citation: Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omede P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. doi: 10.1182/blood-2014-03-563759. Epub 2014 May 22.