Clinical trial NCT04096066: A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant
Official title: Carfilzomib - Lenalidmide - Dexamethasone (KRd) Versus Lenalidomi - Dexamethasone (Rd) in Newly Diagnosed Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation: a Randomized Phas III Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Myeloma
New Diagnosis Tumor
Keywords: Multiple Myeloma
AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE
Proteasome inhibitor
Immunomodulating agents
Lead sponsor: Fondazione EMN Italy Onlus
Sponsor class: OTHER
First posted: 2019-09-19
Enrollment: 84
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The combination of lenalidomide plus low-dose dexamethasone (Rd) is considered the new standard for elderly newly diagnosed multiple myeloma (NDMM) patients. The combination carfilzomib plus lenalidomide-dexamethasone (KRd) in relapsed-refractory MM patients improved the progression-free survival (PFS) of approximately 1 year compared to standard Rd treatment. In a small phase 2 trial (23 pts) the KRd combination in elderly NDMM pts showed a complete response (CR) rate of 79% and a PFS at 3 years of 80%. Cardiovascular adverse events are the most limiting toxicities, especially in elderly patients.

Detailed description: This protocol is a randomized, multicenter study designed to determine the MRD negativity and the PFS of KRd treatment regimen.

Patients will be randomized in a 1:1 ratio to receive carfilzomib-lenalidomide-dexamethasone (KRd - Arm A) or lenalidomide-dexamethasone (Rd - Arm B).

Patients will be stratified basing on international staging system (ISS) and fitness status using a web-based procedure completely concealed to study participants.

All consecutive patients ≥ 65 years with newly diagnosed MM will be enrolled in a large randomized study during a period of 24 months.

Patients will be treated until disease progression or intolerance to the therapy. The only exception is for patients enrolled in KRd arm who achieve at least a VGPR during the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after one and two years of therapy): these patients will stop carfilzomib administration after 2 years, whereas treatment with lenalidomide and dexamethasone will be continued.

Eligibility criteria: Inclusion Criteria:

* Newly diagnosed symptomatic MM based on either standard CRAB criteria (at least 10% of clonal bone marrow plasma cells plus CRAB defined as the onset of any of the following clinical symptoms: hypercalcemia, renal failure, anemia and bone lesions) or at least 10% of bone marrow plasma cells plus the presence of at least one of the following biomarkers of malignancy:

  * 60% or greater clonal plasma cells on bone marrow examination;
  * Serum involved/uninvolved free light chain (FLC) ratio of 100 or greater;
  * More than one focal lesion on magnetic resonance imaging (MRI) that is at least 5 mm or greater in size.
* Patient not eligible for ASCT (age ≥ 65 years or abnormal cardiac, pulmonary and liver function).
* Patient defined as fit or intermediate according to the IMWG (International Myeloma Working Group) frailty score
* Patient has given voluntary written informed consent.
* Patient is able to be compliant with hospital visits and procedures required per protocol.
* Patient agrees to use acceptable methods for contraception.
* Patient has measurable disease according to IMWG criteria.
* Patient has ECOG (Eastern Cooperative Oncology Group) performance status \< 3.
* Pre-treatment clinical laboratory values within 30 days before randomization:

  * Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone marrow is \> 50%)
  * 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: ≥ 30 mL/minute.
* LVEF≥ 40%: 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation; multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available
* Pre-treatment blood pressure value \< 140/90 mmHg even with adequate therapy: 24 hours blood pressure monitoring is the preferred method of evaluation; blood pressure diary at home for 2 weeks is acceptable.
* Females of childbearing potential (FBCP) comply with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding.
* FBCP must follow the Pregnancy Prevention Plan and use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for at least 30 days after the last dose of study drugs\*
* Males must use an effective barrier method of contraception if sexually active with FCBP during the treatment and for at least 90 days after the last administration of study drug/s. Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of carfilzomib.

Exclusion Criteria:

* Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the screening or place the subject at unacceptable risk.
* Patient defined as frail according to the IMWG frailty score.
* Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid \< to the equivalent of dexamethasone 40 mg/day for 4 days).
* Pregnant or lactating females.
* Presence of:

  * Clinical active infectious hepatitis type A, B, C or HIV
  * Acute active infection requiring antibiotics or infiltrative pulmonary disease
  * Pulmonary hypertension and interstitial lung disease
  * Uncontrolled arrhythmias or history of QT prolongation
  * Myocardial infarction or unstable angina ≤ 6 months or other clinically significant heart disease
  * Peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0 (Appendix A)
  * Uncontrolled hypertension defined as persistent hypertension (\>140/90 mmHg) regardless treatment with 3 drugs, including a diuretic.
* Contraindication to any of the required drugs or supportive treatments and hypersensitivity to any excipient of the study drugs.
* Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
* Invasive malignancy within the past 3 years.
* Administration of any experimental drug within 4 weeks prior the baseline or within 5 drug half-lives.

Primary outcomes:
measure: Minimal residual disease (MRD)
timeFrame: 5 years
measure: Progression-free survival (PFS)
timeFrame: 5 years
Secondary outcomes:
measure: Rate of drug reduction or drug discontinuation
timeFrame: 5 years
measure: Cardiovascular assessment
timeFrame: 5 years
measure: Rate of dose reduction, drug discontinuation and toxicities
timeFrame: 5 years
measure: Response rate
timeFrame: 5 years
measure: Progression-free survival 2 (PFS2)
timeFrame: 5 years
measure: Time to progression (TTP)
timeFrame: 5 years
measure: Duration of response (DOR)
timeFrame: 5 years
measure: Overall survival (OS)
timeFrame: 5 years
measure: Time to next therapy (TNT)
timeFrame: 5 years
measure: MRD negativity
timeFrame: 5 years
measure: Prognostic factors
timeFrame: 5 years
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: AO "SS. Antonio e Biagio"
city: Ancona
country: Italy
facility: AOU Ospedali Riuniti Umberto I
city: Ascoli Piceno
country: Italy
facility: Ospedale Mazzoni
city: Bari
country: Italy
facility: Policlinico di Bari
city: Bergamo
country: Italy
facility: Ospedali Riuniti
city: Bolzano
country: Italy
facility: Azienda Sanitaria di Bolzano - Ospedale Lorenz B:Ohler
city: Brescia
country: Italy
facility: A.O. Spedali Civili di Brescia
city: Cagliari
country: Italy
facility: Ospedale "A. Businco"
city: Candiolo
country: Italy
facility: Istituto per la Cura e la RIcerca del Cancro di Candiolo
city: Cuneo
country: Italy
facility: Ospedale Civico S. Croce e Carle
city: Firenze
country: Italy
facility: AOU Careggi
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)
city: Messina
country: Italy
facility: Azienda Ospedaliera Papardo
city: Messina
country: Italy
facility: Policlinico Universitario di Messina
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Milano
country: Italy
facility: Istituto Europeo Oncologico
city: Milano
country: Italy
facility: Istituto Nazionale Tumori
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico di Milano
city: Napoli
country: Italy
facility: Università Federico II-Policlinico
city: Novara
country: Italy
facility: Ospedale Maggiore
city: Orbassano
country: Italy
facility: AO San Luigi Gonzaga
city: Padova
country: Italy
facility: AO di Padova
city: Palermo
country: Italy
facility: AO Cervello
city: Perugia
country: Italy
facility: Ospedale S. Maria della Misericordia
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci
city: Reggio Calabria
country: Italy
facility: AO Bianchi Melacrino Morelli
city: Reggio Emilia
country: Italy
facility: Ausl-Irccs
city: Rimini
country: Italy
facility: Ospedale Infermi
city: Rionero in Vulture
country: Italy
facility: Ospedale Oncologico Regionale
city: Roma
country: Italy
facility: ASL Roma 1
city: Roma
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Tor Vergata
city: Roma
country: Italy
facility: Ospedale S. Eugenio - Università Tor Vergata
city: Roma
country: Italy
facility: Ospedale San Camillo Forlanini
city: Roma
country: Italy
facility: Policlinico Umberto I - Università La Sapienza
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Ospedale Casa Sollievo della Sofferenza
city: Terni
country: Italy
facility: AO S. Maria
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino - PO Molinette - Ematologia U
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino - PO Molinette
city: Udine
country: Italy
facility: Policlinico Universitario di Udine
Study officials:
affiliation: A.O.U. Città della Salute e della Scienza
name: Sara Bringhen
role: PRINCIPAL_INVESTIGATOR
References: