A randomized trial that compares Carfilzomib - Lenalidomide - Dexamethasone (KRd) versus Lenalidomide - Dexamethasone (Rd) in new diagnosed myeloma patients not elegible for trasplant.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione European Myeloma Network Italy O.N.L.U.S.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 May 2019 → ongoing

Decision date (initial)

2024-08-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BMS-Celgene · Amgen

External identifiers

EU CT number

2024-513396-41-00

EudraCT number

2018-002068-15

ClinicalTrials.gov

NCT04096066

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

The primary objective is to determine the efficacy, in term of minimal residual disease (MRD) negativity (MRD after 2 years of treatment), of the addition of Carfilzomib to the Lenalidomide-Dexamethasone drug association in newly diagnosed MM patients not eligible for autologous stem cell transplantation (ASCT);
To determine the PFS of both treatment arms.

Secondary objectives 12

1. To determine the incidence of dose reduction and drug discontinuation in both treatment arms.
2. To determine the benefit of proper cardiovascular baseline assessment and monitoring during treatment in both treatment arms: to mitigate major cardiovascular adverse event incidence, to prolong duration of treatment and to improve efficacy.
3. To determine the safety of both treatment arms.
4. To determine the response rate of both treatment arms.
5. To determine the PFS2 of both treatment arms.
6. To determine the time to progression (TTP) of both treatment arms.
7. To determine the duration of response (DOR) of both treatment arms.
8. To determine the overall survival (OS) of both treatment arms.
9. To determine the time to next therapy (TNT) of both treatment arms.
10. To determine the benefits of both treatment arms
11. To determine the correlation between MRD negativity and PFS, PFS2, TTP, TNT, and OS
12. To determine difference of response and outcome in subgroups with different prognostic factors.

Conditions and MedDRA coding

PATIENTS WITH NEW DIAGNOSIS MULTIPLE MYELOMA WITH AGE >= 65 YEARS OR NOT ELIGIBLE TO ASCT

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Newly diagnosed symptomatic MM based on either standard CRAB criteria (at least 10% of 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.
2. Patient not eligible for ASCT (age ≥ 65 years or abnormal cardiac, pulmonary and liver function).
3. Patient defined as fit or intermediate according to the IMWG (International Myeloma Working Group) frailty score.
4. Patient has given voluntary written informed consent.
5. Patient is able to be compliant with hospital visits and procedures required per protocol.
6. Patient agrees to use acceptable methods for contraception.
7. Patient has measurable disease according to IMWG criteria.
8. Patient has ECOG (Eastern Cooperative Oncology Group) performance status < 3.
9. Pre-treatment clinical laboratory values within 30 days before randomization: Platelet count ≥50 x 10^9/L (≥30 x 10^9 /L if myeloma involvement in the bone marrow is > 50%), Absolute neutrophil count (ANC) ≥ 1 x 10^9/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 UL, Calculated or measured creatinine clearance: ≥ 30 mL/minute.
10. LVEF (left ventricular ejection fraction) ≥ 40%: 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation; multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available
11. 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.
12. Females of childbearing potential (FBCP) comply with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding
13. 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.
14. 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 15

1. Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the screening or place the subject at unacceptable risk.
2. Patient defined as frail according to the IMWG frailty score (pts with age >80 years old).
3. 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)
4. Pregnant or lactating females.
5. Presence of clinical active infectious hepatitis type A, B, C or HIV.
6. Presence of acute active infection requiring antibiotics or infiltrative pulmonary disease.
7. Presence of pulmonary hypertension and interstitial lung disease.
8. Presence of uncontrolled arrhythmias or history of QT prolongation.
9. Presence of myocardial infarction or unstable angina ≤ 6 months or other clinically significant heart disease.
10. Presence of peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0.
11. Presence of incontrolled hypertension defined as persistent hypertension (>140/90 mmHg) regardless treatment with 3 drugs, including a diuretic.
12. Contraindication to any of the required drugs or supportive treatments and hypersensitivity to any excipient of the study drugs.
13. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
14. Invasive malignancy within the past 3 years.
15. Administration of any experimental drug within 4 weeks prior to the baseline or within 5 drug half-lives.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. MRD evaluation will be performed on bone marrow samples obtained after 1 and 2 years of treatment in patients who achieved at least a VGPR during the first year of study treatment. The rate of MRD negativity is determined as the patients with MRD negativity at 2 years of treatment. For patients who withdraw or are lost to follow up before two years of treatment, the best MRD assessment will be considered.
2. PFS will be measured from the date of randomization to the date of first observation of PD, or death from any cause as an event. Subjects who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects who complete the study, have not progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to FU will also be censored at the time of last contact.

Secondary endpoints 12

1. Response rate (sCR, CR, VGPR, PR) of experimental KRd regimen vs Rd regimen.
2. PFS2 will be measured from the date of first randomization to the date of observation of second disease progression or death to any cause as an event. In case of date of second progression is not available, date of start of third line treatment can be used. Subjects who withdraw from the study will be considered at the time of the last complete disease assessment. Subjects who complete the study or were lost to follow-up, have no progressed, and are still alive at final analysis will be censored
3. TTP will be measured from the date of randomization to the date of first observation of PD, or deaths related to PD. Subjects who withdraw from the study or die from causes other than PD will be censored at the time of the last complete disease assessment. Subjects who complete the study, have not progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. Subjects lost to FU will also be censored at the time of last contact.
4. DOR is defined as time between first documentation of response and PD. Responders without disease progression will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the end of the study.
5. OS is defined as the time between randomization and death. Subjects who die will be censored at time of death as an event, regardless cause of death. Subjects who withdraw consent will be censored at the time of withdrawal. Subjects who complete the study and are still alive at the cut-off date of final analysis will be censored at the cut-off date. Subjects lost to FU will also be censored at the time of last contact.
6. TNT will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event. Subjects who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects who complete the study, have not progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. Subjects lost to FU will also be censored at the time of last contact.
7. Toxicity
8. Quality of life defined by EOCTC QLQ-C30 and QLQ-MY20.
9. To determine the incidence of dose reduction and drug discontinuation in both treatment arms.
10. To determine the benefit of proper cardiovascular baseline assessment and monitoring in both treatment arms: to mitigate major cardiovascular adverse event incidence, to prolong duration of treatment, to improve efficacy.
11. To determine the impact of MRD negativity on PFS, PFS2, TTP, TNT and OS.
12. To determine difference of response and outcome (PFS, PFS2, TTP, TNT and OS) in subgroups analysis with different prognostic factors.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione European Myeloma Network Italy O.N.L.U.S.

Sponsor organisation

Fondazione European Myeloma Network Italy O.N.L.U.S.

Address

Via Saluzzo 1 A

City

Turin

Postcode

10125

Country

Italy

Scientific contact point

Organisation

Fondazione European Myeloma Network Italy O.N.L.U.S.

Contact name

Sara Bringhen

Public contact point

Organisation

Fondazione European Myeloma Network Italy O.N.L.U.S.

Contact name

Mario Boccadoro

Third parties 7

Locations

1 EU/EEA country · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications