Carfilzomib + Lenalidomide +Dexamethasone for BTK inhibitors relapsed-refractory or intolerant mantle cell lymphomas

Phase 1

• Conditions: BTK inhibitors relapsed-refractory or intolerant mantle cell lymphomas; MedDRA version: 20.0Level: PTClassification code 10061275Term: Mantle cell lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2018-000540-25-IT
• Lead Sponsor: FONDAZIONE ITALIANA LINFOMI ONLUS

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-06-17
• Last Update Posted: 7 September 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 59

Inclusion Criteria

•Patient has a confirmed diagnosis of MCL according to the WHO 2017 classification;
•Previous treatment with BTKi monotherapy or BTKi containing regimens with R/R disease; and/or patients who discontinued BTKi monotherapy or BTKi containing regimens for adverse events and have active disease necessitating treatment;
•Previous treatment with Lenalidomide is accepted if patient resulted responsive and interrupted Lenalidomide at least 12 months before enrollment to this study;
•Patient age is = 18 < 80 years;
•Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of = 2;
•Understands and voluntarily signs an informed consent form;
•Able to adhere to the study visit schedule and other protocol requirements;
•Patient has at least one site of measurable nodal disease at baseline = 2.0 cm in the longest transverse diameter as determined by CT scan (MRI is allowed only if CT scan cannot be performed). Note: Patients with bone marrow involvement are eligible;
•Adequate hematological counts: ANC > 1.5 x 109/L and platelet count > 75 x 109/L unless due to bone marrow involvement by MCL;
•Total bilirubin up to 2 x ULN unless due to liver involvement by MCL;
•Alkaline phosphatase and transaminases up to 2 x ULN unless due to liver involvement by MCL;
•Creatinine clearance = 30 ml/min; a dose reduction of Lenalidomide for patients with creatinine clearance = 30 mL/min but < 50 mL/min is planned;
•Patient has the ability to swallow capsules or tablets;
•Life expectancy = 2 months;
•Male and Female patients: accordance to comply with Lenalidomide Risk Management Plan for pregnancy prevention.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 30
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 29

Exclusion Criteria

•Patient who have received an experimental drug or used an experimental medical device within 4 weeks before the planned start of treatment. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study;
•Patient has a history of CNS involvement with lymphoma;
•Patient with previous history of malignancies (apart MCL) = 3 years before study accrual with the exception of currently treated basal cell and squamous cell carcinoma of the skin, or carcinoma in situ” of the cervix;
•History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances;
•Patient has any other concurrent severe and/or uncontrolled medical condition(s) (e.g., uncontrolled diabetes mellitus, uncontrolled hypertension, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), active hemorrhage, psychiatric illness, active or uncontrolled infection that in the investigator opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form;
•Creatinine clearance < 30 ml/min;
•Significant neuropathy (Grades 3 - 4, or Grade 2 with pain) within 14 days prior to enrollment;
•Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize Carfilzomib);
•Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment;
•Patients with LVEF <40%
•Patients with New York Health Association (NYHA) Class III and IV heart failure; myocardial infarction in the preceding 6 months; conduction abnormalities, including but not limited to atrial fibrillation, atrioventricular (AV) block, QT prolongation, sick sinus syndrome, ventricular tachycardia;
•Patients with severe bradycardia (heart rate <40 bpm, hypotension, light-headedness, syncope);
•Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to enrollment;
•Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment);
•Patient has a known history of HIV seropositivity;
•Patient has active HBV hepatitis. The following categories of HBV positive patients but with no evidence of active hepatitis may be considered for the study:
- patient is HBsAg + with HBV DNA < 2000 UI/ml (inactive carriers); HBV DNA > 2000 UI/ml is criteria of exclusion;
- patient is HBsAg – HBsAb +;
- patient is HBsAg – but HBcAb +
•Patient with HCV active hepatitis are excluded from the study. Patient with no evidence of active hepatitis and/or advanced chronic liver disease according to liver biopsy or fibro-scan evaluation may be included into the study;
•Previous treatment with Lenalidomide if patient resulted primary refractory to Lenalidomide or interrupted Lenalidomide less than 12 months before enrollment to this study;
•Women who are pregnant or breast-feeding;
•Known hypersensitivity to the active substances or to any of the excipients.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Primary Objective<br>- To evaluate the antitumor efficacy of the association of KRD in terms of 12-month overall survival (OS).;Secondary Objective: Secondary Objectives<br>To evaluate:<br>- Overall response rate (ORR); Complete response (CR), Partial response (PR) and Stable Disease (SD) rate;<br>- Effect of treatment on overall progression free survival (PFS);<br>- Effect on long term OS;<br>- Time to response (TTR);<br>- Duration of treatment (DoT);<br>- Safety profile of the combination.;Primary end point(s): 12-month OS;Timepoint(s) of evaluation of this end point: the probability of survival from the start date of treatment to 12 months, based on the Kaplan-Meier evaluation method.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): ORR, CR, PR and SD rate; PFS ( progression free survival); OS;Timepoint(s) of evaluation of this end point: The overall response rate, complete (CR), partial (PR) and stable disease (SD) responses will be defined according to the Lugano 2014 criteria. The best overall response will be defined as the best maximum response between the start date of the therapy and the last evaluation. Patients without a response assessment (for any reason) will be considered non-responders.; PFS will be defined as the time from the start of therapy to the date of recurrence, progression or death for any cause;<br>Patients who respond and patients who are lost to follow-up will be censored on their last evaluation date.; OS will be defined as the time from the date of initiation of therapy to the date of death for any cause; patients who are lost to follow-up will be censored on their last evaluation date