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Carfilzomib + Lenalidomide and Dexamethasone for BTK Inhibitors Relapsed-refractory or Intolerant MCL (FIL_KLIMT)

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ClinicalTrials.gov Identifier: NCT03891355
Recruitment Status : Recruiting
First Posted : March 27, 2019
Last Update Posted : September 10, 2020
Sponsor:
Information provided by (Responsible Party):
Fondazione Italiana Linfomi ONLUS

Brief Summary:
This is a prospective, multicenter, single arm, phase II trial designed to evaluate activity and the safety of the combination of Carfilzomib (K), Lenalidomide (R) and Dexamethasone (D) in patients with mantle cell lymphoma (MCL) relapsed/refractory (R/R) or intolerant to BTK inhibitor (BTKi) monotherapy or BTKi containing regimens with active disease necessitating treatment.

Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Drug: Carfilzomib Drug: Lenalidomide Drug: Dexamethasone Phase 2

Detailed Description:

This is a prospective, multicenter, single arm, phase II trial designed to evaluate the safety and efficacy of the combination of Carfilzomib (K), Lenalidomide (R) and Dexamethasone (D) in patients with mantle cell lymphoma (MCL) relapsed/refractory (R/R) or intolerant to BTK inhibitor (BTKi) monotherapy or BTKi containing regimens.

The primary endpoint will be assessed 12 months after the start of treatment of the last patient. However, responsive patients (CR, PR, SD) may continue to receive K up to a maximum of 24 cycles and RD up to a maximum of 24 cycles. Patients who will interrupt therapy (for any reason) will be followed up to 12 months after the end of the treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 59 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

This is a prospective, multicenter, single arm, phase II trial designed to evaluate the safety and efficacy of the combination of Carfilzomib (K), Lenalidomide (R) and Dexamethasone (D) in patients with mantle cell lymphoma (MCL) relapsed/refractory (R/R) or intolerant to BTK inhibitor (BTKi) monotherapy or BTKi containing regimens.

The primary endpoint will be assessed 12 months after the start of treatment of the last patient. However, responsive patients (CR, PR, SD) may continue to receive K up to a maximum of 24 cycles and RD up to a maximum of 24 cycles. Patients who will interrupt therapy (for any reason) will be followed up to 12 months after the end of the treatment.

After checking inclusion and exclusion criteria and signing written informed consent, the patient will be enrolled with an identification numeric code.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Carfilzomib (K) Plus Lenalidomide (R) and Dexamethasone (D) for BTK Inhibitors Relapsed-refractory or Intolerant Mantle Cell Lymphomas: a Phase II Study
Actual Study Start Date : September 30, 2019
Actual Primary Completion Date : September 2, 2020
Estimated Study Completion Date : April 30, 2022


Arm Intervention/treatment
Experimental: Carfilzomib (K) plus Lenalidomide (R) and Dexamethasone (D)

Carfilzomib (K) (maximum period of treatment= 24 cycles)

  • K on days 1-2, 8-9, 15-16 during cycles 1-12. The dosage of K will be 20 mg/m2 10' iv infusion on day 1 and 2 during cycle 1 and then 27 mg/m2 10' iv infusion thereafter;
  • K: on days 1-2, 15-16 during cycles 13-24. The dosage of K will be 27 mg/m2 10' iv infusion. Lenalidomide (R) (maximum period of treatment= 24 cycles)
  • R: 25 mg/daily on day 1 to 21 of a 28 days course; for patients with creatinine clearance ≥ 30 mL/min but < 50 mL/min the dosage of R will be 10 mg/daily on day 1 to 21 of a 28 days course.

Dexamethasone (D) (maximum period of treatment= 24 cycles) PO or IV D on days 1-2, 8-9, 15-16, 22-23. The dosage will be 20 mg between 30 minutes and 4 hours prior to K. For patients older than 75 years the dosage may be reduced at 10 mg.

Drug: Carfilzomib
Carfilzomib

Drug: Lenalidomide
Lenalidomide

Drug: Dexamethasone
Dexamethasone




Primary Outcome Measures :
  1. Primary Efficacy Endpoint - 12-months overall survival [ Time Frame: The primary endpoint will be assessed 12 months after the start of treatment of the last patient. ]
    12-month overall survival : probability of surviving from the date of beginning of therapy up to month 12 based on Kaplan-Meier estimator


Secondary Outcome Measures :
  1. Secondary Endpoints 1 - ORR [ Time Frame: The endpoint will be assessed from the date of randomization to the date of the first documented progression, evaluated up to 12 months. ]

    overall response rate will be defined according to Lugano criteria. The best overall

    response will be defined as the best response between the date of beginning of therapy and the last restaging. Patients without response assessment (due to whatever reason) will be considered as non-responders.


  2. Secondary Endpoints 1 - CR [ Time Frame: The endpoint will be assessed from the date of randomization to the date of the first documented progression, evaluated up to 12 months. ]
    complete response rate between the date of beginning of therapy and the last restaging. Patients without response assessment (due to whatever reason) will be considered as non-responders.

  3. Secondary Endpoints 1 - PR [ Time Frame: The endpoint will be assessed from the date of randomization to the date of the first documented progression, evaluated up to 12 months. ]
    partial response rate between the date of beginning of therapy and the last restaging. Patients without response assessment (due to whatever reason) will be considered as non-responders.

  4. Secondary Endpoints 1 - SD [ Time Frame: The endpoint will be assessed from the date of randomization to the date of the first documented progression, evaluated up to 12 months. ]
    rate between the date of beginning of therapy and the last restaging. Patients without response assessment (due to whatever reason) will be considered as non-responders.

  5. Secondary Endpoints 2 - PFS [ Time Frame: The endpoint will be assessed from the date of randomization to the date of the first documented progression, evaluated up to 12 months. ]
    progression-free survival will be defined as the time from beginning of therapy until lymphoma relapse or progression or death as a result of any cause; responding patients and patients who are lost to follow up will be censored at their last assessment date;

  6. Secondary Endpoints 3 - OS [ Time Frame: through the completion of the study, an average of 1 year ]
    overall survival will be defined as the time from beginning of therapy until death as a result of any cause; patients who are lost to follow up will be censored at their last assessment date;

  7. Secondary Endpoints 4 - TTR [ Time Frame: through the completion of the study, an average of 1 year ]
    time to response will be defined for all patients who achieved a response (Complete Response or Partial Response) and is measured from the date of beginning of therapy until the date of response. Patients in relapse or progression will be censored at their last assessment date. Patients death due to any cause will be consider censored or competing event according to different analysis plan

  8. Secondary Endpoints 5 - DoT [ Time Frame: through the completion of the study, an average of 1 year ]
    the duration of the treatment will be defined as the time from beginning of therapy until discontinuation due to any reason.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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;
  • Conjugated 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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03891355


Contacts
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Contact: Alice Di Benedetto 00390131033153 adibenedetto@filinf.it
Contact: Alessandra Dondi 00390594222019 adondi@filinf.it

Locations
Show Show 20 study locations
Sponsors and Collaborators
Fondazione Italiana Linfomi ONLUS
Investigators
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Principal Investigator: Francesco Zaja, Prof. Ospedale Maggiore Azienda Sanitaria Universitaria Trieste Ematologia
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Responsible Party: Fondazione Italiana Linfomi ONLUS
ClinicalTrials.gov Identifier: NCT03891355    
Other Study ID Numbers: FIL_KLIMT
First Posted: March 27, 2019    Key Record Dates
Last Update Posted: September 10, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fondazione Italiana Linfomi ONLUS:
Carfilzomib
Lenalidomide
Dexamethasone
relapsed-refractory or intolerant mantle cell lymphomas
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Dexamethasone
Lenalidomide
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunologic Factors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors