Study of BTK Inhibitor LOXO-305 Versus Approved BTK Inhibitor Drugs in Patients With Mantle Cell Lymphoma (MCL)

Study Overview
=================
Brief Summary
-----------------
This is a study for participants with a type of blood cancer called mantle cell lymphoma (MCL). The main purpose is to compare pirtobrutinib (LOXO-305) to other drugs that work in a similar way that have already been approved by the United States Food and Drug Administration (US FDA). Participation could last up to two years, and possibly longer, if the disease does not progress.

Detailed Description
-----------------
This is a Phase 3 global, randomized, open-label study comparing pirtobrutinib (Arm A) to investigator's choice of ibrutinib, acalabrutinib or zanubrutinib (Arm B) in MCL patients who have received 1 or more lines of therapy and are BTK inhibitor naïve.

Official Title
-----------------
A Phase 3 Open-Label, Randomized Study of LOXO-305 Versus Investigator Choice of BTK Inhibitor in Patients With Previously Treated BTK Inhibitor Naïve Mantle Cell Lymphoma (BRUIN MCL-321)

Conditions
-----------------
Lymphoma, Mantle-Cell

Intervention / Treatment
-----------------
* Drug: Pirtobrutinib
* Drug: Ibrutinib
* Drug: Acalabrutinib
* Drug: Zanubrutinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed MCL diagnosis Previously treated with at least one prior line of systemic therapy for MCL Measurable disease per Lugano criteria Eastern Cooperative Oncology Group (ECOG) 0-2 Absolute neutrophil count ≥ 0.75 × 109/L without granulocyte-colony stimulating factor support within 7 days of screening Hemoglobin ≥ 8 g/dL not requiring transfusion support or growth factors within 7 days of screening Platelets ≥ 50 × 109/L not requiring transfusion support or growth factors within 7 days of screening. AST and ALT ≤ 3.0 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 x ULN. Creatinine clearance of ≥ 30 mL/min according to Cockcroft/Gault Formula Exclusion Criteria: Prior treatment with an approved or investigational BTK inhibitor History of bleeding diathesis History of stroke or intracranial hemorrhage within 6 months of randomization History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor modified T-cell (CAR-T) therapy within 60 days of randomization Clinically significant cardiovascular disease Prolonged QT interval corrected using Fridericia's formula (QTcF) > 470 ms on 2/3 consecutive ECGs, and mean QTcF>470 ms on all 3 ECGs Known HIV infection or active HBV, HCV, or CMV infections. (Certain participants with controlled HBV infections may still be eligible) Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption Ongoing chronic treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers which cannot be stopped within 3-5 half lives of the CYP3A inhibitor therapy prior to start of study drug treatment. Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist. Vaccination with live vaccine within 28 days prior to randomization

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Pirtobrutinib)<br>Orally | Drug: Pirtobrutinib<br>* Oral<br>* Other names: LY3527727;|
| Active Comparator: Arm B (Ibrutinib, Acalabrutinib, or Zanubrutinib)<br>Investigator's choice (based on local availability) of ibrutinib, acalabrutinib or zanubrutinib orally. Options are limited to those that are available/approved in the specific country. | Drug: Ibrutinib<br>* Oral<br>* Other names: Imbruvica;Drug: Acalabrutinib<br>* Oral<br>* Other names: Calquence;Drug: Zanubrutinib<br>* Oral<br>* Other names: Brukinsa;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare progression-free survival (PFS) of pirtobrutinib as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) in patients with previously treated mantle cell lymphoma (MCL) | Assessed per Lugano criteria | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare Event Free Survival (EFS) as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms | Defined as the time from randomization to progressive disease (PD) or start of new treatment for MCL or withdrawal from trial due to toxicity or death | Up to approximately 24 months | 
| To compare Time to Treatment Failure (TTTF) as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms | Time from randomization to time when discontinuation criteria met | Up to approximately 24 months | 
| Time to worsening (TTW) of MCL-related symptoms | Using symptom questions identified from the European Organization for Research and Treatment of Cancer (EORTC) item library. The range of raw scores for these items could be from 0 to 52 with highest score being worse symptoms. | Up to approximately 24 months | 
| Comparative Tolerability as measured by proportion of time with high side effect burden | Using 18 items covering 10 Patient Reported Outcome- Common Terminology Criteria for Adverse Events (PRO-CTCAE) concepts for frequency (0-5 with 5 as most frequent), and/or presence (0-1 with 1 being present), or Severity (0-5 with 5 as most severe) and/or presence (0-1 with 1 being present); these selective adverse events will be framed and then overall side effect burden will be ascertained with the Functional Assessment of Cancer Therapy (FACT) - Item GP5. The range of this item is 0 -4 with 4 as most bothersome. | Up to approximately 24 months | 
| To compare Overall Response Rate (ORR) of pirtobrutinib as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms | Assessed per Lugano criteria | Up to approximately 24 months | 
| To compare Duration of Response (DOR) of pirtobrutinib as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms | Assessed per Lugano criteria | Up to approximately 24 months | 
| To compare Overall Survival of pirtobrutinib as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms | Assessed by survival | Up to approximately 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lymphoma, non-Hodgkin's, Bruton's Tyrosine Kinase Inhibitor, BTKi, Hematologic Disease, Lymphoma, B-Cell, Lymphoma, pirtobrutinib