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.
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
Primary outcome:
1. 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) (Time Frame - Up to approximately 24 months):
Assessed per Lugano criteria
Secondary outcome:
1. To compare Event Free Survival (EFS) as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms (Time Frame - Up to approximately 24 months):
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
2. To compare Time to Treatment Failure (TTTF) as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms (Time Frame - Up to approximately 24 months):
Time from randomization to time when discontinuation criteria met
3. Time to worsening (TTW) of MCL-related symptoms (Time Frame - Up to approximately 24 months):
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.
4. Comparative Tolerability as measured by proportion of time with high side effect burden (Time Frame - Up to approximately 24 months):
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.
5. To compare Overall Response Rate (ORR) of pirtobrutinib as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms (Time Frame - Up to approximately 24 months):
Assessed per Lugano criteria
6. To compare Duration of Response (DOR) of pirtobrutinib as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms (Time Frame - Up to approximately 24 months):
Assessed per Lugano criteria
7. To compare Overall Survival of pirtobrutinib as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms (Time Frame - Up to approximately 24 months):
Assessed by survival
- Experimental: Arm A (Pirtobrutinib)
Orally - Active Comparator: Arm B (Ibrutinib, Acalabrutinib, or Zanubrutinib)
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.
- Pirtobrutinib (LOXO-305 / LY3527727 / ):
Oral - Ibrutinib (Imbruvica):
Oral - Acalabrutinib (Calquence):
Oral - Zanubrutinib (Brukinsa):
Oral
Quelle: ClinicalTrials.gov
