| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| a cancer of white blood cells (developing in a certain part of the lymph node), which help the body fight infections |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10026799 |
| E.1.2 | Term | Mantle cell lymphoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare PFS of pirtobrutinib as monotherapy (Arm A) to Investigator choice of covalent BTK inhibitor monotherapy (Arm B) in patients with previously treated with MCL |
|
| E.2.2 | Secondary objectives of the trial |
-To compare efficacy of pirtobrutinib as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm B) treatment arms
-To evaluate the safety and tolerability of each treatment arm
-To evaluate the patient-reported outcomes |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• At least 18 years of age
• Confirmed diagnosis by local laboratory of MCL with documentation of
overexpression of cyclin D1 with at least one B-cell marker (e.g., CD19,
CD20, or PAX5) and/or t (11;14) by cytogenetics, fluorescent in situ
hybridization (FISH) or polymerase chain reaction.
• Previously treated with at least one prior line of systemic therapy for
MCL.
• Measurable disease by PET-CT and/or CT/MRI as defined by Lugano
criteria and aligned with protocol imaging requirements:
- PET-CT: FDG (fluorodeoxyglucose) avid lymphoma lesion
- at least one nodal lesion (> 1.5 cm in long axis) or extranodal
lesion (> 1.0 cm in long axis) measurable in 2 dimensions, not
previously radiated (unless progression has been radiographically
documented following radiation therapy).
• Documented evidence of radiographically and/or histologically
confirmed PD on the most recent line of therapy or relapse prior to study
enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Adequate organ function
• Must have life expectancy of at least 3 months |
|
| E.4 | Principal exclusion criteria |
• Current suspected or confirmed active CNS involvement with MCL or previous CNS involvement.
• Prior treatment with an approved or investigational BTK inhibitor.
• Major surgery within 4 weeks prior to randomization.
• 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.
• Significant cardiovascular disease.
• Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec during Screening.
• Known human immunodeficiency virus (HIV) infection, regardless of CD4 count.
• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
• Pregnancy during the study or within 3 months of the last dose of study treatment.
• Clinically significant active malabsorption syndrome or other condition likely to affect GI absorption of the study drug.
• Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required.
• History of second malignancy unless in remission for at least 2 years; in-situ carcinomas not requiring treatment intervention, , non-melanoma skin cancer curatively treated, nonmetastatic breast, or nonmetastatic prostate cancer where hormonal therapy is being continued as standard of care are allowed.
Prior/Concomitant Therapy
• 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.
Because of their effect on CYP3A4, use of any of the following within 3 days of study therapy start is prohibited: Grapefruit or grapefruit
products, Seville oranges or products from Seville oranges, Star fruit or star fruit products.
• Steroid use with antineoplastic intent within 7 days of study drug
initiation.
• Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
• Vaccination with a live vaccine within 28 days prior to randomization.
• Have a known hypersensitivity to any of the excipients of pirtobrutinib or to the intended covalent BTK inhibitor if randomized to control arm.
•Laction, or plan to breastfeed during the study or within 2 weeks of the last dose of study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Assessed by independent review committee (IRC)
• PFS per Lugano criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time from the date of randomization until PD or death from any cause, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
Assessed by both Investigator assessment and IRC
• ORR per Lugano criteria
• DOR per Lugano criteria
Assessed by Investigator assessment:
• PFS per Lugano criteria
• OS
• Event-free survival (EFS)
• Time to treatment failure (TTF)
• Time to next treatment (TTNT)
• Progression-free survival 2 (PFS2)
Incidence and severity of serious adverse events (SAEs), adverse events (AEs), deaths, and clinical laboratory abnormalities per Common Terminology
Criteria for Adverse Events (CTCAE v5.0)
• Comparative tolerability: proportion of time with high side-effect burden
• Time to worsening (TTW) of MCL-related symptoms |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR - achieving a BOR of CR or PR
DOR - earlier of the documentation of definitive PD or death from any cause
PFS - PD or death from any cause, whichever occurs first
OS - death from any cause
EFS - date of PD or start of subsequent anticancer therapy for MCL or
withdrawal from treatment due to toxicity or death, whichever occurs
first
TTF - composite endpoint, discontinuation of treatment for any reason
TTNT - date of subsequent anticancer therapy for MCL, or death,
whichever occurs first
PFS 2 - disease progression on next line treatment, or death from any
cause |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 71 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| New Zealand |
| Switzerland |
| Ireland |
| Taiwan |
| Australia |
| Austria |
| Belgium |
| Canada |
| China |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of the study is estimated at approximately 24 months from the last subject randomized |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 23 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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