| 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 progression-free survival (PFS) of LOXO-305 as monotherapy (Arm A) to investigator choice of covalent BTK inhibitor monotherapy (Arm
B) in patients with previously treated mantle cell lymphoma (MCL) |
|
| E.2.2 | Secondary objectives of the trial |
-To compare efficacy of LOXO-305 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 on radiologic assessment as defined by Lugano criteria: at least one nodal lesion (> 1.5 cm in long axis) or extra-nodal 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.
• ECOG 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 on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs, 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, lactation or plan to breastfeed during the study or within 30 days of the last dose of study treatment.
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (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 and non-metastatic breast or prostate cancer where hormonal therapy is being continued as standard of care are allowed.
Prior/Concomitant Therapy
• Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong P-gp inhibitors.
Because of their effect on CYP3A4, use of any of the following within 3 days of study therapy start or planned use during study participation is prohibited: grapefruit or grapefruit products, Seville oranges or products from Seville oranges, star fruit.
• Steroid use with anti-neoplastic intent within 7 days of study drug initiation.
• Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
• Vaccination with live vaccine within 28 days prior to randomization.
• Have a known hypersensitivity to any of the excipients of LOXO-305 or to the intended covalent BTK inhibitor if randomized to control arm. |
|
| 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
• Overall response rate (ORR) per Lugano criteria
• Duration of response (DOR) per Lugano criteria
Assessed by investigator assessment:
• PFS per Lugano criteria
• OS
• EFS
• TTF
• TTNT
• 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
• 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 new treatment for MCL or withdrawal from trial due to toxicity or death, whichever occurs first
TTF - composite endpoint, discontinuation of treatment for any reason
TTNT - date of the next non-protocol-specified therapy for progressive MCL
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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Australia |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| New Zealand |
| Russian Federation |
| Singapore |
| Taiwan |
| United States |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Czechia |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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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