| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mantle cell lymphoma |
| lymfom z plášťových buněk |
|
| E.1.1.1 | Medical condition in easily understood language |
| aggressive lymph node cancer of B-cell origin |
| agresivní nádorové onemocnění z mízních uzlin z B-buněk |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10026798 |
| E.1.2 | Term | Mantle cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective and Endpoint:
• To evaluate the efficacy of polatuzumab vedotin plus BR with respect to progression free survival (PFS)
To evaluate the efficacy of the combination of polatuzumab vedotin plus BR in patients with R/R MCL after failure of Bruton tyrosine-kinase inhibitor (ibrutinib or acalabrutinib) as measured by PFS. PFS will be measured from study treatment start until the first documented disease progression or relapse, or death from any cause, whichever occurs earlier.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives and Endpoints:
• To evaluate the efficacy of polatuzumab vedotin plus BR with respect to secondary efficacy endpoints measured by:
PET-defined objective response rate (ORR, complete or partial remissions) and complete remission (CR) rate using Modified Lugano 2014 Response Criteria (PET-CT criteria) at the time of final response assessment as determined by investigator.
Duration of response (DoR) measured as time from achievement of objective response by PET-CT or CT until disease relapse / progression as determined by investigator.
Event free survival (EFS) as determined by the investigator.
Overall survival (OS) measured from the study treatment start until death from any cause.
Safety Objective:
• To assess the safety and tolerability of the combination of polatuzumab vedotin with BR when administered to patients with R/R MCL
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet the following criteria for study entry:
• Signed written Informed Consent Form
• Adult patients with relapsed or refractory MCL after failure of BTK inhibitor-containing therapy (e.g. ibrutinib, acalabrutinib, zanubrutinib)
• Patients previously treated with bendamustine are eligible for the study treatment, in the case they had achieved objective response (CR or PR) and the last dose of bendamustine was administered ≥ 1 year before the estimated study treatment initiation date (C1D1)
• Tumor tissue at the lymphoma relapse after failure of BTK inhibitor. In case that a re-biopsy is not possible (e.g. urgent need to start study treatment), archival tissue blocks may be used to confirm the diagnosis
• Bone marrow examination by standard trephine biopsy including flow cytometry analysis within 8 weeks before study entry
• Age 18-80 years at the time of signing Informed Consent Form
• ECOG Performance Status of 0, 1, or 2
• Life expectancy ≥ 2 months
• Adequate hematologic function (unless due to underlying disease, as established for example, by extensive bone marrow involvement or due to hypersplenism secondary to the involvement of the spleen by MCL per the investigator), defined as follows:
– Hemoglobin ≥ 80g/L
- Leukocyte count ≥ 3,000/uL
– ANC ≥ 1,500/μL
– Platelet count ≥ 75,000/μL
Enrollment of patients with lower counts is possible only after consulting the medical monitor.
• Adequate cardiac functions according to echocardiography (ECHO) within 6 months before study entry
|
|
| E.4 | Principal exclusion criteria |
• Prior organ transplantation
• Current Grade ≥ 2 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease
• History of other malignancy that could affect compliance with the protocol or interpretation of results
Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible
Patients with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible
Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage
1 or 2) with no requirement for therapy at any time prior to study are eligible.
• Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results.
• Recent major surgery (e.g. within 4 weeks prior to the start of Cycle 1), other than for diagnosis
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or significant infections within 2 weeks before the start of Cycle 1.
• Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
• Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment
• Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma):
INR > 1.5 x upper limit of normal (ULN) in the absence of therapeutic anticoagulation aPTT > 1.5 x ULN in the absence of a lupus anticoagulant
• Serum AST and ALT > 3 x ULN
• Total bilirubin > 1,5 x ULN
Patients with documented Gilbert disease may be enrolled if total bilirubin is < 3.0 x ULN.
• Serum creatinine clearance < 40 mL/min (using Cockcroft-Gault formula or creatinine levels assessed directly from the collected urine)
• Patients with suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay)
• Positive test results for chronic hepatitis B infection defined as positive hepatitis B surface antigen (HBsAg) serology
• Patients with occult or prior hepatitis B infection defined as positive total hepatitis B core antibody and negative HBsAg may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. These patients must be willing to undergo regular DNA testing and appropriate antiviral therapy as indicated.
• Positive test results for hepatitis C virus (HCV) antibody serology testing
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• Known history of HIV seropositive status
• Patients with a history of progressive multifocal leukoencephalopathy
• Pregnancy or lactation or intending to become pregnant during study
• CNS lymphoma
In patients with clinical signs attributable to CNS lymphoma, CT scan (MRI also acceptable) of the head and examination of cerebrospinal fluid will be required prior to study treatment initiation
• Vaccination with live or attenuated vaccines 30 days before initiation of study treatment
• Known hypersensitivity to Polatuzumab Vedotin, Rituximab or bendamustine, or their excipients
• Clinically significant immunosuppression
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• To evaluate the efficacy of polatuzumab vedotin plus BR with respect to progression free survival (PFS)
To evaluate the efficacy of the combination of polatuzumab vedotin plus BR in patients with R/R MCL after failure of Bruton tyrosine-kinase inhibitor (ibrutinib or acalabrutinib) as measured by PFS. PFS will be measured from study treatment start until the first documented disease progression or relapse, or death from any cause, whichever occurs earlier.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim PET-CT should be performed in between C2D15, C3D1 and at the End of treatment and
then during follow up every 3 months during the year 1 of the follow up, and every 6 months during the year 2 of the follow up, or until study end or at any time that progression is suspected via clinical response assessment.
|
|
| E.5.2 | Secondary end point(s) |
To evaluate the efficacy of polatuzumab vedotin plus BR with respect to secondary efficacy endpoints:
To evaluate the efficacy of the combination of polatuzumab vedotin plus BR in patients with R/R MCL after failure of Bruton tyrosine-kinase inhibitor (ibrutinib or acalabrutinib) as measured by:
PET-defined objective response rate (ORR, complete or partial remissions) and complete remission (CR) rate using Modified Lugano 2014 Response Criteria (PET-CT criteria) (Appendix 4) at the time of final response assessment as determined by investigator.
Duration of response (DoR) measured as time from achievement of objective response by PET-CT or CT until disease relapse / progression as determined by investigator.
Event free survival (EFS) as determined by the investigator. EFS will be measured from study treatment start until disease relapse / progression, initiation of a new therapy without documented progression, premature termination of the study or death because of any cause
Overall survival (OS) measured from the study treatment start until death from any cause.
Safety Objective:
• To assess the safety and tolerability of the combination of polatuzumab vedotin with BR when administered to patients with R/R MCL
Safety will be evaluated through the monitoring of adverse events (AEs), including serious adverse events (SAEs), measurement of protocol-specified safety laboratory assessments and vital signs. Incidence, nature, and severity of adverse events, with severity determined through use of NCI CTCAE v5.0. Incidence and nature of study drug discontinuation, dose reduction, and dose delay due to adverse events.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Interim PET-CT should be performed in between C2D15, C3D1 and at the End of treatment and
then during follow up every 3 months during the year 1 of the follow up, and every 6 months during the year 2 of the follow up, or until study end or at any time that progression is suspected via clinical response assessment.
For response assessment Lugano Response Criteria for malignant lymphoma will be followed (Lugano 2014).
Safety assessment will be performed during the treatment phase of the study at C1D1,D2,D3,D8,D15; C2D1,D2, D15; C3-C6D1, D2, End of treatment visit and then during per protocol follow-up visits and
at any time if clinically indicated. Incidence, severity, nature of AEs will be determined according to CTCAE v.5.0. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 study: The length of study will be the time from screening of the first enrolled patient through 2 years after the End of Treatment Visit for the last enrolled patient. |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
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