| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B-Cell Lymphoma (DLBCL) |
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| E.1.1.1 | Medical condition in easily understood language |
| A cancer of B cells, a type of white blood cell responsible for producing antibodies |
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| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 evaluate the safety and tolerability of tafasitamab administered once every 2 weeks (Q2W)/once every 4 weeks (Q4W) in combination with lenalidomide in R/R DLBCL patients
• To determine a recommended dose for tafasitamab Q2W/Q4W administration in combination with lenalidomide in R/R DLBCL patients
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the pharmacokinetic profile of tafasitamab after Q2W/Q4W dosing in combination with lenalidomide
• To assess anti-tumor activity of tafasitamab after Q2W/Q4W dosing in combination with lenalidomide
• To assess the incidence of anti-drug antibodies to tafasitamab |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Capable of giving signed informed consent as described in Appendix 2: Regulatory, Ethical, and Trial Oversight Considerations, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Patient must be at least 18 years of age and of legal age (whichever is higher) in the jurisdiction in which the study is taking place at the time of signing the informed consent.
3. One of the following histologically confirmed diagnoses:
• DLBCL not otherwise specified (NOS)
• T cell/histiocyte-rich large B-cell lymphoma (THRLBCL)
• Epstein-Barr virus (EBV) positive DLBCL of the elderly (EBV-positive DLBCL)
• Grade 3b Follicular Lymphoma
• Composite lymphoma with a DLBCL component with a subsequent DLBCL relapse, according to the Revised European American Lymphoma/World Health Organization (REAL/WHO) classification.
Additionally, patients with the evidence of histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma (i.e., an indolent pathology such as follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia) into DLBCL with a subsequent DLBCL relapse are also eligible.
4. Tumor tissue for retrospective central pathology review must be provided as an adjunct to participation in this study. If archival formalin fixed paraffin embedded tumor tissue acquired ≤3 years prior to screening is not available, a fresh tumor tissue sample from the patient should be obtained. Archival formalin fixed- paraffin embedded tumor tissue acquired >3 years prior to screening is acceptable only in cases where a fresh tumor biopsy cannot be collected due to a safety risk e.g due to co-morbidity, or inaccessible tumor site.
5. Patients must have:
a. Relapsed and/or refractory disease as defined in Appendix 3: Study Specific Definitions
b. At least one bidimensionally measurable disease site. The lesion must have a greatest transverse diameter of ≥ 1.5 cm and greatest perpendicular diameter of ≥ 1.0 cm at baseline. The lesion must be positive on positron emission tomography (PET) scan (for definition see Juweid et al., 2007)
c. Received at least one, but no more than three previous systemic regimens for the treatment of DLBCL and one therapy line must have included a cluster of differentiation-20 (CD20)-targeted therapy (e.g., rituximab [RTX])
d. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
6. Patients that are not eligible to undergo intensive salvage therapy including autologous stem cell transplantation (ASCT). The reason for a patient’s ineligibility must meet one of the criteria described below and documented in the patient’s source data:
a. Inadequate performance status (Karnofsky performance status ≤ 80%
b. Disease not responsive to salvage chemotherapy. Responsiveness is defined as a tumor demonstrating either complete response (CR) or partial response (PR) to salvage chemotherapy
c. Inadequate major organ function (any of the below):
i. symptomatic congestive heart failure
ii. lung function-forced vital capacity (FVC), forced expiratory volume in 1 second (FEV-1), and corrected diffusion capacity of the lung for carbon monoxide (DLCO) ≤ 60%
iii. liver function-total serum bilirubin and transaminases > 2 x upper limit of normal (ULN)
d. History or evidence of significant co-morbid medical or psychiatric illness which would significantly compromise the patient's clinical care and chances of survival
e. Inability to collect adequate stem cell graft (e.g. < 1–2 x 106 CD34+ cells free of tumor contamination/kg recipient body weight)
7. Patients must meet the following laboratory criteria at screening:
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by recent bone marrow aspiration and bone marrow biopsy)
b. Platelet count ≥ 75 × 109/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by recent bone marrow aspiration and bone marrow biopsy)
c. Total serum bilirubin ≤ 2.5 × ULN unless secondary to Gilbert’s syndrome or documented liver involvement by lymphoma. Patients with Gilbert’s syndrome or documented liver involvement by lymphoma may be included if their total bilirubin is ≤ 5 × ULN (see exclusion criterion 6g)
d. Alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) ≤ 3 × ULN or < 5 × ULN in cases of documented liver involvement
e. Serum creatinine CL must be ≥ 60 mL/minute either measured or calculated using a standard Cockcroft and Gault formula
8. Patients who received previous CD19 targeted therapy (other than tafasitamab) must have CD19 positive lymphoma confirmed on a biopsy taken since completing the prior CD19-targeted therapy
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| E.4 | Principal exclusion criteria |
1. General provisions:
a. Patients who are legally institutionalized, or patients under judicial protection
b. Concurrent enrollment in another interventional clinical study
2. Patients who have:
a. Any other histological type of lymphoma including primary mediastinal (thymic) large B-cell (PMBL) or Burkitt lymphoma
b. Known "double/triple hit" genetics (high grade B-cell lymphoma) characterized by simultaneous detection of MYC with BCL2 and/or BCL6 translocation(s). MYC, BCL2, BCL6 testing prior to study enrollment is not required
3. Patients who have:
a. Not discontinued (within 14 days prior to Day 1 dosing): CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy or other lymphoma-specific therapy
b. Undergone major surgery (within 4 wks prior to Day 1 dosing) or suffered from significant traumatic injury
c. Received live vaccines (within 4 wks prior to Day 1 dosing)
d. Required parenteral antimicrobial therapy for active, intercurrent infections (within 14 days prior to Day 1 dosing)
4. Patients who:
a. Have not recovered sufficiently from the adverse toxic effects of prior therapies
b. Were previously treated with tafasitamab or IMiDs® (e.g., thalidomide, LEN)
c. Have a history of hypersensitivity to compounds of similar biological or chemical composition to tafasitamab, IMiDs® and/or the excipients contained in the study treatment formulations
d. Have undergone ASCT within the period ≤ 3 months prior to signing the ICF. Patients with distant history of ASCT must exhibit full hematological recovery before enrollment
e. Have undergone previous allogenic stem cell transplantation
f. Have a history of DVT/embolism, threatening thromboembolism or known thrombophilia or at high risk for a thromboembolic event & who are not willing to take VTE prophylaxis during the entire treatment period
g. Concurrently use other anticancer or experimental treatments
5. History of other malignancy that could affect protocol compliance or interpretation of results. Exceptions:
a. Any malignancy treated with curative intent and malignancy in remission without treatment for > 2 years prior to enrollment are eligible
b. 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
6. Patients with:
a. Positive hepatitis B and/or C serology
b. Known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV)
c. CNS lymphoma involvement – present or past medical history
d. History or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that precludes participation in study or compromises ability to give informed consent
e. History or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
f. GI abnormalities (absorption issues) including inability to take oral medication
g. History or evidence of severe hepatic impairment (total serum bilirubin > 3 mg/dL), jaundice unless secondary to Gilbert’s syndrome or documented liver involvement by lymphoma (see inclusion criterion 7c)
h. History of hypersensitivity to study treatments or excipients or to drugs of similar chemical class
i. Any other medical condition which makes the patient unsuitable for the study
7. Contraception provisions:
Females: Due to the teratogenic potential of LEN, FCBP must follow the rules listed below (otherwise excluded):
All countries except US:
a. Not be pregnant (confirmed negative serum pregnancy test) at screening & urine pregnancy test prior to starting therapy
b. Refrain from breast feeding and donating oocytes during study and for 3 months after last dose
c. Agree to ongoing pregnancy testing during study and after study treatment has ended. This includes pregnancy testing and counseling if a patient misses her period or if there is any abnormality in her menstrual bleeding and applies even if the patient applies complete sexual abstinence
d. Commit to continued abstinence (reviewed monthly) or agree to use highly effective contraception, no interruption, at least 4 wks prior to study start, during treatment, 3 months after the last dose*
US:
e. Not be pregnant - confirmed pregnancy test before treatment start, within 10–14 days & within 24 hrs of treatment (even with abstinence)
f. Refrain from breast feeding and donating oocytes during study & for 3 months after the last dose*
g. Agree to ongoing pregnancy testing during the study (every 4 weeks) & at study therapy has ended (even if
true abstinence is the chosen method of birth control). This includes pregnancy testing and counseling if a patient misses her period or if there is any abnormality in her menstrual bleeding
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence and severity of TEAEs |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1) Primary Analysis all available data up until all patients in the study have either reached C3D28 or discontinued the study prior to C3D28.
2) Final Analysis all available data until approximately 3 years after the last patient was enrolled.
• Tafasitamab serum concentrations after 3 (Ctrough and Cmax) and 12 (Ctrough) treatment cycles
• Best Objective Response Rate (ORR) by Investigator assessment up to treatment Cycle 12 based on Cheson et al. (2007)
• Duration of Response (DoR) by Investigator assessment based on Cheson et al. (2007)
• Progression-Free Survival (PFS) by Investigator assessment based on Cheson et al. (2007)
• Number and percentage of patients developing anti- tafasitamab antibodies up to treatment Cycle 12
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tafasitamab: days 1, 4, 8, 15 cycle 1; day 1, 15 cycles 2 &3; days 1 & 28 cycle 4-12; EOT
ORR: PET CT or PET-MR at screening, day 28 cycle 12; day 1 cycle 13+; EOT; bone marrow assessment at screening, day 15 cycle 3; day 1 cycle 4-12; day 1 cycle 13+
DoR: screening; day 1 cycle 1; day 1 cycle 3, day 1 cycle 4-12; day 1 cycle 13+; EOT
PFS: as per DoR
ADA: day 1 cycle 1-3; day 1, cycles 4, 6, 8, 10; cycle 12; days 1 & 28; EOT
The timing information included here (e.g., 12 treatment cycles, or cycle 13+) is referring to the Final Analysis, as that data will not be available in a Primary Analysis (except only the patients who make it to those later cycles).
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| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity, biomarkers, genetic analysis |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Safety and preliminary efficacy |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Israel |
| United States |
| Austria |
| Czechia |
| France |
| Italy |
| Poland |
| Spain |
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| 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
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The end of the study is reached when all patients still on study treatment have been followed for at least 3 years, or when the final patient on study has completed their last visit, whichever comes first.
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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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