| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Mature T- and NK-cell Neoplasms |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mature T-cell and nature killer (NK)-cell lymphomas are lymphoid malignancies that are derived from proliferation of mature post-thymic lymphocytes. |
|
| 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 | HLGT |
| E.1.2 | Classification code | 10025321 |
| E.1.2 | Term | Lymphomas non-Hodgkin's T-cell |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
To evaluate efficacy of tislelizumab in patients Relapsed or Refractory Mature T- and NK-cell Neoplasms as measured by overall response rate and determined by investigator.
• For cohorts 1 and 2, overall response rate will be measured using the Lugano criteria (Cheson et al 2014) with Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) modification for immunomodulatory drugs (Cheson et al 2016).
• For cohort 3, overall response rate will be measured using the International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) guidelines (Olsen et al 2011).
|
|
| E.2.2 | Secondary objectives of the trial |
For cohorts 1 and 2, efficacy measures will be determined using the Lugano criteria (Cheson et al 2014) with LYRIC modification for
immunomodulatory drugs (Cheson et al 2016). For cohort 3, efficacy measures will be determined using the ISCL/EORTC guidelines (Olsen et al 2011).
• To evaluate the efficacy of tislelizumab, as determined by the investigator and measured by the following:
- Duration of response for all cohorts
- Progression-free survival for all cohorts
- Overall survival for cohorts 1 and 2
- Rate of complete response or complete metabolic response for all cohorts
- Time to response for all cohorts
- Patient-reported outcomes (EQ-5D-5L and EORTC QLQ-C30) for all cohorts
• To evaluate safety and tolerability of tislelizumab for all cohorts |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of relapsed or refractory, mature Tcell and NK-cell neoplasms based on the WHO 2016 classification of tumors of hematopoietic and lymphoid tissue. Patients will be allocated to three cohorts based on their histologic diagnosis:
• Cohort 1: Extranodal NK/T-cell lymphoma (nasal or non-nasal type)
➢ Patients with aggressive NK leukemia are excluded
• Cohort 2: Other mature T-cell neoplasms, limited to the following
histologies:
➢ Peripheral T-cell lymphoma - not otherwise specified (PTCL-NOS)
➢ Angioimmunoblastic T-cell lymphoma (AITL)
➢ Anaplastic large cell lymphoma (ALCL)
• Cohort 3: Stage IB-IVB cutaneous T-cell lymphomas, limited to the following histologies:
➢ Mycosis fungoides (MF)
➢ Sèzary syndrome (SS)
2. Male or female ≥ 18 years of age at the time of informed consent (or
acceptable age according to local regulations, whichever is older)
3. Previously received 1 or more appropriate systemic therapies (e.g. non-anthracycline based regimens such as L-asparaginase-based therapy) for cohort 1 or combination chemotherapy (e.g. CHOP, EPOCH, or similar therapy) for cohort 2. Radiation therapy alone would not be acceptable as previous therapy
• For patients with relapsed or refractory anaplastic large cell lymphoma regardless of anaplastic lymphoma kinase (ALK) status, must have received prior therapy with brentuximab vedotin (applicable only to countries where brentuximab vedotin received marketing approval)
4. Disease progression during or after completion of most recent therapy or refractory disease. Refractory disease is defined as failure to achieve CR or PR to most recent therapy, and most recent therapy was an appropriate systemic therapy for mature T-cell or NK-cell lymphoma
5. For cohorts 1 and 2, patients must have lesions that are measurable by imaging, where measurable is defined as ≥ 1 lesion that is > 1.5 cm for nodal lesions and > 1 cm for extranodal lesions.
For cohort 3, patients are not required to have measurable disease by imaging.
6. Availability of either unstained tissue (block or unstained slides) or stained slides, and pathology report for central confirmation of mature T-cell or NK-cell lymphoma. If stained slides or unstained tissue (block or unstained slides) are not available or are insufficient, a fresh tumor tissue sample is mandatory for central pathology. Central pathology confirmation is not required prior to enrollment.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see table 3 in protocol).
8. Has life expectancy ≥ 6 months.
9. Patients must have forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 60% by pulmonary function test
(PFT), carbon monoxide diffusion capacity (DLCO) > 60% predicted value, and FEV1 and FVC > 50% predicted value; all PFTs must be obtained within 4 weeks prior to the first dose of tislelizumab.
10. Adequate organ function defined as:
• Absolute neutrophil count (ANC) > 1000/mm3(without growth factor
support within 7 days of ANC measurement)
• Platelet > 50000/mm3(without growth factor support or transfusion
within 7 days of platelets measurement)
• Hemoglobin > 80 g/L (prior transfusion is acceptable)
• Creatinine clearance ≥ 30 ml/min (as estimated by the CockcroftGault
equation or as measured by nuclear medicine
scan or 24-hour urine collection) (see Appendix 9 of protocol)
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic
transaminase, and alanine aminotransferase
(ALT)/serum glutamic pyruvic transaminase ≤ 3.0 × upper limit of
normal (ULN)
• Serum total bilirubin < 2.0 × ULN (unless documented Gilbert's
syndrome)
11. Female patients of childbearing potential must be willing to use a highly effective method of birth control/contraception for the duration of the study, and for at least 120 days after the last dose of tislelizumab, and have a negative serum pregnancy test within 7 days of the first dose of study drug. Please refer to Appendix 4 for a list of acceptable birth control/contraception methods and contraceptive guidelines.
12. Non-sterile males must be willing to use a highly effective method of
birth control/contraception for the duration of the study and for at least
120 days after the last dose of tislelizumab
• Sterile males are those for whom azoospermia, in a semen sample examination, has been demonstrated as definitive evidence of infertility.
• Males with “low sperm counts” (consistent with “sub-fertility”) are not to be considered sterile for purposes of this study.
13. Ability to provide written informed consent and can understand and
comply with the requirements of the study
|
|
| E.4 | Principal exclusion criteria |
1. Known central nervous system involvement by leukemia or lymphoma
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 agent
3. Meets one of the following scenarios for hematopoietic stem cell transplantation and/or chimeric antigen receptor T cell (CAR-T) therapy:
• Is eligible for autologous or allogeneic stem cell transplantation, unless patient has refused transplantation
• Has undergone prior allogeneic hematopoietic stem cell transplantation or organ transplantation
• Has received autologous stem cell transplantation within 6 months prior to first dose of study drug
• Has received CAR-T therapy within 12 months prior to first dose of study drug
4. Has received:
• Systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks (or 5 half-lives, whichever is shorter) prior to study Day 1
• Recent treatment with another monoclonal antibody within 4 weeks prior to study Day 1
• Investigational treatment or device within 4 weeks (or 5 half-lives, whichever is shorter) prior to study Day 1
• For cohort 3 patients, phototherapy within 2 weeks or any topical
therapy within 1 week prior to study Day 1
•Or has not recovered from AEs (ie, ≤ Grade 1 or baseline level) due to prior therapy
5. Concurrent or prior malignancy within the past 3 years, except for curatively treated
basal or squamous cell skin cancer, superficial bladder cancer, carcinoma
in situ of the cervix or breast, or localized Gleason score 6 or lower
prostate cancer
6. Active autoimmune diseases or history of autoimmune diseases that
may relapse (see Appendix 3) Note: Patients with the following diseases
are not excluded and may proceed to further screening:
a. Type I diabetes under control
b. Hypothyroidism (provided it is managed with hormone replacement
therapy only)
c. Controlled celiac disease
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis,
alopecia) except when such diseases significantly interfere with
response assessment of patients in cohort 3
e. Any other disease that is not expected to recur in the absence of
external triggering factors
7. Has known history of interstitial lung disease, non-infectious
pneumonitis, pulmonary fibrosis, acute lung diseases or evidence of
dyspnea at rest or pulse oximetry of < 92% while breathing room air
8. Has any condition that required systemic treatment with either
corticosteroids (> 10 mg daily of prednisone or equivalent) or other
immunosuppressive medication within 14 days before study drug
administration. Note: Patients who are currently or have previously been
on any of the following steroid regimens are not excluded:
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or
equivalent)
b. Topical, ocular, intra-articular, intranasal, or inhalational
corticosteroid with minimal systemic absorption except when given for
treatment of MF or SS
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically
(eg, for contrast dye allergy) or for the treatment of a non-autoimmune
condition (eg, delayed-type hypersensitivity reaction caused by contact
allergen
9. Has a known active TB (Bacillus Tuberculosis) infection
10. Known infection with HIV, human T-cell lymphotropic virus (HTLV)-1, -2, or serologic status reflecting active hepatitis B or C infection as follows:
• Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible only if hepatitis B virus (HBV) DNA is undetectable by an assay with sensitivity ≤ 20 IU/mL. If so, patients may either undergo regularly scheduled monitoring of HBV DNA or less frequent monitoring of HBV DNA while on prophylactic antiviral medication as defined by regional standard of care.
• Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible only if HCV RNA is undetectable.
11. Active fungal, bacterial, and/or viral infection requiring systemic
therapy
12. Vaccination with a live vaccine within 35 days prior to the first dose
of study drug
13. Clinically significant cardiovascular disease including the following:
• Myocardial infarction within 6 months before screening
Unstable angina within 3 months before screening
• New York Heart Association Classification III or IV congestive heart
failure
(Appendix 5)
• History of clinically significant arrhythmias (please refer to the protocol)
14. Major surgery within 4 weeks of the first dose of study drug
15. Ongoing alcohol or drug addiction
16. Underlying medical or social conditions that, in the opinion of the investigator
and/or medical monitor, will render the administration of study drug
hazardous or obscure the interpretation of safety or efficacy results.
Please refer to the protocol for the remaining exclusion criteria
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is overall response rate as determined by investigator. Overall response rate is defined as the proportion of
patients achieving a best overall response of complete response or partial response. Efficacy will be assessed every 12 weeks for 96 weeks, then every 24 weeks for an additional 96 weeks, and then yearly until
disease progression.
• For cohorts 1 and 2, overall response rate will be measured using the Lugano criteria (Cheson et al 2014) with LYRIC modification for immunomodulatory drugs (Cheson et al 2016).
• For cohort 3, overall response rate will be measured using the ISCL/EORTC guidelines (Olsen et al 2011).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy will be assessed every 12 weeks for 96 weeks, then every 24
weeks for an additional 96 weeks, and then yearly until disease
progression.
|
|
| E.5.2 | Secondary end point(s) |
• For cohorts 1 and 2, efficacy measures will be determined using the Lugano criteria (Cheson et al 2014) with LYRIC modification for immunomodulatory drugs (Cheson et al 2016). For cohort 3, efficacy measures will be determined using the ISCL/EORTC guidelines (Olsen et al 2011). All measures will be assessed by the investigator.
• Duration of response defined as the time from the first determination of an objective response until progression or death, whichever occurs first, for all cohorts
• Progression-free survival defined as the time from first study drug administration to the date of disease progression or death, whichever occurs first, for all cohorts
• Overall survival, defined as the time from first study drug administration to the date of death due to any reason, for cohorts 1 and
2
• Rate of complete response or complete metabolic response defined as the proportion of patients who achieve complete response or complete metabolic response as best overall response, for all cohorts
• Time to response defined as the time from first study drug administration to the time the response criteria (complete response or
partial response) are first met, for all cohorts
• Patient-reported outcomes measured by EORTC QLQ-C30 and EQ-5D-5L questionnaires for all cohorts
• Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, and vital signs for all cohorts
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
A) Duration of response until progression or death, whichever occurs
first, for all cohorts
B) Progression-free survival at selected timepoints, for all cohorts
C) Overall Survival (OS) at selected timepoints, for cohorts 1 and 2
D) Rate of complete response or complete metabolic response, for all
cohorts
E) Time-to-response at selected timepoints, for all cohorts
F) The EORTC QLQ-C30 and EQ-5D-5L questionnaires will be summarized
for each assessment timepoint, for all cohorts
G) Safety and Pharmacokinetic parameters as assessed by investigator
|
|
| 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 | 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 | 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.8.2.4 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Canada |
| China |
| France |
| Germany |
| Hong Kong |
| Italy |
| Taiwan |
| 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
|
Study termination is defined as the time point when data collection will stop and the final analysis of the study will occur. The study will continue until the last patient has died, becomes lost to follow-up, or withdraws from study, or until sponsor decides to terminate the study.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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