| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| B Cell Malignancies and Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| B Cell Malignancies and Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma |
|
| 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 | HLT |
| E.1.2 | Classification code | 10003900 |
| E.1.2 | Term | B-cell lymphomas NEC |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003908 |
| E.1.2 | Term | B-cell small lymphocytic lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
For dose escalation, Part 1:
To determine the recommended safe dose of TL-895 for dose expansion as single agent, in subjects with refractory/resistant B-cell malignancies who have failed at least 1 but no more than 3 prior lines of therapy.
For dose expansion, Part 2:
To determine the overall response rate (ORR) based on International Workshop on Chronic Lymphocytic Leukemia (iwCLL) response criteria per Investigator assessment |
|
| E.2.2 | Secondary objectives of the trial |
For dose escalation, Part 1:
- Assess the preliminary efficacy of TL-895 by best overall response, DOR and PFS by dose cohorts in subjects with B-cell malignancies
- Evaluate the safety and tolerability of TL-895 in subjects with refractory/resistant B-cell malignancies including MCL and DLBCL (ABC subtype)
- Evaluate the effect of TL-895 on BTK occupancy in PBMCs of subjects with refractory/resistant B-cell malignancies including MCL and DLBCL (ABC subtype)
- Characterize the PK profile of TL-895, in subjects with refractory/resistant B-cell malignancies including MCL and DLBCL (ABC subtype)
For dose expansion, Part 2:
- To determine the complete response (CR)/complete response with incomplete bone marrow recovery (CRi) rate
- To assess the efficacy of TL-895 by DOR
- To evaluate the safety and tolerability of TL-895
- To characterize the PK profile of TL-895
- To evaluate the effect of TL-895 on BTK occupancy in PBMCs |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Showing Dose Expansion, Part 2 only:
1. Adults ≥18 years of age
2. Subject population (relapsed/refractory CLL or relapsed/refractory SLL)
a. Confirmed diagnosis of CLL or SLL per iwCLL 2008 (2) TL-895 TL-895 in Relapsed/Refractory B-cell Malignancies
b. Active disease meeting at least 1 of the iwCLL 2008 criteria for requiring treatment (Appendix I)
c. Previously treated for CLL or SLL with at least one prior regimen according to current guidelines
d. Measurable nodal lesion by computed tomography (CT)
3. ECOG performance status of ≤ 2
4. Adequate hematological function independent of growth factor support for at least 7 days with the exception of pegylated G-CSF and darbepoetin which require at least 14 days, defined as
a. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
b. Platelet count ≥ 50 × 109/L
5. Adequate hepatic function defined by:
a. Total bilirubin level within normal limits (WNL); if total bilirubin is > upper limit of normal (ULN) then subjects are eligible if the direct bilirubin is ≤2.0 x ULN
b. AST ≤ 2.5 × ULN, and ALT ≤ 2.5 × ULN.
6. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according Cockcroft Gault
7. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential, must both use a highly effective contraception method during the study. |
|
| E.4 | Principal exclusion criteria |
Dose Expansion (Part 2) only:
To be eligible for inclusion in the dose expansion part of this trial, subjects must not meet any of the following criteria:
1. Prior anticancer treatment with any BTK or PI3K inhibitor
2. Known history of central nervous system lymphoma or leukemia
3. History of Richter’s transformation or prolymphocytic leukemia
4. Prior therapy with:
• Anticancer treatment with chemotherapy, immunomodulating therapy, biologic therapy,
radiation therapy, or with any other anticancer therapy within 28 days prior to first dose of study treatment.
• Any investigational agent within 28 days prior to first dose of study treatment. Participation in observational study is permitted.
• Allogeneic stem cell transplant or active graft versus host disease following allogeneic transplant within 6 months prior to first dose of study treatment.
• Autologous stem cell transplant within the last 3 months prior to first dose of study treatment.
5. Subjects with a history of bleeding diathesis or major hemorrhage (unrelated to trauma) within 6 months prior to first dose of study treatment
6. History of stroke or intracranial hemorrhage within 6 months prior to first dose of study treatment.
7. Received major surgical intervention within 28 days prior to first dose of study treatment, or history of major organ transplant.
8. Having history of difficulty of swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study treatment.
9. Uncontrolled intercurrent illness including, but not limited to clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; unstable ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements.
10. Grade 2 or higher QTc prolongation (> 480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0]).
11. Subjects with uncontrolled bacterial, fungal, parasitic, or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these subjects may be on antibiotics at time of screening
12. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV)
13. Subjects with known history of human immunodeficiency virus (HIV)
14. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma.
15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
16. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study. Proton-pump inhibitors must be stopped at least 5 days prior to the first dose of TL-895.
17. Women who are pregnant or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Escalation, Part 1
- DLTs during Cycle 1
Dose Expansion, Part 2
- ORR, defined as the proportion of subjects achieving CR, CRi, nodular partial response (nPR), partial response (PR), or PR with lymphocytosis (PR-L) at any time while on the study based on iwCLL response criteria (2), as assessed by investigators |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: Baseline up to 28 Days (Cycle 1)
Part 2: Baseline up to end of study |
|
| E.5.2 | Secondary end point(s) |
Part 1 (dose escalation):
- Best overall response, Duration of response, Progression- free survival time
- Number of subjects With Adverse Events (AEs), Serious AEs, AEs Leading to Death and AEs Leading to Discontinuation
- Number of subjects with abnormalities in laboratory measurements, electrocardiogram (ECG)s, vital signs, and ECOG performance status
- Bruton's tyrosine kinase (BTK)occupancy in Peripheral blood mononuclear cell (PBMCs )
- PK parameters, including Area under the plasma concentration-time curve from time zero to 8 hours after administration (AUC0 8h), Cmax,Tmax, Dose normalized Area under the Curve from time 0 to 8 hours(AUC0-8h), Cmax/dose, Accumulation ratio for Area under the curve AUC0-8h [Racc(AUC0-8h)], Accumulation ratio for maximum plasma concentration Cmax [Racc(Cmax)]
Part 2:
- CR/CRi rate, defined as the proportion of subjects achieving CR/CRi based on iwCLL response criteria
- DOR, defined as time from initial response to disease progression or death from any cause
- Analyses of the safety and tolerability endpoints will include the following measurements or
assessments:
• Incidence, nature, severity of treatment-emergent AEs (TEAEs), and deaths, including the cause of death, from Screening up to the End of Treatment visit
• Clinical laboratory measurements, ECG measures, vital signs, ECOG performance status from Screening up to the End of Treatment visit
- TL-895 PK parameters, including but not limited to:
• Predose concentration (C0h)
• Concentration at 2 hours post-dose (C2h)
• Cmax
• Tmax
• AUC
- BTK occupancy in PBMCs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1:
- Months 3 and 6
- Screening up to EOT visit
- Screening up to EOT visit
- screening, Pre-dose , 2 hours post dose on Day 1, 15 ; post dose on Day 22
- Pre-dose, Hour 0.5, 1, 2, 3, 4, 6, 8 post dose on Day 1, 15 ; Hour 2 post dose on Day 22
Part 2:
- From Screening up to the End of Treatment visit
- From initial response to disease progression or death from any cause
- From Screening up to the End of Treatment visit
- C1 D1 and D8: Predose (within 30 minutes prior to the morning dose), 0.5, 1.0, 2.0, 3.0, 4.0 and 6.0 hours (± 15 mins) post the morning dose; C2D1 and C3D1: Predose (within 30 minutes prior to the morning dose),
- C1 D1 and D8, and C2 D1 |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| safety, dose escalation, cohort expansion |
|
| 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 | 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose Escalation and 2 cohorts for Dose Expansion |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| 2 Cohorts of IMP for Dose Expansion |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Belarus |
| Brazil |
| Hungary |
| Poland |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| The study will be considered complete 2 years after the last subject is enrolled, at which time subjects who remain on study treatment will be evaluated for eligibility to enroll in a rollover study. |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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