| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic lymphocytic leukaemia/Small Lymphocytic Lymphoma is a type of cancer that affects the white blood cells and tends to progress slowly over many years. |
|
| 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 | 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 | 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 evaluate PFS of pirtobrutinib plus venetoclax and rituximab (Arm A) compared to venetoclax and rituximab (Arm B) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effectiveness of Arm A compared to Arm B based on overall response rate (ORR) and time to event(s) outcomes
• To evaluate the safety and tolerability of each treatment arm
• To evaluate the effectiveness of Arm A compared to Arm B in patient-reported disease-related symptoms and physical functioning |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age 18 and older at time of enrollment
2. Confirmed diagnosis by local laboratory report of CLL/SLL as defined by iwCLL 2018 criteria, including the following:
a) B-cells coexpressing the surface antigen CD5 together with at least one B-cell antigen (CD19, CD20, CD23) and either or light-chain restricted. In atypical cases, inclusion may be considered after discussion with the Sponsor and Sponsor approval (for CLL/SLL patients)
b) ≥ 5 × 109 B lymphocytes/L (5000/µL) in the peripheral blood (for CLL patients)
c) Prolymphocytes may comprise ≤ 55% of blood lymphocytes (for CLL patients)
3. A requirement for therapy consistent with iwCLL 2018 criteria for initiation of therapy such that at least 1 of the following should be met:
a) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (such as hemoglobin < 10 g/dL) and/or thrombocytopenia (such as platelets ≤ 100 × 109/L)
b) Massive (i.e., spleen edge ≥ 6 cm below the left costal margin) or progressive or symptomatic splenomegaly (> 13 cm)
c) Massive nodes (i.e., ≥ 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
d) Progressive lymphocytosis with an increase of > 50% over a 2-month period or lymphocyte doubling time < 6 months. Factors contributing to lymphocytosis other than CLL/SLL (e.g., infections, steroid administration) should be excluded
e) Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids
f) Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine)
g) Disease-related symptoms (also known as B-symptoms) as defined by any of the following:
i. Unintentional weight loss ≥ 10% within the previous 6 months
ii. Significant fatigue (i.e., ECOG PS 2; cannot work or unable to perform usual activities)
iii. Fevers of 100.4°F (38.0°C) or higher for 2 or more weeks without evidence of infection
iv. Night sweats for 1 month or more without evidence of infection
4. Known 17p status (wildtype for 17p locus or positive for 17p deletion) by FISH as indicated in Section 1.2.2
5. Previously treated with at least one line of therapy that may include a covalent BTK inhibitor (patients may be eligible if they have previously received a covalent BTK inhibitor or if they have not previously received a covalent BTK inhibitor). There is no limit on prior number of lines of therapy
6. ECOG 0 to 2
7. Must have adequate organ function, as described in the Protocol. These values must be met during the Screening Period. Results from the most recent assessment during the Screening Period will be used for eligibility. Please refer to the Protocol for the table of values.
8. Patients who have received investigational agents, anticancer treatment, and/or radiotherapy are required to have the following washout periods prior to planned C1D1:
a) Targeted agents: 5 half-lives or 14 days, whichever is shorter
b) Cytotoxic chemotherapy: 28 days
c) Anticancer therapeutic monoclonal antibodies: 28 days
d) Palliative limited field radiation: 7 days
e) Broad field radiation (≥ 30% of bone marrow or whole brain radiotherapy): 28 days
9. Prior treatment-related AEs must have recovered to Grade ≤1 or pretreatment baseline or are controlled with appropriate medical treatment without meeting other exclusion criteria (with the exception of alopecia)
10. Willingness of men and WOCBP, and their partners, to both observe highly effective birth control methods as outlined in Section 10.2 for the duration of treatment and for 6 months following the last dose of study treatment or 12 months after the last dose of rituximab, whichever is later. For more details and examples of highly effective birth control methods with a failure rate of less than 1% refer to the Protocol.
Notes:
· Women with a history of breast cancer may not use hormone containing contraception (a, b, or d). One of the other listed methods above should be selected.
· Women of childbearing potential using hormonal contraception methods should also use a barrier method as a second form of contraception.
· Sperm and oocyte donation are prohibited during the duration of participation on this protocol and for 6 months after the last dose of study treatment, or at least 12 months following last dose of rituximab, whichever is later.
11. Willing and capable of giving signed informed consent as described in Section 10.1.2, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
12. Able to swallow oral study medication
13. Able to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
|
|
| E.4 | Principal exclusion criteria |
1. Known or suspected Richter’s Transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin lymphoma at any time preceding enrollment
2. Known or suspected history of CNS involvement by CLL/SLL
3. Patients who experienced a major bleeding event on a prior BTK inhibitor. Refer to Protocol for definition.
4. Active second malignancy. Patients with treated second malignancy who are in remission with life expectancy > 2 years and with documented Sponsor approval are eligible. Examples include:
a) Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
b) Adequately treated cervical carcinoma in situ without current evidence of disease
c) Localized (e.g., lymph node negative) breast cancer treated with curative intent with no evidence of active disease present for more than 3 years and receiving adjuvant hormonal therapy
d) Localized prostate cancer undergoing active surveillance
e) History of treated and cured Hodgkin lymphoma or NHL < 5 years from diagnosis
5. Major surgery within 4 weeks of planned start of study therapy
6. A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic, that, in the opinion of the Investigator, would adversely affect the patient’s participation in this study or interpretation of study outcomes
7. Recent history (within the last 60 days) of allogeneic or autologous SCT or CAR-T therapy
8. Active uncontrolled auto-immune cytopenia (e.g., AIHA, ITP) not on a stable regimen and dose for at least 4 weeks prior to study enrollment
9. Significant cardiovascular disease, defined as any of the following:
a) Unstable angina or acute coronary syndrome within the past 3 months prior to randomization
b) History of myocardial infarction within 3 months prior to randomization
c) Documented LVEF by any method of ≤ 40% within the 12 months prior to randomization, unless subsequent measurements (≥ 2 of any kind, separated by a minimum of 3 weeks) documents LVEF recovery to > 40%
d) ≥ Grade 3 NYHA functional classification system of heart failure, uncontrolled or symptomatic arrhythmias
10. Prolongation of the QTcF > 470 msec on at least 2 of 3 consecutive ECGs and mean QTcF > 470 msec on all 3 ECGs during Screening
a) QTcF is calculated using Fridericia’s Formula (QTcF = QT/(RR^0.33)
b) Correction of suspected drug-induced QTcF prolongation or prolongation due to electrolyte abnormalities can be attempted at the Investigator’s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation or electrolyte supplementation.
c) Correction of QTc for underlying BBB permissible
11. Hepatitis B or hepatitis C testing indicating active/ongoing infection. Refer to Protocol for screening laboratory tests.
12. Known active cytomegalovirus (CMV) infection. Patients with negative status are eligible
13. Evidence of other clinically significant uncontrolled condition(s).Refer to Protocol.
14. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Patients with unknown or negative status are eligible
15. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the orally administered study treatments
16. Prior exposure to venetoclax or other BCL2 inhibitor
17. Prior exposure to noncovalent (reversible) BTK inhibitor
18. Concurrent use of investigational agent or anticancer therapy at the time of C1D1 except for hormonal therapy (refer to inclusion criteria 8 for required wash-out period)
19. Use of > 20 mg prednisone QD or equivalent dose of steroid per day at the time of C1D1. Patients may not be on prednisone of any dose intended for antineoplastic use
20. Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist
21. Current treatment with strong CYP3A4 inhibitors or inducers. Because of their effect on CYP3A4, use within 3 days of study treatment start or planned use during study participation is prohibitedRefer to Protocol for more details.
22. Vaccination with a live vaccine within 28 days prior to randomization
23. Pregnancy, lactation, or plan to breastfeed during the study or within 30 days of the last dose of study treatment
24. Patients with the following hypersensitivity:
a) Known hypersensitivity to any component or excipient of pirtobrutinib and venetoclax
b) Prior significant hypersensitivity to rituximab requiring permanent discontinuation or prior allergic or anaphylactic reaction to rituximab (does not include manageable infusion related reaction)
c) Known allergy to allopurinol and inability to take uric acid lower agents (i.e., xanthine oxidase inhibitor, rasburicase, or febuxostat)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria 2018, assessed by Independent Review Committee (IRC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time from the date of randomization until disease progression or death from any cause, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
• Assessed by Investigator:
- PFS
- OS
- Time to next treatment (TTNT), defined as time from the date of randomization to the date of the initiation of the subsequent anticancer therapy for CLL/SLL or death due to any cause, whichever occurs first (Section 9.4.4 for full definition).
- Event free survival (EFS) defined as the time from date of randomization to the date of disease progression (PD) or start of new treatment for CLL/SLL, discontinuation from study treatment due to toxicity or death due to any cause, whichever occurs first.
• Assessed by Investigator and IRC:
- ORR
• Including but not limited to SAEs, AEs, deaths and clinical laboratory abnormalities per National Cancer Institute Common Terminology Criteria in Adverse Events version 5.0 (NCI CTCAE v5.0)
• TTW of CLL/SLL-related symptoms
• TTW of physical functioning
PFS - The time from the date of randomization until disease progression or death from any cause, whichever occurs first.
OS- The time from randomization until death from any cause. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
TTNT - The time from the date of randomization to the date of the initiation of the subsequent anticancer therapy for CLL/SLL or death due to any cause, whichever occurs first
EFS - The time from date of randomization to the date of disease progression or start of new treatment for CLL/SLL or withdrawal from study due to toxicity or death, whichever occurs first.
EFS defined as the time from date of randomization to the
date of PD, start of new treatment for CLL/SLL discontinuation from
study due to toxicity or death, due to any cause, whichever occurs first
ORR - The number of patients who achieve a best overall response (BOR) of CR, CRi, nPR, or partial remission (PR) divided by the total number of patients randomized to each treatment arm. |
|
| 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 | Yes |
| 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 | 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| 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 |
| Singapore |
| United States |
| Switzerland |
| Russian Federation |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Norway |
| Poland |
| Spain |
| Sweden |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
|
| 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
|
| The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure shown in the Schedule of Assessments (SoA) for the last participant in the trial globally, which is estimated at approximately 60 months from the first patient randomized to allow approximately from the first patient 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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