| 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 as monotherapy (Arm A) compared to BR (Arm B). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effectiveness of Arm A compared to Arm B based on ORR and time to event(s) outcomes.
• To evaluate the effectiveness of Arm A compared to Arm B based on patient reported outcomes.
•To evaluate the safety and tolerability of each treatment arm |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if all of the following
criteria apply:
Age
1. Age 18 years or older per local regulations at time of enrollment.
Type of Patient and Disease Characteristics
2. Confirmed diagnosis by redacted local laboratory report of CLL/SLL as
defined by iwCLL 2018 criteria including the following:
a) B-cells co-express CD5 and CD23; express at least one B-cell antigen
(CD19 or CD20) and be either κ or λ light-chain restricted. Atypical cases
may be considered with Sponsor approval.
b) ≥ 5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood for CLL
patients. For SLL patients, <5 × 109 B cells/L (5000/μL) in the
peripheral blood is allowed.
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., Eastern Cooperative Oncology Group [ECOG]
performance scale 2 or worse; cannot work or unable to perform usual
activities).
iii) Fevers ≥ 100.5°F or 38.0°C for 2 or more weeks without evidence of
infection.
iv) Night sweats for ≥ 1 month without evidence of infection.
4. Eastern Cooperative Oncology Group (ECOG) 0-2.
5. Must have adequate organ function, as defined below. Results from
the most recent laboratory tests prior to enrollment will be used for
eligibility.
6. Patients are required the have had the following washout periods
prior to planned C1D1:
a) Palliative limited field radiation: 7 days
b) Broad field radiation (≥ 30% of bone marrow or whole brain
radiotherapy): 28 days
Contraception
7. Willingness women of childbearing potential (WOCBP), and their
partners, to both observe barrier method and highly effective birth
control methods as outlined in Section 10.2 (Appendix 2; and below) for
the duration of treatment and for 1 month following the last dose of
pirtobrutinib or 12 months after the last dose of rituximab, whichever is
later.
WOCBP are defined as women following menarche, and who are not
postmenopausal (or 2 years of non-therapy-induced amenorrhea, or
surgically sterile). WOCBP must utilize 2 effective contraception methods
with at least 1 form of highly effective contraception method as outlined
below. In addition, male partners must use a barrier method (condoms)
for the duration of treatment and for 1 month following the last dose of
study treatment or 12 months after the last dose of rituximab. Male
patients enrolled in Arm B with partners who are WOCBP must use a
barrier method (condoms) and their partner must also use a highly
effective form of contraception as listed below for the duration of
treatment and for 12 months after the last dose of rituximab.
For further please refer to Protocol. |
|
| E.4 | Principal exclusion criteria |
Patients are excluded from the study if any of the following criteria apply:
Medical Conditions
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. Presence of 17p deletion by fluorescence in-situ hybridization (FISH) (refer to Section 8.10.2)
3. Known or suspected history of central nervous system (CNS) involvement by CLL/SLL.
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 non-melanomatous 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's disease or NHL within 5 years from diagnosis.
5. Major surgery, within 4 weeks of planned start of study treatment.
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. Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) not on a stable regimen and dose for at least 4 weeks prior to study enrollment
8. Significant cardiovascular disease defined as any of the following:
a) Unstable angina or acute coronary syndrome within the past 2 months,
b) History of myocardial infarction within 3 months prior to planned start of study drug,
c) Documented LVEF by any method of ≤ 40%
d) ≥ Grade 3 NYHA functional classification system of heart failure, uncontrolled or symptomatic arrhythmias
9. Prolongation of the QT interval corrected (QTc) for heart rate using Fredericia’s Formula (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 Fredericia’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 bundle branch block (BBB) permissible.
10. Hepatitis B or hepatitis C testing indicating active/ongoing infection based on Screening laboratory tests as defined as:
a) Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before randomization. Patients who are hepatitis B PCR positive will be excluded.
b) Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before randomization. Patients who are hepatitis C RNA positive will be excluded.
c) For optional crossover, repeat testing is not required.
11. Active cytomegalovirus (CMV) infection.
12. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) or other clinically significant active disease process which in the opinion of the Investigator and Medical Monitor may pose a risk for patient participation. Screening for chronic conditions is not required.
13. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Patients with unknown or negative status are eligible.
14. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study treatments.
Please refer to Protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Assessed by IRC:
• PFS per iwCLL 2018 response criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time from the date of randomization until PD or death from any cause, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
• Assessed by Investigator:
- PFS per iwCLL 2018 criteria
- OS
- TTNT, defined as time from the date of randomization to the date of the next systemic anticancer therapy for CLL/SLL (see Section 9 for full definition).
• Assessed by Investigator and IRC:
- ORR
• DOR
• Patient reported outcomes of:
- TTW of CLL/SLL-related symptoms
- TTW of physical functioning as measured by the physical function domain of the EORTC-QLQ-C30
• Including, but not limited to, serious adverse events (SAEs), adverse
events (AEs), deaths, and clinical laboratory abnormalities per National
Cancer Institute Common Terminology Criteria for Adverse Events v5.0
(NCI CTCAE v5.0) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS - the time from the date of randomization until PD (per iwCLL 2018 criteria, Section 10.6, Appendix 6) or death from any cause, whichever occurs first.
ORR - the proportion of patients who achieve a BOR of CR, CRi, nPR, or PR at or before the initiation of subsequent anticancer therapy.
OS is defined as the time from randomization until death from any cause.
TTNT - the time from the date of randomization to the date of the initiation of the next systemic anticancer therapy for CLL/SLL or the first dose date of
pirtobrutinib for Arm B patients who crossed over to receive pirtobrutinib or death due to any cause, whichever occurred first. |
|
| 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
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 73 |
| 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 |
| New Zealand |
| Ireland |
| Taiwan |
| Australia |
| Austria |
| Brazil |
| Bulgaria |
| China |
| Czechia |
| France |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| 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
|
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 SoA
for the last participant in the trial globally, which is estimated at
approximately 52 months from the first patient randomized to allow 16
months recruitment and 36 months of follow-up. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 4 |
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