| 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 progression-free survival (PFS) of pirtobrutinib as monotherapy (Arm A) compared to investigator’s choice of idelalisib plus rituximab
(IdelaR) or bendamustine plus rituximab (BR) (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 based on patient reported outcomes |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age 18 or older per local regulations at time of enrollment.
2.Confirmed diagnosis by redacted 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.
b) ≥ 5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood. For
SLL patients, history of ≥ 5 × 109 B lymphocytes/L (5000/μL) in the
peripheral blood is allowed.
c)Prolymphocytes may comprise ≤ 55% of blood lymphocytes.
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.Known 17p deletion status(wildtype for 17p locus or positive for 17p
deletion)by FISH see Section 1.2.2.
5.Previously treated with a covalent BTK inhibitor, investigational or
approved, and either alone or in combination with other agents. Patients
may have received an unlimited number of lines of prior therapy.
6.Eastern Cooperative Oncology Group(ECOG)0-2.
7.Must have adequate organ function, as defined below. These values
must be met during the Screening Period. Results from the most recent
assessment will be used for eligibility.
8.Patients are required to have had the following washout periods
prior to planned C1D1:
a)Targeted agents or cytotoxic chemotherapy: 5 half-lives or 2 weeks,
whichever is shorter
b)Anticancer therapeutic monoclonal antibodies: 4 weeks; patients
who crossover are not required to observe this washout period
c)Palliative limited field radiation: 7 days
d)Broad field radiation(≥ 30% of bone marrow or whole brain
radiotherapy): 28 days
9.Prior treatment related AEs must have recovered to Grade ≤1,
pretreatment baseline, or are controlled with medications without
meeting other exclusion criteria (with the exception of alopecia).
10.Willingness of men and women of childbearing potential(WOCBP),
and their partners, to observe barrier and/or highly effective birth
control methods as outlined in Section 10.2(Appendix 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.
When pirtobrutinib is taken with hormonal contraceptive (e.g., birth
control pills), pirtobrutinib might affect the birth control. More effective
birth control, such as using 2 birth control methods, should be
considered.
For more information on WOCBP and contraception see Protocol.
Highly effective birth control methods with a failure rate of less than 1%
per year when used consistently and correctly are recommended See the
Protocol for examples.
Notes:
• Women with a history of breast cancer may not use hormone
containing contraception (a, b, or d above). 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 donation and oocyte donation are prohibited during the
duration of participation on this protocol and for 6 months after the last
dose of study drug, 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 Appendix 1 which includes compliance with the
requirements and restrictions listed in the informed consent form(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's lymphoma at
any time preceding enrollment.
2. Known or suspected history of central nervous system (CNS)
involvement by CLL/SLL.
3. Patients who experienced a major bleeding event on a prior BTK
inhibitor. Refer to Protocol for definition of major bleeding.
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.
5. Major surgery, within 4 weeks of planned start of study treatment.
6. History of or ongoing drug-induced pneumonitis.
7. Ongoing drug-induced liver injury, primary biliary cirrhosis and/or
extrahepatic obstruction caused by cholelithiasis and cirrhosis of the
liver.
8. History of allogeneic or autologous SCT or CAR-T therapy within the
past 60 days.
9. 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.
10. Significant cardiovascular disease. For definitions see Protocol.
11. Prolongation of the QT interval corrected (QTc) for heart rate using
Fridericia's Formula (QTcF) > 470 msec on at least 2 of 3 consecutive
electrocardiograms (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 bundle branch block (BBB)
permissible.
12. Hepatitis B or hepatitis C testing indicating active/ongoing infection.
Refer to Protocol for screening laboratory tests.
13. Known active cytomegalovirus (CMV) infection. Patients with
negative status are eligible.
14. 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.
15. Known Human Immunodeficiency Virus (HIV) infection, regardless of
CD4 count. Patients with unknown or negative status are eligible.
16. Clinically significant active malabsorption syndrome or other
condition likely to affect gastrointestinal (GI) absorption of the oraladministered
study treatments.
17. Ongoing inflammatory bowel disease.
18. Prior exposure to non-covalent (reversible) BTK inhibitor.
19. Concurrent use of investigational agent or anticancer therapy except
hormonal therapy.
20. Patients requiring therapeutic anticoagulation with warfarin or
another Vitamin K antagonist.
21. 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.
22. For patients planned to receive idelalisib: Current treatment with
strong cytochrome P450 (CYP) 3A4 (CYP3A4) inhibitors or inducers
(refer to Section 10.4). Because of their effect on CYP3A4, use of any of
the following within 3 days of use of idelalisib and during study
treatment is prohibited:
a) Grapefruit or products from grapefruit
b) Seville oranges or products from Seville oranges
c) Star fruit or products from star fruit
d) Preparations containing St. John's Wort
23. Vaccination with a live vaccine within 28 days prior to
randomization.
24. Pregnancy, lactation, or plan to breastfeed during the study or within
30 days of the last dose of study treatment.
25. Patients with the following hypersensitivity:
a) Known hypersensitivity, including anaphylaxis, to any component or
excipient of pirtobrutinib. For patients planned to receive idelalisib,
known hypersensitivity, including anaphylaxis, to any component or
excipient of idelalisib. For patients planned to receive bendamustine,
known hypersensitivity, including anaphylaxis, to any component or
excipient of bendamustine.
b) Prior toxic epidermal necrolysis with any drug, for patients who are
planned to receive idelalisib
c) Prior significant hypersensitivity to rituximab requiring
discontinuation, prior allergic or anaphylactic reaction to rituximab
(does not include manageable infusion related reaction)
d) Known allergy to allopurinol and inability to take uric acid lower
agents (i.e., rasburicase or febuxostat)
e) For optional crossover, patients with hypersensitivity to idelalisib,
bendamustine, or rituximab would not be excluded. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Assessed by Independent Review Committee (IRC):
• PFS per iwCLL 2018 |
|
| 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
- Overall survival (OS)
- Time to next treatment (TTNT), defined as time from the date of randomization to the date of the next systemic anticancer therapy for CLL/SLL
(Section 9 for full definition).
- Time to treatment failure (TTF), defined as a composite endpoint measuring time from randomization to time when discontinuation criteria
met (Section 7).
- Event free survival (EFS) defined as the time from date of randomization to the date of PD or start of new treatment for CLL/SLL or discontinuation from trial due to toxicity or death, whichever occurs first.
• Assessed by investigator and IRC:
- ORR
- Duration of response (DOR)
• Including, but not limited to, serious adverse events (SAEs), adverse events (AEs), deaths and clinical laboratory abnormalities per National Cancer Institute Common Terminology Criteria in Adverse Events v5.0 (NCI CTCAE v5.0)
• Patient reported outcomes of:
- Time to worsening (TTW) of CLL/SLL-related symptoms
- TTW of physical functioning |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS - The time from the date of randomization until PD or death from
any cause, whichever occurs first
ORR - achieve a BOR of CR, PR
DOR - The time from the date of the first documented response of CR,
CRi, nPR, or PR to the earlier of the documentation of definitive PD or
death from any cause
OS - 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 non-protocol-specified therapy for CLL/SLL or death
due to any cause, whichever occurred first
EFS - date of PD or start of new treatment for CLL/SLL or
discontinuation from study due to toxicity or death, whichever occurs
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 | No |
| 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 103 |
| 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 |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
| Switzerland |
| Russian Federation |
| Turkey |
| Austria |
| Belgium |
| Croatia |
| Czechia |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Poland |
| Spain |
| 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 36.5 months from the first patient randomized to allow 12.5 months recruitment and 24 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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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