| 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 overall response rate (ORR) of pirtobrutinib (Arm A) compared to ibrutinib (Arm B) |
|
| E.2.2 | Secondary objectives of the trial |
*To evaluate the effectiveness of Arm A compared to Arm B based on event-free survival (EFS), progression-free survival (PFS), ORR, duration of response (DOR), overall survival (OS), and time to next treatment (TTNT)
*To evaluate the safety and tolerability of each treatment arm
*To evaluate the patient-reported outcomes of Arm A compared to Arm B |
|
| 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, and to include the following:
a) B-cells co-expressing the surface antigen CD5 together with at least one B-cell antigen (CD19, CD20, CD23) and either κ or λ 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 as defined by any of the following:
i) Unintentional weight loss ≥ 10% within the previous 6 months
ii) Fevers ≥ 100.5°F or 38.0°C for 2 or more weeks without evidence of infection
iii) Night sweats for ≥ 1 month without evidence of infection
4. Known 17p deletion status (wildtype or deleted)
5. ECOG 0 to 2.
6. Must have adequate organ function, as defined per protocol. These values must be met during the Screening Period as well as predose on C1D1.
7. 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 greater
b) Therapeutic monoclonal antibodies: 4 weeks
c) Palliative limited field radiation: 7 days
d) Broad field radiation (≥ 30% of bone marrow or whole brain radiotherapy): 28 days
8. 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).
Contraception
9. Willingness of men and WOCBP, and their partners, to observe barrier and highly effective birth control methods as outlined in Section 10.2 (and below) for the duration of treatment and for 6 months following the last dose of study treatment.
Highly effective birth control methods with a failure rate of less than 1% per year when used consistently and correctly are recommended (CTFG 2020):
a. Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally
b. Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant
c. IUD
d. IUS
e. Bilateral tubal occlusion
f. Vasectomized partner
g. Sexual abstinence: Considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study drug. The reliability of sexual abstinence will be evaluated in relation to the duration of the study and to the usual lifestyle of the patient.
Informed Consent
10. 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.
Other Inclusions
11. Able to swallow oral study medication.
12. Able to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. |
|
| 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 DLBCL, prolymphocytic leukemia, or Hodgkin’s lymphoma at any time preceding enrollment
2. Known or suspected history of CNS involvement by CLL/SLL
3. Previous or concurrent cancer distinct from CLL/SLL within 3 years prior to randomization; patients with prior cancers may be enrolled with documented Sponsor approval, examples include:
a) Curatively treated nonmelanomatous skin cancer or lentigo maligna melanoma
b) Curatively treated cervical carcinoma in situ
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 (may be receiving adjuvant hormonal therapy)
d) Localized prostate cancer undergoing active surveillance
4. Major surgery within 4 weeks of planned start of study drug
5. 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
6. Ongoing drug-induced liver injury, primary biliary cirrhosis, and/or extrahepatic obstruction caused by cholelithiasis and/or cirrhosis of the liver
7. History of allogeneic or autologous SCT or CAR-T therapy within the past 60 days
8. Active uncontrolled autoimmune cytopenia (e.g., autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura) 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 2 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 > 40%, and/or
d) ≥ Grade 3 New York Heart Association functional classification system of heart failure, uncontrolled or symptomatic arrhythmias
10. Prolongation of the QTc for heart rate using Fridericia’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 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 permissible
11. Hepatitis B or hepatitis C testing indicating active/ongoing infection based on Screening laboratory tests as defined as:
a) HBV: Patients with positive HBsAg are excluded. Patients with positive anti-HBc and negative HBsAg require hepatitis B PCR evaluation before randomization. Patients who are hepatitis B PCR-positive will be excluded.
b) HCV: Patients with positive hepatitis C antibody are excluded. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C RNA before randomization. Patients who are hepatitis C RNA-positive will be excluded.
12. Known active CMV infection. Patients with negative status are eligible.
13. 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.
14. Known 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 GI absorption of the oral-administered study treatments
16. Ongoing inflammatory bowel disease
Prior/Concomitant Therapy
17. Prior exposure to BTK inhibitor (covalent or noncovalent)
18. Concurrent use of investigational agent or anticancer therapy except hormonal therapy
19. Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist
20. 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
21. Vaccination with a live vaccine within 28 days prior to randomization
22. Patients receiving chronic therapy with a strong CYP3A inhibitor (except posaconazole and voriconazole) which cannot be stopped within 3-5 half lives of the CYP3A inhibitor therapy prior to start of study drug treatment.
Other Exclusions - Please refer to protocol
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR as assessed by Independent Review Committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia criteria (iwCLL 2018) criteria; ORR is defined as the proportion of patients who achieve a best overall response (BOR) of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), nodular partial remission (nPR), or partial remission (PR) at or before the initiation of subsequent anti-cancer therapy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The interim analysis of ORR is planned when the first 455 patients (70% of 650 patients) are followed for at least 9 months since enrollment or discontinue study whichever occurs first.
If the interim analysis of ORR is not significant, a final analysis of ORR will be performed when all the patients (100% of patients enrolled) are followed for at least 9 months since enrollment or discontinue study, whichever occurs first |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
EFS is defined as a composite endpoint of the following, whichever occurs first:
• Treatment discontinuation due to adverse event (AE)/toxicity
• Atrial fibrillation or atrial flutter of any grade (assessed by Investigator)
• Progressive disease (PD) (by IRC per iwCLL 2018 criteria) or death
PFS is defined as the time from the date of randomization until PD (per iwCLL 2018 criteria) or death from any cause, whichever occurs first.
Additional secondary endpoints:
• Assessed by IRC and Investigator:
- ORR, including PR with lymphocytosis (PR-L), assessed by both IRC and the Investigator
- DOR; DOR is defined as 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 (per iwCLL 2018 criteria) or death from any cause
- DOR, including PR-L
• Assessed by Investigator:
- EFS and PFS evaluated per iwCLL 2018
- ORR evaluated per iwCLL 2018
- OS; OS is defined as the time from randomization until death from any cause
- TTNT; TTNT is defined as time from the date of randomization to the date of the initiation of the next systemic anticancer therapy for CLL/SLL or death due to any cause, whichever occurred first |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
*If interim analysis of ORR is significant, the interim analysis of EFS will be performed when 173 EFS events (75% of total EFS events) have been observed.
* If the interim analysis of EFS is significant, the first interim analysis of PFS will also be performed. If the first interim analysis of PFS is not significant, the second interim analysis of PFS will be performed when 176 PFS events (70% of total PFS events) have been observed. If the second interim analysis of PFS is not significant, a final analysis of PFS will be performed when 251 PFS events (100% of total PFS events) have been observed.
* If the final analysis of ORR is significant, the interim analysis of EFS will be performed at the same timepoint |
|
| 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 | 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) | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| Japan |
| Korea, Republic of |
| New Zealand |
| Taiwan |
| United States |
| Turkey |
| Belgium |
| Czechia |
| France |
| Germany |
| Hungary |
| 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 patient in the study or last scheduled procedure shown in the Schedule of Assessment (SoA) for the last patient in the study globally, which is estimated at approximately 72 months from the first patient randomized to allow 30 months recruitment and 42 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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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