Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: pirtobrutinib
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: pirtobrutinib
CAS Number: 2101700-15-4
Current Sponsor code: LOXO-305
Other descriptive name: LY3527727
Concent
Sponsors
Loxo Oncology Inc
Eligibility
Sex/Gender
All
Inclusion criteria
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 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, whichev
Exclusion criteria
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 foll
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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).;Secondary Objective: •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;Primary end point(s): Assessed by Independent Review Committee (IRC): • PFS per iwCLL 2018;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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;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 | — |
Countries
Australia, Austria, Belgium, Canada, China, Croatia, Czechia, Czech Republic, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Singapore, Spain, Switzerland, Taiwan, Turkey, United Kingdom, United States
Contacts
Public ContactMedical and Scientific Services
IQVIA RDS GmbH
Outcome results
None listed