A Phase 3 Study Comparing LOXO-305 to Investigator’s Choice of Idelalisib plus Rituximab or Bendamustine plus Rituximab
- Conditions
- Chronic Lymphocytic Leukemia/Small Lymphocytic LymphomaMedDRA version: 21.0Level: LLTClassification code 10008976Term: Chronic lymphocytic leukemiaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2020-004554-30-FR
- Lead Sponsor
- oxo Oncology Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 250
Patients are eligible to be included in the study only if all of the following criteria apply:
Age
1. Age 18 and 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 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.
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 as well as pre-dose on Cycle 1 Day 1 (C1D1).
8. Patients are required the 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) 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
9. Prior treatment related AEs must have recovered to Grade = 1 or pretreatment baseline with the exception of alopecia.
Contraception
10. Willingness of men and women of reproductive potential to observe conventional and highly effective or acceptable birth control methods 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.
Informed Consent
11. Willing and capable of giving signed informed consent which includes compliance with the requirements and re
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. Known or suspected history of central nervous system (CNS) involvement by CLL/SLL.
3. History of Grade =2 arrhythmia on prior covalent BTK inhibitor.
4. Patients who experienced a major bleeding event on a prior BTK inhibitor.
NOTE: major bleeding is defined as bleeding having one or more of the following features: life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g/dL; or bleeding in a critical area or organ (e.g. retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
5. 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.
6. Major surgery, within 4 weeks of planned start of study treatment.
7. History of or ongoing drug-induced pneumonitis.
8. Ongoing drug-induced liver injury, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis and cirrhosis of the liver.
9. History of allogeneic or autologous SCT or CAR-T therapy within the past 60 days
10. 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
11. Significant Cardiovascular disease defined as:
a) Unstable angina or acute coronary syndrome within the past 2 months,
b) History of myocardial infection within 3 months prior to planned start of LOXO-305,
c) Documented LVEF by any method of = 40% in the 12 months prior to planned start of LOXO-305,
d) = Grade 3 NYHA functional classification system of heart failure, uncontrolled or symptomatic arrhythmias
12. 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.
13. Hepatitis B or hepatitis C testing indicating active/ongoing infection based on screening labs as defined as:
a) Hepatitis B virus (HBV): Patients with positive hep
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate progression-free survival (PFS) of LOXO-305 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<br>•To evaluate the safety and tolerability of each treatment arm<br>•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):<br>• 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 Outcome Measures
Name Time Method