| 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 LOXO-305 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 |
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 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 (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 restrictions listed in the informed consent form (ICF) and in this protocol.
Other Inclusions
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 |
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 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.
14. Known active cytomegalovirus (CMV) infection. Unknown or negative status eligible.
15. 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.
16. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Patients with unknown or negative status are eligible.
17. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study treatments.
18. Ongoing inflammatory bowel disease.
19. Prior exposure to non-covalent (reversible) BTK inhibitor. |
|
| 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
TTF - A composite endpoint measuring time from randomization to discontinuation of treatment for any reason
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 | 12 |
| 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 |
| Russian Federation |
| Singapore |
| Taiwan |
| United States |
| Austria |
| Belgium |
| Croatia |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Romania |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Czechia |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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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