A Phase 3 Study Comparing Pirtobrutinib (LOXO-305) to Bendamustine plus Rituximab in Untreated Patients with CLL/SLL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Loxo Oncology Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Dec 2021 → ongoing

Decision date (initial)

2024-05-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company

External identifiers

EU CT number

2024-511599-33-00

EudraCT number

2021-001234-20

WHO UTN

U1111-1300-4904

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic, Pharmacogenomic, Pharmacodynamic

To evaluate PFS of pirtobrutinib as monotherapy (Arm A) compared to BR (Arm B).

Secondary objectives 3

1. To evaluate the effectiveness of Arm A compared to Arm B based on ORR and time to event(s) outcomes.
2. To evaluate the effectiveness of Arm A compared to Arm B based on patient reported outcomes.
3. To evaluate the safety and tolerability of each treatment arm

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

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 including the following: a) B-cells co-express CD5 and CD23; express at least one B-cell antigen (CD19 or CD20) and be either κ or λ light-chain restricted. Atypical cases may be considered with Sponsor approval. b) ≥ 5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood for CLL patients. For SLL patients, <5 × 109 B cells/L (5000/μL) in the peripheral blood is allowed. c) Prolymphocytes may comprise ≤ 55% of blood lymphocytes (for CLL patients).
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. Eastern Cooperative Oncology Group (ECOG) 0-2.
5. Must have adequate organ function, as defined below. Results from the most recent laboratory tests prior to enrollment will be used for eligibility.
6. Patients are required the have had the following washout periods prior to planned C1D1: a) Palliative limited field radiation: 7 days b) Broad field radiation (≥ 30% of bone marrow or whole brain radiotherapy): 28 days Contraception
7. Willingness women of childbearing potential (WOCBP), and their partners, to both observe barrier method and highly effective birth control methods as outlined in Section 10.2 (Appendix 2; and below) for the duration of treatment and for 1 month following the last dose of pirtobrutinib or 12 months after the last dose of rituximab, whichever is later. WOCBP are defined as women following menarche, and who are not postmenopausal (or 2 years of non-therapy-induced amenorrhea, or surgically sterile). WOCBP must utilize 2 effective contraception methods with at least 1 form of highly effective contraception method as outlined below. In addition, male partners must use a barrier method (condoms) for the duration of treatment and for 1 month following the last dose of study treatment or 12 months after the last dose of rituximab. Male patients enrolled in Arm B with partners who are WOCBP must use a barrier method (condoms) and their partner must also use a highly effective form of contraception as listed below for the duration of treatment and for 12 months after the last dose of rituximab. For further please refer to Protocol.

Exclusion criteria 14

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. Presence of 17p deletion by fluorescence in-situ hybridization (FISH) (refer to Section 8.10.2)
3. Known or suspected history of central nervous system (CNS) involvement by CLL/SLL.
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. 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.
5. Major surgery, within 4 weeks of planned start of study treatment.
6. 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.
7. 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
8. Significant cardiovascular disease defined as any of the following: a) Unstable angina or acute coronary syndrome within the past 2 months, b) History of myocardial infarction within 3 months prior to planned start of study drug, c) Documented LVEF by any method of ≤ 40% d) ≥ Grade 3 NYHA functional classification system of heart failure, uncontrolled or symptomatic arrhythmias
9. 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.
10. Hepatitis B or hepatitis C testing indicating active/ongoing infection based on Screening laboratory tests 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.
11. Active cytomegalovirus (CMV) infection.
12. 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.
13. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Patients with unknown or negative status are eligible.
14. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study treatments. Please refer to Protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Assessed by IRC: PFS per iwCLL 2018 response criteria

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Loxo Oncology Inc.

Sponsor organisation

Loxo Oncology Inc.

Address

281 Tresser Boulevard Floor 9th

City

Stamford

Postcode

06901-3238

Country

United States

Scientific contact point

Organisation

Loxo Oncology Inc.

Contact name

Lilly Clinical Trials Information desk

Public contact point

Organisation

Loxo Oncology Inc.

Contact name

Lilly Clinical Trials Information desk

Third parties 11

Locations

10 EU/EEA countries · 47 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 128 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications