An Early Phase Study with the Drug LOXO-305 in Patients with PreviouslyTreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma(CLL/SLL) or Non-Hodgkin Lymphoma (NHL)

Phase 1

• Conditions: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)and Non-Hodgkin Lymphoma (NHL); MedDRA version: 21.1Level: PTClassification code: 10003908Term: B-cell small lymphocytic lymphoma Class: 100000004864; MedDRA version: 22.0Level: PTClassification code: 10029547Term: Non-Hodgkin's lymphoma Class: 100000004864; MedDRA version: 21.0Level: LLTClassification code: 10008976Term: Chronic lymphocytic leukemia Class: 10029104; Therapeutic area: Diseases [C] - Hemic and Lymphatic Diseases [C15]

• Registration Number: CTIS2023-509270-37-00
• Lead Sponsor: oxo Oncology Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2024-04-30
• Last Update Posted: 21 August 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 938

Inclusion Criteria

Phase 1 dose escalation and expansion and Phase 2: Inclusion criteria / 1: Phase 1: Histologically confirmed B-cell malignancy (e.g., CLL/SLL, WM, NHL) failed or intolerant to either = 2 prior standard-of-care regimens given in combination or sequentially OR have received 1 prior BTK-containing regimen when a BTK inhibitor is approved as first line therapy., Phase 2 Inclusion criteria All patients must have disease requiring treatment. For CLL/SLL patients, indications for treatment are defined by IWCLL. Patients with NHL with measurable disease who will be evaluated by Lugano criteria must have at least 1 site of radiographically assessable disease (i.e., lymph node longest diameter [LDi] > 1.5 cm not necessary for disease assessable by positron emission tomography (PET)/computerized tomography (CT), extra nodal site > 1.0 cm in LDi). Patients with WM must have measurable disease, defined as the presence of serum immunoglobulin M (IgM) with a minimum IgM level of > 2 × the upper limit of normal (ULN) based on local laboratory testing. Patients with nonmeasurable disease are eligible and will be assigned to Cohort 7., Phase 1b pirtobrutinib combinations Inclusion criteria 1/ Arm A: (venetoclax + pirtobrutinib): Histologically confirmed relapsed/recurrent CLL/SLL in whom venetoclax is appropriate standard salvage treatment; no prior venetoclax is permitted., Phase 1b pirtobrutinib combinations Inclusion criteria 1/ Arm B: (rituximab + venetoclax + pirtobrutinib [VR-305]): Histologically confirmed relapsed/refractory (r/r) CLL/SLL in whom venetoclax + rituximab is appropriate standard salvage treatment; prior anti-CD20 therapy is allowed; no prior venetoclax is permitted., Phase 1b pirtobrutinib combinations Inclusion criteria 2 Adequate hematologic status, defined as the following within 7 days of C1D1 before treatment; see also Exclusion Criterion 8: a. ANC = 0.75× 109/L; the patient may enroll if there is documented bone marrow involvement considered to impair hematopoiesis. b. Platelet count = 50 × 109/L not requiring transfusion support; the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis. c. Hb = 8 g/dL not requiring transfusion support or growth factors; the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis. d. Patient must be responsive to transfusion support if given for thrombocytopenia or anemia. Patients known to be refractory where increase in platelets to transfusion support is sustained for < 24 hours are not eligible., Inclusion Criteria for All Patients 1 Eastern Cooperative Oncology Group (ECOG) 0 to 2, Inclusion Criteria for All Patients 2 At least 18 years of age, Inclusion Criteria for All Patients 3 Confirmation of availability of tumor sample obtained after most recent treatment as described in Section 7.4 of the protocol, Inclusion Criteria for All Patients 4 Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin time (PT) or (international normalized ratio [INR]) not greater than 1.5 × ULN, Inclusion Criteria for All Patients 5 Adequate hepatic function, defined as: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = 2.5 × ULN or = 5 × ULN with documented liver metastases b. Total bilirubin = 1.5 × ULN or = 3 × ULN with documented liver metastases and/or Gilbert’s Dis

Exclusion Criteria

Investigational agent or anticancer therapy within 5 half-lives or 14 days, whichever is shorter, prior to planned start of specified study therapy except antineoplastic and immunosuppressant monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of pirtobrutinib. In addition, no concurrent systemic anticancer therapy is permitted. a. Continuation of certain standard-of-care anticancer therapies, including hormonal therapy for breast and prostate cancer, is allowed, provided they are not on the list of prohibited concomitant medications. Refer to Section 6.4.2 for allowed and Section 6.4.3 for prohibited medications., Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs during Screening. QTcF is calculated using Fridericia’s Formula: QTcF = QT/(RR0.33). a. Correction of suspected drug-induced QTcF prolongation 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., Patients who experienced a major bleeding event with a BTK inhibitor NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)., Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which, in the opinion of the Investigator and the Sponsor, makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required., Patients who have tested positive for human immunodeficiency virus (HIV) are excluded due to potential drug-drug interactions between antiretroviral medications and pirtobrutinib and risk of opportunistic infections with both HIV and irreversible BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result should be negative for enrollment., Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of any of the orally administered study drugs, Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (refer to Appendix I) and/or strong p-glycoprotein (P-gp) inhibitors (Phase 1b only) (refer to Appendix J), Pregnancy or lactation, Active second malignancy unless in remission and with life expectancy > 2 years. Refer to Protocol Exclusion Criteria (Section 4.2) for examples of allowed second malignancies., For patients enrolled to Phase 1b Arm A or B: Patients with prior treatment with venetoclax or other BCL-2 inhibitors, Prior treatment with pirtobrutinib, Major surgery within 4 weeks prior to planned start of specified study therapy, Patients with the following are excluded: • Known hypersensitivity to any component or excipient of pirtobrutinib • For patients enrolled to Phase 1b Arm B, prior significant hypersensitivity, allergy, or anaphylactic reaction to rituximab/

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified