Study of XL114 in Subjects With Non-Hodgkin's Lymphoma

Exelixis

Status and phase: Terminated; Phase 1

Conditions: Small Lymphocytic Lymphoma (SLL); Non-Hodgkin's Lymphoma (NHL); Mantle Cell Lymphoma (MCL); Activated B-Cell Type Diffuse Large B-Cell Lymphoma (ABC-DLBCL); Chronic Lymphocytic Leukemia (CLL)

Treatments: Drug: XL114

Study type: Interventional

Funder types: Industry

Identifiers

NCT05144347

XL114-101

Details and patient eligibility

About

This is a Phase 1, non-randomized, open-label, dose-escalation and expansion study, evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical antitumor activity of XL114 administered alone orally to subjects with Non-Hodgkin's Lymphoma (NHL). The objectives of the study also include determining the recommended dose (RD) and/or maximum tolerated dose (MTD) of XL114.

Enrollment: 2 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Dose-Escalation Stage (Cohort A) and Cohort-Expansion Stage (B-E): The subject has received standard life-prolonging therapies or are not qualified to receive such therapies.
• Dose-Escalation Stage (Cohort A): Subjects with histologically documented diagnosis of B-cell or T-cell Non-Hodgkin's Lymphoma as defined by the World Health Organization (WHO) classification. Note: Refer to exclusion criteria for lymphoma subtypes which are excluded from study participation.
• Cohort-Expansion Stage Cohort B (ABC-DLBCL subtype): Subjects with histologically documented activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) subtype. Note: De novo or transformed diffuse large B-cell lymphoma (DLBCL) from previously diagnosed indolent lymphoma (eg, follicular lymphoma) is allowed.
• Cohort-Expansion Stage Cohort C (MCL): Subjects with histologically documented MCL with monoclonal B-cells that show a chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1.
• Cohort-Expansion Stage Cohort D (CLL/SLL): Subjects with histologically documented CLL/SLL per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines.
• Cohort-Expansion Stage Cohort E, Biomarker Cohort (ABC-DLBCL, MCL, and SLL): Subjects with ABC-DLBCL, MCL, and SLL that fulfill the subject disease characteristics criteria as described for Cohorts B, C, or D.
• Cohort-Expansion Stage: Subjects with ABC-DLBCL, MCL, and SLL must have measurable disease by revised criteria for response assessment of lymphoma.
• Cohort-Expansion Stages: Must have archival tumor tissue available, which was collected up to 2 years prior to consent for this study. If archival tumor tissue is not available, a fresh tumor biopsy may be obtained (if safe to acquire) up to 60 days prior to first dose.
• Biomarker Cohort: Subjects must provide a fresh tumor biopsy up to 60 days prior to first dose, at week 2, day 1 (W2D1) after initiation of XL114, and at disease progression. Note: The tumor tissue requirement in the Expansion and Biomarker cohorts doesn't apply for subjects with CLL.
• Recovery to baseline or ≤ Grade 1 severity (Common Terminology Criteria for Adverse Events version 5 [CTCAE v5]) from AEs, unless AEs are clinically nonsignificant or stable.
• Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram (ECHO) or multigated acquisition (MUGA) scan per local standard.
• Age 18 years or older on the day of consent.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1
• Adequate organ and marrow function
• Sexually active fertile subjects and their partners must agree to highly effective methods of contraception.
• Female subjects of childbearing potential must not be pregnant at screening.

Exclusion criteria

• Receipt of prior therapies as defined in the protocol
• The following lymphoma types/manifestations are not eligible for this study: Burkitt's lymphoma (BL), Burkitt-like lymphoma (BLL), lymphoblastic lymphoma/leukemia (LBL), post-transplant lymphoproliferative disease (PTLD), primary mediastinal (thymic) large B-cell lymphoma (PMBL), lymphomas involving the central nervous system (CNS) or meninges
• History of autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
• History of solid organ or allogeneic hematopoietic stem cell transplantation.
• Concomitant anticoagulation with the oral anticoagulants apixaban, betrixaban, rivaroxaban, and dabigatran.
• Use of a strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4) within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter.
• Uncontrolled, significant intercurrent or recent illness
• Major surgery (eg, GI surgery) within 3 weeks before first dose of study treatment.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 470 ms per electrocardiogram (ECG).
• Pregnant or lactating females.
• Inability to swallow XL114 tablets.
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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2 participants in 2 patient groups

XL114 Dose-Escalation Cohorts

Experimental group

Description:

Subjects (Cohort A1-An) will accrue in cohorts of 3-12 subjects in a i3+3 design.

Treatment:

Drug: XL114

XL114 Expansion Cohorts

Experimental group

Description:

The recommended dose from the Dose-Escalation stage, will be used in subjects with activated B-cell-like diffuse large B-cell lymphoma \[ABC-DLBCL\] (Cohort B), mantle cell lymphoma \[MCL\] (Cohort C), chronic lymphocytic leukemia \[CLL\]/small lymphocytic lymphoma \[SLL\] (Cohort D). Subjects will also be enrolled in a Biomarker cohort (Cohort E).

Treatment:

Drug: XL114