Clinical trial NCT05144347: Study of XL114 in Subjects With Non-Hodgkin's Lymphoma
Official title: A Dose-Escalation and Expansion Study of the Safety and Pharmacokinetics of XL114 Administered in Subjects With Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Non-Hodgkin's Lymphoma (NHL)
Activated B-Cell Type Diffuse Large B-Cell Lymphoma (ABC-DLBCL)
Mantle Cell Lymphoma (MCL)
Chronic Lymphocytic Leukemia (CLL)
Small Lymphocytic Lymphoma (SLL)
Keywords: Mucosa-associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT-1)
B-cell Malignancies
Fatty Acid Binding Protein 5 (FABP-5)
Lead sponsor: Exelixis
Sponsor class: INDUSTRY
First posted: 2021-12-03
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose-escalation followed by Cohort-expansion in NHL-specific expansion cohorts
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Dose-Escalation Stage: Recommended Dose (RD) and/or Maximum Tolerated Dose (MTD) for XL114
timeFrame: 4-6 months
measure: Cohort-Expansion Stage: Objective Response Rate (ORR)
timeFrame: 4-6 months
Secondary outcomes:
measure: Safety of XL114, as evaluated by Adverse Events (AEs)
timeFrame: 4-6 months
measure: Tolerability of XL114, as evaluated by Dose Intensity, Dose Modifications, and Study Discontinuation due to AEs
timeFrame: 4-6 months
measure: Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax)
timeFrame: 4-6 months
measure: Dose-Escalation Stage: Maximum Plasma Concentration (Cmax)
timeFrame: 4-6 months
measure: Dose-Escalation Stage: Area Under the Plasma Concentration-Time Curve Over the Last 24-hour Dosing Interval (AUC 0-24)
timeFrame: 4-6 months
measure: Dose-Escalation Stage: Terminal Half-Life
timeFrame: 4-6 months
measure: Dose-Escalation Stage: Apparent Clearance (CL/F)
timeFrame: 4-6 months
measure: Cohort-Expansion Stage: Antitumor Activity of XL114 (Objective Response Rate [ORR])
timeFrame: 4-6 months
measure: Cohort-Expansion Stage: Antitumor Activity of XL114 (Duration of Response [DOR])
timeFrame: 4-6 months
measure: Cohort-Expansion Stage: Antitumor Activity of XL114 (Progression Free Survival [PFS])
timeFrame: 4-6 months
measure: Cohort-Expansion Stage: Overall Survival (OS) of XL114
timeFrame: 4-6 months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Exelixis Clinical Site #3
state: Arizona
city: Indianapolis
country: United States
facility: Exelixis Clinical Site #1
state: Indiana
city: Pittsburgh
country: United States
facility: Exelixis Clinical #4
state: Pennsylvania
city: Spokane
country: United States
facility: Exelixis Clinical Site #2
state: Washington
Study officials:
References: