Activated B-Cell Type Diffuse Large B-Cell Lymphoma (ABC-DLBCL), Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Non-Hodgkin's Lymphoma (NHL), Small Lymphocytic Lymphoma (SLL)
Conditions
Keywords
Mucosa-associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT-1), B-cell Malignancies, Fatty Acid Binding Protein 5 (FABP-5)
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.
Interventions
DRUGXL114
Tablets of XL114
Sponsors
Exelixis
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose-escalation followed by Cohort-expansion in NHL-specific expansion cohorts
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Escalation Stage: Recommended Dose (RD) and/or Maximum Tolerated Dose (MTD) for XL114 | 4-6 months | To determine the RD and/or MTD of XL114 administered orally in subjects with NHL |
| Cohort-Expansion Stage: Objective Response Rate (ORR) | 4-6 months | To evaluate preliminary efficacy of XL114 by estimating the ORR based on lymphoma-specific response criteria as assessed by the Investigator |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax) | 4-6 months | To evaluate the Tmax of XL114. |
| Dose-Escalation Stage: Maximum Plasma Concentration (Cmax) | 4-6 months | To evaluate the Cmax of XL114. |
| Dose-Escalation Stage: Area Under the Plasma Concentration-Time Curve Over the Last 24-hour Dosing Interval (AUC 0-24) | 4-6 months | To evaluate the AUC 0-24 of XL114. |
| Dose-Escalation Stage: Terminal Half-Life | 4-6 months | To evaluate the terminal half-life of XL114. |
| Safety of XL114, as evaluated by Adverse Events (AEs) | 4-6 months | To evaluate the safety of XL114 through the evaluation of incidence and severity of treatment emergent nonserious adverse events (AEs) and serious adverse events (SAEs)at each dose level and their relationship to study drug treatment. |
| Cohort-Expansion Stage: Antitumor Activity of XL114 (Objective Response Rate [ORR]) | 4-6 months | To evaluate the antitumor activity of XL114 as measured by ORR based on lymphoma-specific response criteria as assessed by a Blinded Independent Radiology Committee (BIRC) for selected cohorts. |
| Cohort-Expansion Stage: Antitumor Activity of XL114 (Duration of Response [DOR]) | 4-6 months | To evaluate the antitumor activity of XL114 as measured by DOR based on lymphoma-specific response criteria as assessed by the Investigator or by a Blinded Independent Radiology Committee (BIRC) for selected cohorts. |
| Cohort-Expansion Stage: Antitumor Activity of XL114 (Progression Free Survival [PFS]) | 4-6 months | To evaluate the antitumor activity of XL114 as measured by PFS based on lymphoma-specific response criteria as assessed by the Investigator or by a Blinded Independent Radiology Committee (BIRC) for selected cohorts. |
| Cohort-Expansion Stage: Overall Survival (OS) of XL114 | 4-6 months | To evaluate duration of overall survival (OS) |
| Dose-Escalation Stage: Apparent Clearance (CL/F) | 4-6 months | To evaluate the CL/F of XL114. |
| Tolerability of XL114, as evaluated by Dose Intensity, Dose Modifications, and Study Discontinuation due to AEs | 4-6 months | To evaluate the tolerability of XL114 through the evaluation of dose intensity, dose modifications and study treatment discontinuation due to AEs related to XL114. |
Countries
United States
Outcome results
None listed