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

Primary Purpose

Non-Hodgkin's Lymphoma (NHL), Activated B-Cell Type Diffuse Large B-Cell Lymphoma (ABC-DLBCL), Mantle Cell Lymphoma (MCL)

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
XL114
Sponsored by
Exelixis
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-Hodgkin's Lymphoma (NHL) focused on measuring Mucosa-associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT-1), B-cell Malignancies, Fatty Acid Binding Protein 5 (FABP-5)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Exelixis Clinical Site #3
  • Exelixis Clinical Site #1
  • Exelixis Clinical #4
  • Exelixis Clinical Site #2

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

XL114 Dose-Escalation Cohorts

XL114 Expansion Cohorts

Arm Description

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

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).

Outcomes

Primary Outcome Measures

Dose-Escalation Stage: Recommended Dose (RD) and/or Maximum Tolerated Dose (MTD) for XL114
To determine the RD and/or MTD of XL114 administered orally in subjects with NHL
Cohort-Expansion Stage: Objective Response Rate (ORR)
To evaluate preliminary efficacy of XL114 by estimating the ORR based on lymphoma-specific response criteria as assessed by the Investigator

Secondary Outcome Measures

Safety of XL114, as evaluated by Adverse Events (AEs)
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.
Tolerability of XL114, as evaluated by Dose Intensity, Dose Modifications, and Study Discontinuation due to AEs
To evaluate the tolerability of XL114 through the evaluation of dose intensity, dose modifications and study treatment discontinuation due to AEs related to XL114.
Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax)
To evaluate the Tmax of XL114.
Dose-Escalation Stage: Maximum Plasma Concentration (Cmax)
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)
To evaluate the AUC 0-24 of XL114.
Dose-Escalation Stage: Terminal Half-Life
To evaluate the terminal half-life of XL114.
Dose-Escalation Stage: Apparent Clearance (CL/F)
To evaluate the CL/F of XL114.
Cohort-Expansion Stage: Antitumor Activity of XL114 (Objective Response Rate [ORR])
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])
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])
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
To evaluate duration of overall survival (OS)

Full Information

First Posted
November 10, 2021
Last Updated
July 7, 2023
Sponsor
Exelixis
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1. Study Identification

Unique Protocol Identification Number
NCT05144347
Brief Title
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

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Terminated
Why Stopped
Due to Sponsor reasons.
Study Start Date
April 12, 2022 (Actual)
Primary Completion Date
November 1, 2022 (Actual)
Study Completion Date
November 1, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Exelixis

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
Dose-escalation followed by Cohort-expansion in NHL-specific expansion cohorts
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
XL114 Dose-Escalation Cohorts
Arm Type
Experimental
Arm Description
Subjects (Cohort A1-An) will accrue in cohorts of 3-12 subjects in a i3+3 design.
Arm Title
XL114 Expansion Cohorts
Arm Type
Experimental
Arm 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).
Intervention Type
Drug
Intervention Name(s)
XL114
Intervention Description
Tablets of XL114
Primary Outcome Measure Information:
Title
Dose-Escalation Stage: Recommended Dose (RD) and/or Maximum Tolerated Dose (MTD) for XL114
Description
To determine the RD and/or MTD of XL114 administered orally in subjects with NHL
Time Frame
4-6 months
Title
Cohort-Expansion Stage: Objective Response Rate (ORR)
Description
To evaluate preliminary efficacy of XL114 by estimating the ORR based on lymphoma-specific response criteria as assessed by the Investigator
Time Frame
4-6 months
Secondary Outcome Measure Information:
Title
Safety of XL114, as evaluated by Adverse Events (AEs)
Description
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.
Time Frame
4-6 months
Title
Tolerability of XL114, as evaluated by Dose Intensity, Dose Modifications, and Study Discontinuation due to AEs
Description
To evaluate the tolerability of XL114 through the evaluation of dose intensity, dose modifications and study treatment discontinuation due to AEs related to XL114.
Time Frame
4-6 months
Title
Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax)
Description
To evaluate the Tmax of XL114.
Time Frame
4-6 months
Title
Dose-Escalation Stage: Maximum Plasma Concentration (Cmax)
Description
To evaluate the Cmax of XL114.
Time Frame
4-6 months
Title
Dose-Escalation Stage: Area Under the Plasma Concentration-Time Curve Over the Last 24-hour Dosing Interval (AUC 0-24)
Description
To evaluate the AUC 0-24 of XL114.
Time Frame
4-6 months
Title
Dose-Escalation Stage: Terminal Half-Life
Description
To evaluate the terminal half-life of XL114.
Time Frame
4-6 months
Title
Dose-Escalation Stage: Apparent Clearance (CL/F)
Description
To evaluate the CL/F of XL114.
Time Frame
4-6 months
Title
Cohort-Expansion Stage: Antitumor Activity of XL114 (Objective Response Rate [ORR])
Description
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.
Time Frame
4-6 months
Title
Cohort-Expansion Stage: Antitumor Activity of XL114 (Duration of Response [DOR])
Description
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.
Time Frame
4-6 months
Title
Cohort-Expansion Stage: Antitumor Activity of XL114 (Progression Free Survival [PFS])
Description
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.
Time Frame
4-6 months
Title
Cohort-Expansion Stage: Overall Survival (OS) of XL114
Description
To evaluate duration of overall survival (OS)
Time Frame
4-6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Facility Information:
Facility Name
Exelixis Clinical Site #3
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85719
Country
United States
Facility Name
Exelixis Clinical Site #1
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46250
Country
United States
Facility Name
Exelixis Clinical #4
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Exelixis Clinical Site #2
City
Spokane
State/Province
Washington
ZIP/Postal Code
99208
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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