Clinical Trials /

A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL

NCT03740529

Description:

This is an open-label, multi-center Phase 1/2 study of oral LOXO-305 in patients with CLL/SLL and NHL who have failed or are intolerant to standard of care.

Related Conditions:
  • Blastoid Variant Mantle Cell Lymphoma
  • Central Nervous System Lymphoma
  • Chronic Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Mantle Cell Lymphoma
  • Non-Hodgkin Lymphoma
  • Primary Central Nervous System Lymphoma
  • Richter Syndrome
  • Transformed Non-Hodgkin Lymphoma
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL
  • Official Title: A Phase 1/2 Study of Oral LOXO-305 in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL)

Clinical Trial IDs

  • ORG STUDY ID: LOXO-BTK-18001 (BRUIN)
  • NCT ID: NCT03740529

Conditions

  • Chronic Lymphocytic Leukemia
  • Waldenstrom Macroglobulinemia
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • B-cell Lymphoma
  • Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
LOXO-305Phase 1 Dose Expansion (LOXO-305 Monotherapy)
VenetoclaxVenclexta, VenclyxtoPhase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm A
RituximabRituxan, MabTheraPhase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm B

Purpose

This is an open-label, multi-center Phase 1/2 study of oral LOXO-305 in patients with CLL/SLL and NHL who have failed or are intolerant to standard of care.

Detailed Description

      This study includes 3 parts: phase 1 (LOXO-305 monotherapy dose escalation and dose
      expansion), phase 1b (LOXO-305 combination therapy dose expansion), and phase 2 (LOXO-305
      monotherapy dose expansion). In phase 1, patients will be enrolled using an accelerated
      titration design. The starting dose of LOXO-305 in oral tablet form is 25 mg/day (e.g., 25 mg
      once daily [QD]). Once the MTD and/or RP2D is identified in phase 1 dose escalation,
      enrollment will continue to phase 1 dose expansion and can commence to phase 1b (Arms A and
      B). For phase 2, patients will be enrolled to one of seven phase 2 dose expansion cohorts
      depending on tumor histology and prior treatment history. Cycle length will be 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I Dose Escalation (LOXO-305) Monotherapy)ExperimentalDose Escalation and determination of MTD; multiple dose levels of LOXO-305 to be evaluated
  • LOXO-305
Phase 2 (LOXO-305 Monotherapy) Cohort 3ExperimentalCLL/SLL patients with no prior therapy.
  • LOXO-305
Phase 2 (LOXO-305 Monotherapy) Cohort 1ExperimentalNon-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.
  • LOXO-305
Phase 2 (LOXO-305 Monotherapy) Cohort 4ExperimentalCLL/SLL patients treated with prior therapy, BTK inhibitor naïve.
  • LOXO-305
Phase 2 (LOXO-305 Monotherapy) Cohort 2ExperimentalCLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.
  • LOXO-305
Phase 2 (LOXO-305 Monotherapy) Cohort 5ExperimentalWM patients treated with a prior BTK inhibitor-containing regimen.
  • LOXO-305
Phase 2 (LOXO-305 Monotherapy) Cohort 6ExperimentalMZL patients treated with a prior BTK inhibitor-containing regimen.
  • LOXO-305
Phase 2 (LOXO-305 Monotherapy) Cohort 7Experimental(Not otherwise specified) Defined as CLL/SLL or NHL not otherwise specified in Cohorts 1 through 6, inclusive of CLL/SLL, Richter's transformation, or low grade NHL with transformation, blastoid MCL, and patients with history of CNS involvement or primary CNS lymphoma. In the event the Sponsor electively closes Cohorts 2-4 prior to completion, patients with CLL/SLL who are ineligible to participate in or unable to access late Phase studies of LOXO-305 would remain eligible to enroll in this cohort.
  • LOXO-305
Phase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm AExperimentalRelapsed/Refractory CLL will receive the recommended Phase 2 dose of LOXO-305 in combination with Venetoclax
  • LOXO-305
  • Venetoclax
Phase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm BExperimentalRelapsed/Refractory CLL will receive the recommended Phase 2 dose of LOXO-305 in combination with Venetoclax and Rituximab
  • LOXO-305
  • Venetoclax
  • Rituximab
Phase 1 Dose Expansion (LOXO-305 Monotherapy)ExperimentalPatients to receive the recommended Phase 2 dose of LOXO-305.
  • LOXO-305

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed CLL/SLL, WM, or NHL intolerant to either ≥ 2 prior standard
             of care regimens given in combination or sequentially OR have received 1 prior BTK
             inhibitor-containing regimen when a BTK inhibitor is approved as first line therapy
             (Phase 1) OR with prior treatment defined by phase 2 cohort (Phase 2 Patients only).

          -  Adequate hematologic function (Phase 1 and 1b Patients only).

          -  Responsive to transfusion support if given for thrombocytopenia or anemia (Phase 1 and
             1b Patients only).

          -  Histologically confirmed relapsed/recurrent CLL in whom venetoclax is appropriate
             standard salvage treatment; no prior venetoclax is permitted (Phase 1b Arm A Patients
             only).

          -  Histologically confirmed relapsed/refractory CLL in whom venetoclax + rituximab is
             appropriate standard salvage treatment; no prior venetoclax is permitted (Phase 1b Arm
             B Patients only).

          -  Eastern Cooperative Oncology Group (ECOG) 0-2.

          -  Adequate hepatic and renal function.

          -  Ability to receive study drug therapy orally.

          -  Willingness of men and women of reproductive potential (defined as following menarche
             and not postmenopausal [and 2 years of non-therapy-induced amenorrhea] or surgically
             sterile) to observe conventional and effective birth control.

        Exclusion Criteria:

          -  Investigational agent or anticancer therapy within 5 half-lives prior to planned start
             of specified study therapy except therapeutic monoclonal antibody treatment must be
             discontinued a minimum of 4 weeks prior to the first dose of LOXO-305. In addition, no
             concurrent systemic anticancer therapy is permitted.

          -  Major surgery within 4 weeks prior to planned start of specified study therapy.

          -  Radiotherapy with a limited field of radiation for palliation within 7 days of the
             first dose of study treatment.

          -  Pregnancy or lactation.

          -  Patients requiring therapeutic anticoagulation with warfarin.

          -  Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2
             or greater at the time of starting study treatment except for alopecia.

          -  History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen
             receptor-modified T-cell (CAR-T) therapy within the past 60 days (180 days before the
             PK trigger) prior to planned start of specified study therapy.

          -  Known central nervous system (CNS) involvement by systemic lymphoma. Patients with
             previous treatment for CNS involvement who are neurologically stable and without
             evidence of disease may be eligible and enrolled to phase 2 Cohort 7 if a compelling
             clinical rationale is provided by the Investigator and with documented Sponsor
             approval.

          -  Active uncontrolled auto-immune cytopenia where new therapy introduced or concomitant
             therapy escalated within the 4 weeks prior to study enrollment is required to maintain
             adequate blood counts.

          -  Clinically significant, uncontrolled cardiac, cardiovascular disease or history of
             myocardial infarction within 6 months prior to planned start of LOXO-305.

          -  Active uncontrolled systemic bacterial, viral, fungal or parasitic infection.

          -  Patients who have tested positive for Human Immunodeficiency Virus (HIV) are excluded.
             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.

          -  Current treatment with certain strong CYP3A4 inhibitors or inducers and/or strong P-gp
             inhibitors.

          -  For patients enrolled to phase 1b Arm A or B: Patients with prior treatment with
             venetoclax or other BCL-2 inhibitors.

          -  Prior treatment with LOXO-305.

          -  Active second malignancy unless in remission and with life expectancy > 2 years.

          -  Known hypersensitivity to any component or excipient of LOXO-305.

          -  For patients enrolled to phase 1b Arm B: Patients with prior significant
             hypersensitivity, allergy, or anaphylactic reaction to rituximab/biosimilar requiring
             discontinuation.

          -  Patients with prior significant hypersensitivity to rituximab requiring
             discontinuation, prior allergic or anaphylactic reaction to rituximab (Phase 1b Arm B
             Patients only).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase I

Secondary Outcome Measures

Measure:To determine the safety profile and tolerability of LOXO-305 including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events.
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase I
Measure:To characterize the pharmacokinetics (PK) properties of LOXO-305 by collecting and evaluating serum at protocol specified time points.
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase I
Measure:To assess the preliminary anti-tumor activity of LOXO-305 based on overall response rate (ORR) as assessed by investigator.
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase I
Measure:ORR as assessed by the Investigator.
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase II
Measure:Best overall response (BOR) as assessed by the Investigator and IRC.
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase II
Measure:Duration of response (DOR) as assessed by the Investigator and IRC.
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase II
Measure:Progression free survival (PFS) as assessed by the Investigator and IRC.
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase II
Measure:Overall survival (OS).
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase II
Measure:To determine the safety profile and tolerability of LOXO-305 including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase II
Measure:To characterize the pharmacokinetics (PK) properties of LOXO-305 by collecting and evaluating serum at protocol specified time points.
Time Frame:Up to 24 Months
Safety Issue:
Description:Phase II
Measure:To characterize the pharmacokinetics (PK) properties of LOXO-305 by collecting and evaluating serum at protocol specified time points.
Time Frame:Up to 24 months
Safety Issue:
Description:For Phase 1b
Measure:To assess the preliminary anti-tumor activity of LOXO-305 in combination based on overall response rate (ORR) as assessed by investigator.
Time Frame:Up to 24 months
Safety Issue:
Description:For Phase 1b
Measure:Symptomatic Response: Change from Baseline in Mantle Cell Lymphoma (MCL)-related symptoms selected from the European Organisation for Research and Treatment of Cancer (EORTC) Item Library
Time Frame:Baseline, End of Treatment (Estimated Up to 24 Months)
Safety Issue:
Description:Individual EORTC symptom scores range from 1 (not at all) to 4 (very much) with higher scores representing more severe symptom severity.
Measure:Functional Response: Change from Baseline in Physical Functioning as Measured by Physical Functioning Scale from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ)
Time Frame:Baseline, End of Treatment (Estimated Up to 24 Months)
Safety Issue:
Description:EORTC physical function item scores range from 1 (not at all) to 4 (very much) with higher scores indicating poorer functioning.The total EORTC physical functioning score ranges from 0-100 where a higher score indicates higher/healthier level of functioning.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Loxo Oncology, Inc.

Trial Keywords

  • Loxo
  • LOXO-305
  • BTK
  • Bruton's tyrosine kinase
  • CLL
  • SLL
  • NHL
  • Chronic Lymphocytic Leukemia
  • C481S
  • C481
  • Ibrutinib
  • Acalabrutinib
  • Zanubrutinib
  • BGB-3111
  • GS-4059
  • ONO-4059
  • Tirabrutinib
  • Small Lymphocytic Lymphoma
  • Mantle Cell Lymphoma
  • Waldenstrom macroglobulinemia
  • Non-Hodgkin Lymphoma
  • BTK Intolerant
  • C481S Mutation
  • Marginal zone lymphoma
  • DLBCL (Diffuse Large B-cell lymphoma)
  • Follicular Lymphoma
  • PI3KD
  • Idelalisib
  • Umbralisib
  • BCL2
  • Venetoclax
  • Rituximab
  • Primary CNS Lymphoma
  • Richter's Transformation

Last Updated

December 2, 2020