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:
  • Chronic Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • 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
  • 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)
VenetoclaxVenclextaPhase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm A
RituximabRituxan, MabTheraPhase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm B
R-CHOPRituximab (Rituxan), Cyclophosphamide (Cytoxan, Neosar), Doxorubicin (Adriamycin, Rubex), Vincristine (Oncovin, Vincasar PFS), PrednisonePhase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm C

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
      C). Subsequent enrollment to phase 1b (Arm B) and phase 2 will follow when appropriate. For
      phase 2, patients will be enrolled to one of six phase 2 dose expansion cohorts depending on
      tumor histology, tumor genotype, 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 Dose Expansion (LOXO-305 Monotherapy) Cohort 3ExperimentalWM/MCL/MZL Failed BTKi C481 mutant will receive the recommended Phase 2 dose of LOXO-305.
  • LOXO-305
Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 1ExperimentalCLL/SLL Failed BTKi C481 mutant will receive the recommended Phase 2 dose of LOXO-305.
  • LOXO-305
Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 4ExperimentalWM/MCL/MZL Failed BTKi no C481 mutation will receive the recommended Phase 2 dose of LOXO-305.
  • LOXO-305
Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 2ExperimentalCLL/SLL Failed BTKi no C481 mutant will receive the recommended Phase 2 dose of LOXO-305.
  • LOXO-305
Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 5ExperimentalCLL/SLL/WM/MCL/MZL/other NHL intolerant to prior BTKi will receive the recommended Phase 2 dose of LOXO-305.
  • LOXO-305
Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 6ExperimentalUnknown BTK C481 substitution mutation and other patients not meeting the definitions of Cohorts 1 through 5 will receive the recommended Phase 2 dose of LOXO-305.
  • LOXO-305
Phase 1 Dose Expansion (LOXO-305 Monotherapy)ExperimentalPatients to receive the recommended Phase 2 dose of LOXO-305.
  • 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 1b Dose Expansion (LOXO-305 Combination Therapy) Arm CExperimentalCD20(+) non-GCB DLBCL/FL/MCL with less than or equal to 1 prior regimen of treatment and greater than or equal to 1 site of measurable disease will receive the recommended Phase 2 dose of LOXO-305 in combination with Rituximab-CHOP (R-CHOP)
  • LOXO-305
  • Rituximab
  • R-CHOP

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-containing regimen when a BTK inhibitor is approved as first line therapy (Phase 1
             and 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 (Phase 1b Arm A Patients only)

          -  Histologically confirmed relapsed/refractory CLL in whom venetoclax + rituximab is
             appropriate standard salvage treatment (Phase 1b Arm B Patients only)

          -  Histologically confirmed CD20(+) non-GCB DLBCL, FL, or MCL who have received ≤1 prior
             regimen of treatment, with ≥ 1 site of measurable disease, and for which appropriate
             treatment is the combination of rituximab with standard CHOP (R-CHOP) chemotherapy
             (Phase 1b Arm C 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 to observe conventional and
             effective birth control.

        Exclusion Criteria:

          -  Investigational agent or anticancer therapy within 5 half-lives prior to planned start
             of LOXO-305 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
             investigational therapy is permitted.

          -  Major surgery within 4 weeks prior to planned start of LOXO-305.

          -  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).

          -  Known central nervous system (CNS) involvement by lymphoma.

          -  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.

          -  Tested positive for Human Immunodeficiency Virus (HIV) is excluded.

          -  Clinically significant active malabsorption syndrome.

          -  Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
             inducers and/or strong P-gp inhibitors

          -  Treatment with proton pump inhibitors (PPIs) within 7 days of starting LOXO-305.

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

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

          -  Patients with prior significant hypersensitivity to rituximab requiring
             discontinuation, prior allergic or anaphylactic reaction to rituximab (Phase 1b Arm B
             and Arm C 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 pharmacokinetic properties and interactions between LOXO-305 and combination drugs by evaluating serum at 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

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
  • Rituximab-CHOP (R-CHOP)

Last Updated

March 11, 2020