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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03740529
Recruitment Status : Recruiting
First Posted : November 14, 2018
Last Update Posted : March 13, 2020
Sponsor:
Information provided by (Responsible Party):
Loxo Oncology, Inc.

Tracking Information
First Submitted Date  ICMJE November 6, 2018
First Posted Date  ICMJE November 14, 2018
Last Update Posted Date March 13, 2020
Actual Study Start Date  ICMJE November 16, 2018
Estimated Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 11, 2020)
  • Maximum Tolerated Dose (MTD) [ Time Frame: Up to 24 Months ]
    Phase I
  • Recommended dose for further study [ Time Frame: Up to 24 Months ]
    Phase I
  • To assess the preliminary anti-tumor activity of LOXO-305 based on ORR as assessed by an Independent Review Committee (IRC). [ Time Frame: Up to 24 months ]
    Phase II
  • To evaluate the safety of LOXO-305 in combination with venetoclax (Arm A) by assessing incidence and severity of treatment-emergent adverse events as determined by CTCAE v5.0 [ Time Frame: Up to 24 Months ]
    For Phase 1b
  • To evaluate the safety of LOXO-305 in combination with venetoclax and rituximab (Arm B) by assessing incidence and severity of treatment-emergent adverse events as determined by CTCAE v5.0 [ Time Frame: Up to 24 Months ]
    For Phase 1b
  • To evaluate the safety of LOXO-305 in combination with R-CHOP (Arm C) by assessing incidence and severity of treatment-emergent adverse events as determined by CTCAE v5.0 [ Time Frame: Up to 24 Months ]
    For Phase 1b
Original Primary Outcome Measures  ICMJE
 (submitted: November 12, 2018)
  • Maximum Tolerated Dose (MTD) [ Time Frame: Up to 24 Months ]
    Phase I
  • Recommended dose for further study [ Time Frame: Up to 24 Months ]
    Phase I
  • To assess the preliminary anti-tumor activity of LOXO-305 based on ORR as assessed by an Independent Review Committee (IRC). [ Time Frame: Up to 24 months ]
    Phase II
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 11, 2020)
  • 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 ]
    Phase I
  • 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 ]
    Phase I
  • 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 ]
    Phase I
  • ORR as assessed by the Investigator. [ Time Frame: Up to 24 Months ]
    Phase II
  • Best overall response (BOR) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II
  • Duration of response (DOR) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II
  • Progression free survival (PFS) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II
  • Overall survival (OS). [ Time Frame: Up to 24 Months ]
    Phase II
  • 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 ]
    Phase II
  • 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 ]
    Phase II
  • 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 ]
    For Phase 1b
  • 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 ]
    For Phase 1b
Original Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2018)
  • 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 ]
    Phase I
  • 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 ]
    Phase I
  • 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 ]
    Phase I
  • ORR as assessed by the Investigator. [ Time Frame: Up to 24 Months ]
    Phase II
  • Best overall response (BOR) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II
  • Duration of response (DOR) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II
  • Progression free survival (PFS) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II
  • Overall survival (OS). [ Time Frame: Up to 24 Months ]
    Phase II
  • 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 ]
    Phase II
  • 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 ]
    Phase II
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL
Official Title  ICMJE 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)
Brief Summary 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Lymphocytic Leukemia
  • Waldenstrom Macroglobulinemia
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • B-cell Lymphoma
  • Small Lymphocytic Lymphoma
Intervention  ICMJE
  • Drug: LOXO-305
    Oral LOXO-305
  • Drug: Venetoclax
    Oral
    Other Name: Venclexta
  • Drug: Rituximab
    IV
    Other Names:
    • Rituxan
    • MabThera
  • Drug: R-CHOP
    IV
    Other Names:
    • Rituximab (Rituxan)
    • Cyclophosphamide (Cytoxan, Neosar)
    • Doxorubicin (Adriamycin, Rubex)
    • Vincristine (Oncovin, Vincasar PFS)
    • Prednisone
Study Arms  ICMJE
  • Experimental: Phase I Dose Escalation (LOXO-305) Monotherapy)
    Dose Escalation and determination of MTD; multiple dose levels of LOXO-305 to be evaluated
    Intervention: Drug: LOXO-305
  • Experimental: Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 3
    WM/MCL/MZL Failed BTKi C481 mutant will receive the recommended Phase 2 dose of LOXO-305.
    Intervention: Drug: LOXO-305
  • Experimental: Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 1
    CLL/SLL Failed BTKi C481 mutant will receive the recommended Phase 2 dose of LOXO-305.
    Intervention: Drug: LOXO-305
  • Experimental: Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 4
    WM/MCL/MZL Failed BTKi no C481 mutation will receive the recommended Phase 2 dose of LOXO-305.
    Intervention: Drug: LOXO-305
  • Experimental: Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 2
    CLL/SLL Failed BTKi no C481 mutant will receive the recommended Phase 2 dose of LOXO-305.
    Intervention: Drug: LOXO-305
  • Experimental: Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 5
    CLL/SLL/WM/MCL/MZL/other NHL intolerant to prior BTKi will receive the recommended Phase 2 dose of LOXO-305.
    Intervention: Drug: LOXO-305
  • Experimental: Phase 2 Dose Expansion (LOXO-305 Monotherapy) Cohort 6
    Unknown 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.
    Intervention: Drug: LOXO-305
  • Experimental: Phase 1 Dose Expansion (LOXO-305 Monotherapy)
    Patients to receive the recommended Phase 2 dose of LOXO-305.
    Intervention: Drug: LOXO-305
  • Experimental: Phase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm A
    Relapsed/Refractory CLL will receive the recommended Phase 2 dose of LOXO-305 in combination with Venetoclax
    Interventions:
    • Drug: LOXO-305
    • Drug: Venetoclax
  • Experimental: Phase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm B
    Relapsed/Refractory CLL will receive the recommended Phase 2 dose of LOXO-305 in combination with Venetoclax and Rituximab
    Interventions:
    • Drug: LOXO-305
    • Drug: Venetoclax
    • Drug: Rituximab
  • Experimental: Phase 1b Dose Expansion (LOXO-305 Combination Therapy) Arm C
    CD20(+) 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)
    Interventions:
    • Drug: LOXO-305
    • Drug: Rituximab
    • Drug: R-CHOP
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 11, 2020)
403
Original Estimated Enrollment  ICMJE
 (submitted: November 12, 2018)
190
Estimated Study Completion Date  ICMJE April 2021
Estimated Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Patient Advocacy 1-855-LOXO-305 clinicaltrials@loxooncology.com
Listed Location Countries  ICMJE Australia,   France,   Poland,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03740529
Other Study ID Numbers  ICMJE LOXO-BTK-18001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Loxo Oncology, Inc.
Study Sponsor  ICMJE Loxo Oncology, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Donald Tsai, MD, PhD Loxo Oncology
PRS Account Loxo Oncology, Inc.
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP