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

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ClinicalTrials.gov Identifier: NCT03740529
Recruitment Status : Recruiting
First Posted : November 14, 2018
Last Update Posted : December 7, 2018
Sponsor:
Information provided by (Responsible Party):
Loxo Oncology, Inc.

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.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Waldenstrom's Macroglobulinemia Mantle Cell Lymphoma Marginal Zone Lymphoma B-cell Lymphoma Small Lymphocytic Lymphoma Drug: LOXO-305 Phase 1 Phase 2

Detailed Description:
This study includes 2 parts: phase 1 (dose escalation) and phase 2 (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, 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 : Interventional  (Clinical Trial)
Estimated Enrollment : 190 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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's Lymphoma (NHL)
Actual Study Start Date : November 16, 2018
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : April 2021


Arm Intervention/treatment
Experimental: LOXO-305
Phase I: Dose Escalation and determination of MTD; multiple dose levels of LOXO-305 to be evaluated
Drug: LOXO-305
Oral LOXO-305

Experimental: CLL/SLL Failed BTKi C481 mutant
Phase II: CLL/SLL Failed BTKi C481 mutant will receive the recommended Phase II dose of LOXO-305.
Drug: LOXO-305
Oral LOXO-305

Experimental: CLL/SLL Failed BTKi no C481 mutation
Phase II: CLL/SLL Failed BTKi no C481 mutation will receive the recommended Phase II dose of LOXO-305.
Drug: LOXO-305
Oral LOXO-305

Experimental: WM/MCL/MZL Failed BTKi C481 mutant
Phase II: WM/MCL/MZL Failed BTKi C481 mutant will receive the recommended Phase II dose of LOXO-305.
Drug: LOXO-305
Oral LOXO-305

Experimental: WM/MCL/MZL Failed BTKi no C481 mutation
Phase II: WM/MCL/MZL Failed BTKi no C481 mutation will receive the recommended Phase II dose of LOXO-305.
Drug: LOXO-305
Oral LOXO-305

Experimental: CLL/SLL/WM/MCL/MZL/other NHL intolerant to prior BTKi
Phase II: CLL/SLL/WM/MCL/MZL/other NHL intolerant to prior BTKi will receive the recommended Phase II dose of LOXO-305.
Drug: LOXO-305
Oral LOXO-305

Experimental: Other
Phase II: Unknown BTK C481 substitution mutation and other patients not meeting the definitions of Cohorts 1 through 5 will receive the recommended Phase II dose of LOXO-305.
Drug: LOXO-305
Oral LOXO-305




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: Up to 24 Months ]
    Phase I

  2. Recommended dose for further study [ Time Frame: Up to 24 Months ]
    Phase I

  3. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. ORR as assessed by the Investigator. [ Time Frame: Up to 24 Months ]
    Phase II

  5. Best overall response (BOR) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II

  6. Duration of response (DOR) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II

  7. Progression free survival (PFS) as assessed by the Investigator and IRC. [ Time Frame: Up to 24 Months ]
    Phase II

  8. Overall survival (OS). [ Time Frame: Up to 24 Months ]
    Phase II

  9. 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

  10. 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed CLL/SLL or NHL intolerant to standard of care therapies.
  • Histologically confirmed CLL/SLL or NHL which has failed standard of care therapies
  • ≥ 2 prior lines of therapy.
  • No more than 2 lines of prior chemotherapy-containing treatment regimens for initial phase 1 patients then no restriction.
  • For initial phase 1 patients, able to tolerate potentially subtherapeutic doses of LOXO-305 for the 28-day DLT window in the opinion of the investigator and with documented sponsor approval.
  • Eastern Cooperative Oncology Group (ECOG) 0-2.
  • Adequate hematologic, 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:

  • Transformation (e.g., Richter's transformation, prolymphocytic leukemia, transformed NHL, blastoid lymphoma) prior to planned start of LOXO-305.
  • Investigational agent or anticancer therapy within 2 weeks prior to planned start 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.
  • 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 100 days (180 days before the PK trigger).
  • Known central nervous system (CNS) involvement by lymphoma.
  • Active uncontrolled auto-immune cytopenia.
  • 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.
  • 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03740529


Contacts
Contact: Patient Advocacy 1-855-LOXO-305 clinicaltrials@loxooncology.com

Locations
United States, Tennessee
Sarah Cannon Research Institute at Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
Contact: Ian W Flinn, MD, PhD         
Sponsors and Collaborators
Loxo Oncology, Inc.
Investigators
Study Director: Nora Ku, MD LOXO Oncology

Responsible Party: Loxo Oncology, Inc.
ClinicalTrials.gov Identifier: NCT03740529     History of Changes
Other Study ID Numbers: LOXO-BTK-18001
First Posted: November 14, 2018    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Loxo Oncology, Inc.:
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's Lymphoma
BTK Intolerant
C481S Mutation
Marginal zone lymphoma
DLBCL (Diffuse Large B-cell lymphoma)
Follicular Lymphoma

Additional relevant MeSH terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Lymphoma, Non-Hodgkin
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders