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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.

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 Macroglobulinemia Mantle Cell Lymphoma Marginal Zone Lymphoma B-cell Lymphoma Small Lymphocytic Lymphoma Drug: LOXO-305 Drug: Venetoclax Drug: Rituximab Drug: R-CHOP Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 403 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 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: Phase I Dose Escalation (LOXO-305) Monotherapy)
Dose Escalation and determination of MTD; multiple dose levels of LOXO-305 to be evaluated
Drug: LOXO-305
Oral 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.
Drug: LOXO-305
Oral 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.
Drug: LOXO-305
Oral 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.
Drug: LOXO-305
Oral 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.
Drug: LOXO-305
Oral 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.
Drug: LOXO-305
Oral 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.
Drug: LOXO-305
Oral LOXO-305

Experimental: Phase 1 Dose Expansion (LOXO-305 Monotherapy)
Patients to receive the recommended Phase 2 dose of LOXO-305.
Drug: LOXO-305
Oral 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
Drug: LOXO-305
Oral LOXO-305

Drug: Venetoclax
Oral
Other Name: Venclexta

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
Drug: LOXO-305
Oral LOXO-305

Drug: Venetoclax
Oral
Other Name: Venclexta

Drug: Rituximab
IV
Other Names:
  • Rituxan
  • MabThera

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)
Drug: LOXO-305
Oral LOXO-305

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




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

  4. 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

  5. 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

  6. 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


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

  11. 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

  12. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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, 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)

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

Locations
Show Show 20 study locations
Sponsors and Collaborators
Loxo Oncology, Inc.
Investigators
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Study Director: Donald Tsai, MD, PhD Loxo Oncology
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Responsible Party: Loxo Oncology, Inc.
ClinicalTrials.gov Identifier: NCT03740529    
Other Study ID Numbers: LOXO-BTK-18001
First Posted: November 14, 2018    Key Record Dates
Last Update Posted: March 13, 2020
Last Verified: March 2020

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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 Lymphoma
BTK Intolerant
C481S Mutation
Marginal zone lymphoma
DLBCL (Diffuse Large B-cell lymphoma)
Follicular Lymphoma
PI3KD
Idelalisib
Umbralisib
BCL2
Additional relevant MeSH terms:
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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
Prednisone
Cyclophosphamide
Rituximab
Doxorubicin
Vincristine
Venetoclax