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

• ClinicalTrials.gov Identifier: NCT03740529
• Recruitment Status: Active, not recruiting
• First Posted: November 14, 2018
• Last Update Posted: March 26, 2024
• Sponsor: Loxo Oncology, Inc.
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company ( Loxo Oncology, Inc. )

Tracking Information

• First Submitted Date: November 6, 2018
• First Posted Date: November 14, 2018
• Last Update Posted Date: March 26, 2024
• Actual Study Start Date: November 16, 2018
• Estimated Primary Completion Date: September 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 12, 2022)

• 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 pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC). [ Time Frame: Up to 24 months ]
  Phase II
• To evaluate the safety of pirtobrutinib 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 pirtobrutinib 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

Original Primary Outcome Measures (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

Current Secondary Outcome Measures (submitted: January 12, 2022)

• To determine the safety profile and tolerability of pirtobrutinib 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 pirtobrutinib 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 pirtobrutinib 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 pirtobrutinib 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 pirtobrutinib by collecting and evaluating serum at protocol specified time points. [ Time Frame: Up to 24 Months ]
  Phase II
• To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points. [ Time Frame: Up to 24 months ]
  For Phase 1b
• To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator. [ Time Frame: Up to 24 months ]
  For Phase 1b
• 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) ]
  Individual EORTC symptom scores range from 1 (not at all) to 4 (very much) with higher scores representing more severe symptom severity.
• 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) ]
  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.

Original Secondary Outcome Measures (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: 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)
• Brief Summary: This is an open-label, multi-center Phase 1/2 study of oral LOXO-305 (pirtobrutinib) 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 (pirtobrutinib monotherapy dose escalation and dose expansion), Phase 1b (pirtobrutinib combination therapy dose expansion), and Phase 2 (pirtobrutinib monotherapy dose expansion). In Phase 1, patients will be enrolled using an accelerated titration design. The starting dose of pirtobrutinib 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Pirtobrutinib
  Oral
  Other Names:

  • LOXO-305
  • LY3527727
• Drug: Venetoclax
  Oral
  Other Name: Venclexta, Venclyxto
• Drug: Rituximab
  IV
  Other Names:

  • Rituxan
  • MabThera

Study Arms

• Experimental: Phase I Dose Escalation (Pirtobrutinib Monotherapy)
  Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated
  Intervention: Drug: Pirtobrutinib
• Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 3
  CLL/SLL patients with no prior therapy.
  Intervention: Drug: Pirtobrutinib
• Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 1
  Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.
  Intervention: Drug: Pirtobrutinib
• Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 4
  CLL/SLL patients treated with prior therapy, BTK inhibitor naïve.
  Intervention: Drug: Pirtobrutinib
• Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 2
  CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.
  Intervention: Drug: Pirtobrutinib
• Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 5
  WM patients treated with a prior BTK inhibitor-containing regimen.
  Intervention: Drug: Pirtobrutinib
• Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 6
  MZL patients treated with a prior BTK inhibitor-containing regimen.
  Intervention: Drug: Pirtobrutinib
• Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 7
  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 pirtobrutinib may be eligible to enroll in this cohort Diffuse large B-cell lymphoma (DLBCL) is excluded. MCL without prior BTK inhibitor treatment is excluded. Patients enrolling to Cohort 7 must have received one or more prior therapies or have no available approved therapy with demonstrated clinical benefit with the exception of untreated Richter's transformation, which is allowed.
  Intervention: Drug: Pirtobrutinib
• Experimental: Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A
  Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax
  Interventions:

  • Drug: Pirtobrutinib
  • Drug: Venetoclax
• Experimental: Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B
  Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab
  Interventions:

  • Drug: Pirtobrutinib
  • Drug: Venetoclax
  • Drug: Rituximab
• Experimental: Phase 1 Dose Expansion (Pirtobrutinib Monotherapy)
  Patients to receive the recommended Phase 2 dose of pirtobrutinib
  Intervention: Drug: Pirtobrutinib

Publications *

• Cohen JB, Shah NN, Alencar AJ, Gerson JN, Patel MR, Fakhri B, Jurczak W, Tan XN, Lewis KL, Fenske T, Coombs CC, Flinn IW, Lewis DJ, Gouill SL, Palomba ML, Woyach JA, Pagel JM, Lamanna N, Barve MA, Ghia P, Eyre TA, Zinzani PL, Ujjani CS, Koh Y, Izutsu K, Lech-Maranda E, Tam CS, Sundaram S, Yin M, Nair B, Tsai DE, Balbas M, Mato AR, Cheah CY, Wang ML. MCL-133 Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results From the Phase 1/2 BRUIN Study. Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S394-S395. doi: 10.1016/S2152-2650(22)01569-5.
• Aslan B, Kismali G, Iles LR, Manyam GC, Ayres ML, Chen LS, Gagea M, Bertilaccio MTS, Wierda WG, Gandhi V. Pirtobrutinib inhibits wild-type and mutant Bruton's tyrosine kinase-mediated signaling in chronic lymphocytic leukemia. Blood Cancer J. 2022 May 20;12(5):80. doi: 10.1038/s41408-022-00675-9.
• Kipps TJ. Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancer J. 2021 Jul-Aug 01;27(4):306-313. doi: 10.1097/PPO.0000000000000536.
• Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi: 10.1016/S0140-6736(21)00224-5.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: October 12, 2020): 860
• Original Estimated Enrollment (submitted: November 12, 2018): 190
• Estimated Study Completion Date: January 2028
• Estimated Primary Completion Date: September 2027 (Final data collection date for primary outcome measure)

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 or 14 days, whichever is shorter, prior to planned start of specified study therapy except antineoplastic and immunosuppressant monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of pirtobrutinib. 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 pirtobrutinib.
• 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 pirtobrutinib.
• Active second malignancy unless in remission and with life expectancy > 2 years.
• Known hypersensitivity to any component or excipient of pirtobrutinib.
• 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Italy, Japan, Korea, Republic of, Poland, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03740529
• Other Study ID Numbers: LOXO-BTK-18001 (BRUIN); 2018-003340-24 ( EudraCT Number ); J2N-OX-JZNA ( Other Identifier: Eli Lilly and Company )
• 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: Not Provided
• Current Responsible Party: Eli Lilly and Company ( Loxo Oncology, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Loxo Oncology, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Eli Lilly and Company

Investigators

• Study Director: Donald Tsai, MD, PhD; Loxo Oncology

• PRS Account: Eli Lilly and Company
• Verification Date: March 2024