Phase 1/2 study of LOXO-305 orally in patients with chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) or non-Hodgkin lymphoma (NHL) previously treated

Australia, France, Italy, Japan, Poland, South Korea, Sweden, Switzerland, United Kingdom, United States (ICTRP)

Identifiant de l'essai ICTRP
NCT03740529 (ICTRP)

Titre officiel (approuvé par le comité d'éthique)
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). (BASEC)

Titre académique
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) (ICTRP)

Titre public
A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL (ICTRP)

Maladie en cours d'investigation
Chronic Lymphocytic LeukemiaWaldenstrom MacroglobulinemiaMantle Cell LymphomaMarginal Zone LymphomaB-cell LymphomaSmall Lymphocytic Lymphoma (ICTRP)

Intervention étudiée
Drug: PirtobrutinibDrug: VenetoclaxDrug: Rituximab (ICTRP)

Type d'essai
Interventional (ICTRP)

Plan de l'étude
Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Critères d'inclusion/exclusion
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). (ICTRP)

non disponible

Critères d'évaluation principaux et secondaires
Maximum Tolerated Dose (MTD);Recommended dose for further study;To assess the preliminary anti-tumor activity of pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC).;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;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 (ICTRP)

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.;To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.;To assess the preliminary anti-tumor activity of pirtobrutinib based on overall response rate (ORR) as assessed by investigator.;ORR as assessed by the Investigator.;Best overall response (BOR) as assessed by the Investigator and IRC.;Duration of response (DOR) as assessed by the Investigator and IRC.;Progression free survival (PFS) as assessed by the Investigator and IRC.;Overall survival (OS).;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;To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.;To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.;To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator.;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;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) (ICTRP)

Date d'enregistrement
non disponible

Inclusion du premier participant
non disponible

Sponsors secondaires
Eli Lilly and Company (ICTRP)

Contacts supplémentaires
Donald Tsai, MD, PhD, Loxo Oncology (ICTRP)

ID secondaires
2018-003340-24, J2N-OX-JZNA, LOXO-BTK-18001 (BRUIN), 17539 (ICTRP)

Résultats-Données individuelles des participants
non disponible

Informations complémentaires sur l'essai
https://clinicaltrials.gov/study/NCT03740529 (ICTRP)