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

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Loxo Oncology

Status and phase

Active, not recruiting
Phase 2
Phase 1

Conditions

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

Treatments

Drug: Venetoclax
Drug: Rituximab
Drug: Pirtobrutinib

Study type

Interventional

Funder types

Industry

Identifiers

NCT03740529
2018-003340-24 (EudraCT Number)
J2N-OX-JZNA (Other Identifier)
LOXO-BTK-18001 (BRUIN)

Details and patient eligibility

About

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.

Full 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.

Enrollment

860 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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).

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

860 participants in 11 patient groups

Phase I Dose Escalation (Pirtobrutinib Monotherapy)
Experimental group
Description:
Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated
Treatment:
Drug: Pirtobrutinib
Phase 2 (Pirtobrutinib Monotherapy) Cohort 3
Experimental group
Description:
CLL/SLL patients with no prior therapy.
Treatment:
Drug: Pirtobrutinib
Phase 2 (Pirtobrutinib Monotherapy) Cohort 1
Experimental group
Description:
Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.
Treatment:
Drug: Pirtobrutinib
Phase 2 (Pirtobrutinib Monotherapy) Cohort 4
Experimental group
Description:
CLL/SLL patients treated with prior therapy, BTK inhibitor naïve.
Treatment:
Drug: Pirtobrutinib
Phase 2 (Pirtobrutinib Monotherapy) Cohort 2
Experimental group
Description:
CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.
Treatment:
Drug: Pirtobrutinib
Phase 2 (Pirtobrutinib Monotherapy) Cohort 5
Experimental group
Description:
WM patients treated with a prior BTK inhibitor-containing regimen.
Treatment:
Drug: Pirtobrutinib
Phase 2 (Pirtobrutinib Monotherapy) Cohort 6
Experimental group
Description:
MZL patients treated with a prior BTK inhibitor-containing regimen.
Treatment:
Drug: Pirtobrutinib
Phase 2 (Pirtobrutinib Monotherapy) Cohort 7
Experimental group
Description:
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.
Treatment:
Drug: Pirtobrutinib
Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A
Experimental group
Description:
Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax
Treatment:
Drug: Pirtobrutinib
Drug: Venetoclax
Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B
Experimental group
Description:
Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab
Treatment:
Drug: Pirtobrutinib
Drug: Rituximab
Drug: Venetoclax
Phase 1 Dose Expansion (Pirtobrutinib Monotherapy)
Experimental group
Description:
Patients to receive the recommended Phase 2 dose of pirtobrutinib
Treatment:
Drug: Pirtobrutinib

Trial contacts and locations

56

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Data sourced from clinicaltrials.gov

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