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)
Professor Chan Cheah
Loxo Oncology, Inc
- Chronic Lymphocytic Leukemia
- Non-Hodgkin’s Lymphoma
- Small Lymphocytic Lymphoma
This trial includes monotherapy and combination treatment parts. cMonotherapy is suitable for patients who have B-cell lymphoma or Chronic Lymphocytic Leukaemia (CLL) that have been untreated or previously treated. Patients will be allocated to a group depending on their disease type and treatment history. The study drug LOXO-305 is a second generation Bruton Tyrosine Kinase (BTK) inhibitor which blocks a protein inside cancer cells causing them to die. Patients will take LOXO-305 daily by mouth.
Combination therapy is suitable for patient with CLL who have been previously treated. Arm A patients are treated with venetoclax together with LOXO-305 by mouth. Both drugs work together by blocking certain proteins in lymphoma cells to destroy them. Patients enrolled in Arm B will receive rituximab by vein in addition to venetoclax and LOXO-305.
Include, but not limited to, the following:
Inclusion Criteria for ALL Patients:
- ECOG 0-2.
- Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin time (PT) or (international normalized ratio [INR]) not greater than 1.5 × the ULN.
- Adequate hepatic and renal function.
- Ability to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
- 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 highly effective birth control methods with failure rates of < 1% for the duration of treatment and for 6 months following the last dose of study treatment; this must include barrier methods such as condom or diaphragm with spermicidal gel.
Specific Inclusion Criteria for Phase 2 Monotherapy:
- Cohort 1 MCL: Confirmed diagnosis of non-blastoid MCL with documentation of overexpression of cyclin D1 and/or t(11;14) and treated with a prior BTK inhibitor-containing regimen.
- Cohort 2 CLL/SLL: Confirmed diagnosis of CLL/SLL by IWCLL 2018 criteria and treated with 2 or more prior regimens, including a BTK inhibitor containing regimen.
- Cohort 3 CLL/SLL: Confirmed diagnosis of CLL/SLL by IWCLL 2018 and not previously treated.
- Cohort 4 CLL/SLL: Confirmed diagnosis of CLL/SLL by IWCLL 2018 and previously treated, BTK inhibitor naive.
- Cohort 5 WM: Confirmed diagnosis of WM with documentation of MYD88 mutation who have received prior therapy with a BTK inhibitor-containing regimen.
- Cohort 6 MZL: Confirmed diagnosis of MZL who have received a prior BTK inhibitor-containing regimen.
- Cohort 7: (Not otherwise specified) 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 LOXO-305 would remain eligible to enroll in this cohort..
- All patients must have disease requiring treatment. For CLL/SLL patients, indications for treatment are defined by IWCLL. Patients with NHL who will be evaluated by Lugano criteria must have at least 1 site of radiographically assessable disease (i.e., lymph node longest diameter (LDi) > 1.5 cm, extra nodal site > 1.0 cm in LDi, or unequivocal hepatomegaly or splenomegaly due to disease) or in the absence of measurable lymphadenopathy, documentation of bone marrow involvement, elevated IgM levels and/or lymphocytosis. Patients with WM must have measurable disease, defined as the presence of serum immunoglobulin M (IgM) with a minimum IgM level of > 2 × the upper limit of normal (ULN) based on local laboratory testing.
Specific Inclusion Criteria for Phase 1b Combinations:
- Arm A (Venetoclax + LOXO-305): Histologically confirmed r/r CLL/SLL in whom venetoclax is an appropriate salvage treatment; no prior venetoclax is permitted.
- Arm B (Rituximab + venetoclax + LOXO-305): Histologically confirmed r/r CLL/SLL in whom venetoclax + rituximab (RV) is an appropriate salvage treatment; prior antiCD20 therapy is allowed; no prior venetoclax is permitted.
- Adequate haematologic status within 7 days of C1D1.
Exclusion Criteria for ALL Patients
- Investigational agent or anticancer therapy within 5 half-lives prior to planned start of specified study therapy 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 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, except for patients receiving radiation to more than 30% of the bone marrow, or receiving whole brain radiotherapy, which must be completed at least 4 weeks prior to the first dose of study treatment.
- Patients requiring therapeutic anticoagulation with warfarin.
- Any unresolved toxicities from prior therapy greater than CTCAE v5.0 Grade 2 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 60 days 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 (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) where new therapy introduced or concomitant therapy escalated within the 4 weeks prior to study enrollment is required to maintain adequate blood counts.
- Significant cardiovascular disease.
- Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
- Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the Investigator and the Sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
- Patients who have tested positive for Human Immunodeficiency Virus (HIV).
- Current treatment with certain strong CYP3A4 inhibitors or inducers.
- Pregnancy or lactation.
- Active second malignancy unless in remission with life expectancy > 2 years and with documented Sponsor approval.
- Prior treatment with LOXO-305.