study of xl114 in subjects with non-hodgkin's lymphoma

Conditions: Non-Hodgkin's Lymphoma (NHL); Activated B-Cell Type Diffuse Large B-Cell Lymphoma (ABC-DLBCL); Mantle Cell Lymphoma (MCL); Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL)

Summary: this is a phase 1, non-randomized, open-label, dose-escalation and expansion study, evaluating the safety, tolerability, pharmacokinetics (pk), pharmacodynamics (pd), and preliminary clinical antitumor activity of xl114 administered alone orally to subjects with non-hodgkin's lymphoma (nhl). the objectives of the study also include determining the recommended dose (rd) and/or maximum tolerated dose (mtd) of xl114.


Eligibility criteria:
inclusion criteria: * dose-escalation stage (cohort a) and cohort-expansion stage (b-e): the subject has received standard life-prolonging therapies or are not qualified to receive such therapies. * dose-escalation stage (cohort a): subjects with histologically documented diagnosis of b-cell or t-cell non-hodgkin's lymphoma as defined by the world health organization (who) classification. note: refer to exclusion criteria for lymphoma subtypes which are excluded from study participation. * cohort-expansion stage cohort b (abc-dlbcl subtype): subjects with histologically documented activated b-cell diffuse large b-cell lymphoma (abc-dlbcl) subtype. note: de novo or transformed diffuse large b-cell lymphoma (dlbcl) from previously diagnosed indolent lymphoma (eg, follicular lymphoma) is allowed. * cohort-expansion stage cohort c (mcl): subjects with histologically documented mcl with monoclonal b-cells that show a chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin d1. * cohort-expansion stage cohort d (cll/sll): subjects with histologically documented cll/sll per the international workshop on chronic lymphocytic leukemia (iwcll) guidelines. * cohort-expansion stage cohort e, biomarker cohort (abc-dlbcl, mcl, and sll): subjects with abc-dlbcl, mcl, and sll that fulfill the subject disease characteristics criteria as described for cohorts b, c, or d. * cohort-expansion stage: subjects with abc-dlbcl, mcl, and sll must have measurable disease by revised criteria for response assessment of lymphoma. * cohort-expansion stages: must have archival tumor tissue available, which was collected up to 2 years prior to consent for this study. if archival tumor tissue is not available, a fresh tumor biopsy may be obtained (if safe to acquire) up to 60 days prior to first dose. * biomarker cohort: subjects must provide a fresh tumor biopsy up to 60 days prior to first dose, at week 2, day 1 (w2d1) after initiation of xl114, and at disease progression. note: the tumor tissue requirement in the expansion and biomarker cohorts doesn't apply for subjects with cll. * recovery to baseline or ≤ grade 1 severity (common terminology criteria for adverse events version 5 \[ctcae v5\]) from aes, unless aes are clinically nonsignificant or stable. * left ventricular ejection fraction (lvef) \> 50% as determined by echocardiogram (echo) or multigated acquisition (muga) scan per local standard. * age 18 years or older on the day of consent. * eastern cooperative oncology group performance status (ecog ps) of 0-1 * adequate organ and marrow function * sexually active fertile subjects and their partners must agree to highly effective methods of contraception. * female subjects of childbearing potential must not be pregnant at screening. exclusion criteria: * receipt of prior therapies as defined in the protocol * the following lymphoma types/manifestations are not eligible for this study: burkitt's lymphoma (bl), burkitt-like lymphoma (bll), lymphoblastic lymphoma/leukemia (lbl), post-transplant lymphoproliferative disease (ptld), primary mediastinal (thymic) large b-cell lymphoma (pmbl), lymphomas involving the central nervous system (cns) or meninges * history of autoimmune hemolytic anemia (aiha) or idiopathic thrombocytopenic purpura (itp). * history of solid organ or allogeneic hematopoietic stem cell transplantation. * concomitant anticoagulation with the oral anticoagulants apixaban, betrixaban, rivaroxaban, and dabigatran. * use of a strong inhibitor or inducer of cytochrome p450 3a4 (cyp3a4) within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter. * uncontrolled, significant intercurrent or recent illness * major surgery (eg, gi surgery) within 3 weeks before first dose of study treatment. * corrected qt interval calculated by the fridericia formula (qtcf) \> 470 ms per electrocardiogram (ecg). * pregnant or lactating females. * inability to swallow xl114 tablets. * diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy

Keywords: mucosa-associated lymphoid tissue lymphoma translocation protein 1 (malt-1) b-cell malignancies fatty acid binding protein 5 (fabp-5)