study of volasertib and belinostat in patients with relapsed and refractory aggressive b-cell and t-cell lymphomas

Conditions: Relapsed and Refractory Aggressive B- and T-cell Lymphomas; Lymphoma

Summary: this phase 1, multicenter, open-label study is designed to find the rp2d of volasertib, a plk1 inhibitor, and belinostat, an hdac inhibitor, when given in combination to patients with relapsed or refractory b-cell or t-cell lymphoma. a standard 3+3 dose-escalation design will be employed with study enrollment beginning at dose level 1.


Eligibility criteria:
inclusion criteria: a patient must meet all of the following inclusion criteria to be eligible to participate in the study. * histologically confirmed aggressive b-cell or t-cell lymphoma including the following: * b-cell lymphomas * dlbcl (including transformed follicular lymphoma) * mantle cell lymphoma * burkitt lymphoma * peripheral t-cell lymphoma (ptcl) excluding cutaneous t-cell lymphoma * disease that is relapsed or refractory after a minimum of 2 previous therapies, if b-cell lymphoma, or a minimum of 1 previous therapy, if ptcl * for patients who have had autologous stem cell transplant, disease relapse must be more than 100 days following transplant. * for patients who have had allogeneic stem cell transplant, all of the following conditions must be met: * ≥ 6 months since allogeneic transplant * graft vs. host disease (gvhd) is not present * patient is not currently on immunosuppressive therapy * at least one site of measurable disease by pet/ct: a node measurable in 2 diameters and with longest diameter \>1.5cm or an extranodal lesion measurable in 2 diameters and with longest diameter \>1cm. * age ≥ 18 years of age * eastern cooperative oncology group (ecog) performance status of 0, 1, or 2 (see appendix 1) * life expectancy of at least 3 months * cbc with differential providing evidence of adequate bone marrow function as defined below: * absolute neutrophil count (anc) ≥ 1500/mm3 without growth factor support for 7 days * platelets ≥ 75,000/mm3 (without transfusion for 7 days) * adequate renal function defined as: creatinine ≤ 1.5 x upper limit of normal (uln) or calculated or actual creatinine clearance ≥ 60 ml/min (see appendix 2 for the cockcroft -gault formula to calculate creatinine clearance) * adequate hepatic function as defined below: * ast ≤ 2.5 x uln * alt ≤ 2.5 x uln * total bilirubin ≤ 1.5 mg/dl * note: patients with documented gilbert's syndrome are eligible if total bilirubin is ≤ 3.0 mg/dl. * serum potassium and serum magnesium within normal limits note: electrolytes may be corrected with supplementation. * for a woman of childbearing potential (wcbp), a negative serum pregnancy test performed within 14 days prior to study enrollment (7 days prior to initiation of study treatment) note: wcbp is defined as any woman who has not had a hysterectomy or bilateral oophorectomy and is not postmenopausal (i.e., she has had menses in the preceding 24 consecutive months) * wcbp and male patients must agree to use a highly effective method of birth control for the duration of study treatment and for 6 months following completion of study treatment note: a highly effective method of contraception is defined as one that results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (iuds), sexual abstinence or vasectomised partner. * ability to understand and willingness to sign a written informed consent document exclusion criteria: a patient who meets any of the following exclusion criteria is ineligible to participate in the study. * any investigational treatment within 30 days prior to initiation of study treatment * plans for concurrent treatment with other investigational agents * plans for other concurrent cancer treatment including steroids for cancer control * chemotherapy or large field radiotherapy within 3 weeks prior to initiation of study treatment * previous histone deacetylase inhibitor administered as cancer treatment. * history of brain metastasis including leptomeningeal metastasis * qtc interval ≥450 (i.e., ≥ grade 0, per ctcae version 4) on ecg prior to initiation of study treatment. if baseline qtc on screening ecg is ≥ 450 ms (i.e., ≥ grade 1) * check potassium and magnesium serum levels * correct any identified hypokalemia and/or hypomagnesemia and repeat ecg to confirm qtc interval * for patients with baseline hr \ 100 bpm, manual read of qt by cardiologist is required, with fridericia correction applied to determine the qtcf interval. * note: for patients with hr 60-100 bpm, no manual read of qtc is required. * any of the following related to risk of torsades de pointes and sudden cardiac death: * history of sustained ventricular tachycardia (vt, ventricular fibrillation (vf), torsades de pointes, or resuscitated cardiac arrest unless currently addressed with an implanted cardiac defibrillator * concomitant treatment with an anti-arrhythmic agent to prevent or control arrhythmia. agents used for rate-control of atrial fibrillation are permitted provide that they are not prohibited due to potential drug interactions (see section 6.4) * known congenital long qt syndrome * second degree atrioventricular (av) block type ii, third degree av block, or ventricular rate \< 50 bpm * any of the following related to ischemic heart disease: * angina with ordinary physical activity * note: if angina only occurs with strenuous, rapid, or prolonged exertion, the patient is eligible. * myocardial infarction within 6 months prior to study enrollment * note: if myocardial infarction occurred within 6-12 months prior to study enrollment, patient must be asymptomatic and have had a negative cardiac risk assessment (e.g., treadmill stress test, nuclear medicine stress test, or stress echocardiogram) * ecg with evidence of cardiac ischemia (i.e., st depression of ≥ 2 mm, measured from isoelectric line to st segment; t-wave inversion ≥ 4 mm measured from isoelectric line to peak of t-wave) * any of the following related to heart failure: * new york heart association (nyha) class ii, iii or iv congestive heart failure (see appendix 3) or known left ventricular ejection fraction \< 40% by muga scan or \< 50% by echocardiogram or mri * known hypertrophic cardiomegaly or restrictive cardiomyopathy * clinically significant infection including active hepatitis b or hepatitis c requiring treatment * known human immunodeficiency virus (hiv) seropositivity nnote: hiv testing is not required * history of allergic reactions attributed to compounds similar to the chemical or biologic composition of belinostat or volasertib * history of another primary malignancy, excluding non-melanoma skin cancer, cervical carcinoma in situ, and/or other in situ cancers treated by local excision, that has not been in remission for at least 2 years * pregnancy or breastfeeding * medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk, interfere with the patient's participation in the study, or hinder evaluation of study results