Study of Volasertib and Belinostat in Patients With Relapsed and Refractory Aggressive B-cell and T-cell Lymphomas

Study Overview
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Brief Summary
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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.

Official Title
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Phase 1 Study of Volasertib and Belinostat in Patients With Relapsed and Refractory Aggressive B-cell and T-cell Lymphomas

Conditions
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Relapsed and Refractory Aggressive B- and T-cell Lymphomas, Lymphoma

Intervention / Treatment
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* Drug: volasertib
* Drug: belinostat


Participation Criteria
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Eligibility Criteria
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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 < 60 or > 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All subjects<br>Subjects have relapsed and refractory aggressive B- and T-cell lymphomas and will receive both Belinostat and Volasertib. | Drug: volasertib<br>* Volasertib (BI6727) is a small molecule inhibitor of the polo-like kinase 1 (PLK1) protein. Infusion for 60 minutes. Dosing will start at 25 mg/m^2, is schedule to increase to 100mg/m^2, and be administered on days 1 and 8 of each 28-day cycle.<br>Drug: belinostat<br>* Belinostat is a histone deacetylase inhibitor. Infusion will take 30 minutes. Dosing will start at 600 mg/m^2 , is scheduled to increase to 1000 mg/m^2, and will be administered on days 1,2,3 and 8,9,10 of each 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Doses (MTD) | Dose escalation will follow the traditional 3+3 plan to determine the MTD and the recommended phase 2 doses (RP2D). The MTD will be defined as that dose level at which ≤ 1/6 patients experience Dose Limited Toxicity (DLT), with ≥ 2/6 experiencing DLT at the next higher dose level. If the MTD is not reached at dose level 5, consideration will be given to amending the dose level escalation schema to add an additional dose level. | up to 2 years | 
| Adverse Events | To evaluate the safety and toxicity of volasertib and belinostat when given in combination | up to 2 years |