Clinical trial NCT02875002: Study of Volasertib and Belinostat in Patients With Relapsed and Refractory Aggressive B-cell and T-cell Lymphomas
Official title: Phase 1 Study of Volasertib and Belinostat in Patients With Relapsed and Refractory Aggressive B-cell and T-cell Lymphomas
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Relapsed and Refractory Aggressive B- and T-cell Lymphomas
Lymphoma
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Massey Cancer Center
name: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
First posted: 2016-08-22
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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 \< 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

Primary outcomes:
measure: Maximum Tolerated Doses (MTD)
timeFrame: up to 2 years
measure: Adverse Events
timeFrame: up to 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer
state: Maryland
city: Richmond
country: United States
facility: Massey Cancer Center
state: Virginia
Study officials:
affiliation: Yale University
name: Steven Gore, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Iris Isufi, MD
role: PRINCIPAL_INVESTIGATOR
References: