PXD101 and Bortezomib in Treating Patients With Advanced Solid Tumors or Lymphomas

Phase 1

Completed

• Conditions: Recurrent Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Burkitt Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Angioimmunoblastic T-cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma
• Interventions: Drug: belinostat; Drug: bortezomib; Other: pharmacological study

• Registration Number: NCT00348985
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase I trial is studying the side effects and best dose of PXD101 and bortezomib in treating patients with advanced solid tumors or lymphomas. PXD101 and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PXD101 may also cause cancer cells to look more like normal cells, and to grow and spread more slowly. Giving PXD101 together with bortezomib may kill more cancer cells.

Detailed Description

OBJECTIVES:

I. Evaluate the safety profile and determine the maximum tolerated dose of PXD101 in combination with bortezomib in patients with advanced solid tumors or lymphomas.

II. Determine the pharmacokinetics of the combination of PXD101 and bortezomib in these patients.

III. Evaluate selected biomarkers of drug effect in these patients. IV. Evaluate the activity of this regimen, in terms of objective response rate, in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive PXD101 IV over 30 minutes on days 1-5 and bortezomib IV on days 1, 4, 8, and 11 (2, 5, 8, and 11 during course 1). Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-9 patients receive escalating doses of bortezomib and PXD101 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Blood is collected at baseline and periodically during course 1 of study treatment for pharmacokinetic studies.

After completion of study treatment, patients are followed periodically for 4 weeks.

Study Timeline

• Study Start: 2006-03
• Study First Submitted: 2006-07-05
• Study First Submitted QC: 2006-07-05
• Study First Posted: 2006-07-06
• Primary Completion: 2010-01
• Status Verified: 2013-05
• Last Update Submitted: 2013-05-01
• Last Update Posted: 2013-05-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 55

Inclusion Criteria

• Histologically or cytologically confirmed solid tumor or lymphoma that is refractory to standard therapy or for which no standard therapy exists

• No active, untreated, or symptomatic brain metastases

  • Patients with treated brain metastases are eligible provided metastasis are stable and the patient is off all steroids and anticonvulsants

• ECOG performance status 0-2

• Life expectancy ≥ 12 weeks

• WBC ≥ 3,000/mm^3

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Bilirubin ≤ 1.5 mg/dL

• AST and ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN in the presence of liver metastases)

• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD101, bortezomib, boron, or mannitol

• No peripheral neuropathy > grade 1

• No uncontrolled intercurrent illness, including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Psychiatric illness or social situation that would preclude study requirements

• No significant cardiovascular disease, including any of the following:

  • Myocardial infarction within the past 6 months
  • New York Heart Association class III-IV heart failure
  • Unstable angina pectoris
  • Uncontrolled hypertension
  • Condition requiring antiarrhythmic therapy
  • Ischemic or severe valvular heart disease
  • Acute ischemia or active conduction system abnormalities by ECG

• No marked baseline prolongation of QT/QTc interval (repeated demonstration of a QTc interval > 500 msec), long QT syndrome, or required use of concurrent medication during PXD101 administration that may cause torsade de pointes

• No severe medical or psychiatric problems of that would preclude study compliance

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, carmustine, or mitomycin C)

• At least 4 weeks since prior radiotherapy and recovered

• At least 2 weeks since prior palliative radiotherapy to sites involving < 35% of bone marrow reserve

• At least 4 weeks since prior investigational agents

• At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor

• No prior stem cell or bone marrow transplantation

• No concurrent radiotherapy or immunotherapy

• No concurrent hormonal therapy

  • Luteinizing hormone-releasing hormone agonists, selective estrogen receptor modulators, or aromatase inhibitors as chronic maintenance therapy allowed

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No other concurrent investigational agents

• No other concurrent anticancer agents or therapies

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PXD101 in Combination with Bortezomib (PS-341)	pharmacological study	Patients receive PXD101 IV over 30 minutes on days 1-5 and bortezomib IV on days 1, 4, 8, and 11 (2, 5, 8, and 11 during course 1).
PXD101 in Combination with Bortezomib (PS-341)	belinostat	Patients receive PXD101 IV over 30 minutes on days 1-5 and bortezomib IV on days 1, 4, 8, and 11 (2, 5, 8, and 11 during course 1).
PXD101 in Combination with Bortezomib (PS-341)	bortezomib	Patients receive PXD101 IV over 30 minutes on days 1-5 and bortezomib IV on days 1, 4, 8, and 11 (2, 5, 8, and 11 during course 1).

Primary Outcome Measures

Name	Time	Method
Frequency and severity of treatment-related adverse events graded per NCI CTCAE version 3.0	Day 21
Maximum tolerated dose of PXD101 in combination with bortezomib	Day 21	Defined as the dose level below that which results in drug-related dose limiting toxicity (DLT) in \>= 2 of 6 new patients.
Changes in biological markers (p21, cleaved PARP, IkB, p65 Rel A, p-AKT, p-ERK and apoptosis) from pre- to post-treatment	Baseline and day 21
Objective response rate	4 weeks

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics of the combination of PXD101 with bortezomib	Baseline, end of infusion, then 15 minutes, 30 minutes, 1, 2, 4 and 6 hours from the end of infusion (days 1 and 2)

Trial Locations

Locations (1)

University of Colorado; 🇺🇸 Denver, Colorado, United States