Panobinostat and Fluorouracil Followed By Leucovorin Calcium in Treating Patients With Stage IV Colorectal Cancer Who Did Not Respond to Previous Fluorouracil-Based Chemotherapy

University of Southern California

Status and phase

Terminated

Phase 1

Conditions

Stage IV Rectal Cancer

Recurrent Colon Cancer

Stage IV Colon Cancer

Recurrent Rectal Cancer

Treatments

Genetic: western blotting

Genetic: gene expression analysis

Procedure: biopsy

Drug: panobinostat

Drug: fluorouracil

Drug: leucovorin calcium

Genetic: RNA analysis

Genetic: reverse transcriptase-polymerase chain reaction

Genetic: polymorphism analysis

Other: laboratory biomarker analysis

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT01238965

NCI-2010-02149

3C-08-1

Details and patient eligibility

About

Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving panobinostat together with fluorouracil and leucovorin calcium may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and the best dose of giving panobinostat, fluorouracil, and leucovorin calcium together in treating patients with stage IV colorectal cancer who did not respond to previous fluorouracil-based chemotherapy.

Full description

PRIMARY OBJECTIVES:

I. To determine the safety and feasibility of combining LBH589 with infusional 5-FU chemotherapy in the treatment of Stage IV colorectal cancer patients who have progressed on standard 5-FU regimens.

II. To determine the efficacy of LBH589 alone to produce consistent decreases in tumor thymidylate synthase (TS) expression.

SECONDARY OBJECTIVES:

I. To determine the time to tumor progression, progression free and overall survival of patients with advanced or metastatic colorectal cancer treated with LBH589 combined with infusional 5-FU.

II. To determine if TS repression by LBH589 predicts response to the combination of LBH589 and infusional 5-FU in patients who have already progressed on standard regimens containing 5-FU.

III. To obtain preliminary data on gene expression levels of TS, DPD and TP as well as germline polymorphisms of TS being associated with clinical outcome and toxicity.

IV. To obtain preliminary data on acetylation on peripheral blood mononuclear cells to establish biological activity in these patients at time of biopsies.

OUTLINE: Patients receive oral panobinostat 3 times a week. Patients also receive leucovorin calcium IV over 2 hours on days 1 and 15 followed by fluorouracil IV continuously over 46 hours on days 1-2 and 15-16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Enrollment

7 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Patients must have histologically or cytologically confirmed advanced/metastatic colorectal cancer
Must have measurable disease
Must have received prior therapy (in any setting) with 5-FU, CPT-11, and oxaliplatin; (may have received prior erbitux and bevacizumab, but it is not required)
Must have received at least one prior chemotherapy regimen for advanced disease
Tumor must be accessible for core biopsy at the beginning of treatment and patients have a high intratumoral TS expression level prior to the beginning of treatment
Life expectancy of > 12 weeks
ECOG performance status 0-2 (Karnofsky >= 50%)
Normal organ and marrow function as defined below:
Serum albumin >= 3g/dL
AST/SGOT and ALT/SGPT =< 2.5 x upper limit of normal(ULN)or =< 5.0 x ULN if the transaminase elevation is due to liver metastasis
Serum bilirubin =< 1.5 x ULN
Serum creatinine =< 1.5 x ULN or 24-hr creatinine clearance >= 50 ml/min
Serum potassium >= LLN
Serum phosphorous >= LLN
Serum total calcium (corrected for serum albumin) or serum ionized calcium >= LLN
Serum magnesium >= LLN
TSH and free T4 within normal limits(WNL)(patients may be on thyroid hormone replacement)
Leukocytes >= 3,000/μL
Absolute neutrophil count >= 1,500/μL
Platelets >= 100,000/μL
Hemoglobin >= 9 mg/dL
Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of LBH589 will be determined following review by the Principal Investigator
Ability to understand and willing to sign a written informed consent document
INR is =< 1.5 times ULN unless receiving therapeutic anticoagulation
Patient is highly unlikely to conceive as indicated by at least one "yes" answer to the following questions:
1. patient is a male and agrees to use an adequate method of contraception for the duration of the study, and for 30 days after the last dose of study medication;
2. surgically sterilized female;
3. postmenopausal female >= 45 years of age with > 2 years since last menses;
4. non-sterilized premenopausal female and agrees to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study and for 30 days after the last dose of study medication
Baseline MUGA must demonstrate LVEF >= the lower limit of the institutional normal
Clinically euthyroid; Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism

Exclusion criteria

Male patients whose sexual partners are WOCBP not using effective birth control
May not have received any other investigational agents within 28 days of study entry (chemotherapy, any investigational drug or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy).
May not receive other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) while on this study
Patients with known brain metastases are excluded from this clinical trial
History of allergic reactions attributed to compounds of similar chemical or biologic composition to LBH589; including sodium butyrate, trichostatin A (TSA), trapoxin (TPX), MS-27-275 and depsipeptide
Severe and/or uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant or breast feeding or patients of reproductive potential not using two effective methods of birth control; women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of oral LBH589
History of another primary malignancy within 5 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin
Unresolved diarrhea > CTCAE grade 1
Acute infection requiring intravenous antibiotic, antiviral, or antifungal medications within 2 weeks prior to the start of study drugs
Known positivity for human immunodeficiency virus (HIV) or hepatitis C
Screening ECG with a QTc > 450 msec
Patients with congenital long QT syndrome
History of sustained ventricular tachycardia
Any history of ventricular fibrillation or torsades de pointes
Bradycardia defined as heart rate < 50 beats per minute; patients with a pacemaker and heart rate >= 50 beats per minute are eligible
Myocardial infarction or unstable angina within 6 months of study entry
Congestive heart failure (NY Heart Association class III or IV)
Right bundle branch block and left anterior hemiblock (bifascicular block)
Prior cancer treatment with an HDAC inhibitor (e.g., vorinostat, Depsipeptide, MS-275, LAQ-824, PXD-101, and valproic acid)
Uncontrolled hypertension
Concomitant use of drugs with a risk of causing torsades de pointes
Any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
Patients needing valproic acid for any medical condition during the study or within 5 days prior to first LBH589

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

7 participants in 1 patient group

Arm I

Experimental group

Description:

Patients receive oral panobinostat 3 times a week. Patients also receive leucovorin calcium IV over 2 hours on days 1 and 15 followed by fluorouracil IV continuously over 46 hours on days 1-2 and 15-16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Treatment: