Vorinostat and Gemcitabine in Treating Patients With Metastatic or Unresectable Solid Tumors

Phase 1

Completed

Brief Summary: This phase I trial is studying the side effects and best dose of vorinostat and gemcitabine in treating patients with metastatic or unresectable solid tumors. Drugs used in chemotherapy, such as vorinostat and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Detailed Description: PRIMARY OBJECTIVES:

I. Determine the dose-limiting toxicity, maximum tolerated dose, and pharmacokinetics of vorinostat (SAHA) and gemcitabine in patients with metastatic or unresectable epithelial solid tumors.

SECONDARY OBJECTIVES:

II. Determine tumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation, open-label study.

Patients receive oral vorinostat (SAHA) once daily on days 1-14 and gemcitabine IV over 1-2 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA and gemcitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A minimum of 6 patients are treated at the MTD.

After completion of study treatment, patients are followed for 30 days.

Recruitment & Eligibility

Inclusion Criteria

ECOG 0-2 OR Karnofsky 60-100%
AST and ALT =< 2.5 times ULN
Bilirubin =< 1.5 times upper limit of normal (ULN)
Platelet count >= 100,000/mm3
Absolute neutrophil count >= 1,500/mm3
Creatinine normal OR creatinine clearance ≥ 60 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Any number and type of prior chemotherapies are allowed including prior use of gemcitabine chemotherapy. A washout phase of at least 2 weeks since use of prior chemotherapy or radiation therapy, 6 weeks if the last regimen included nitrosoureas or mitomycin C, is required.
Patients must have histologically confirmed epithelial malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
Ability to understand and the willingness to sign a written informed consent document.
Patients must have at least one measurable lesion as per the RECIST Criteria that can be accurately measured in at least one dimension, with minimum lesion size equal to or more than twice the slice thickness of the imaging study used.

Exclusion Criteria

No symptomatic congestive heart failure
No cardiac arrhythmia
No ongoing or active infection
No psychiatric illness or social situation that would preclude study compliance
No history of allergy, significant side effects, or poor tolerance to gemcitabine
No history of allergic reaction attributed to compounds of similar chemical or biological composition to vorinostat (SAHA)
At least 2 weeks since prior radiotherapy
Recovered from prior therapy
No concurrent combination antiretroviral therapy for HIV-positive patients
No other uncontrolled illness
More than 2 weeks since prior valproic acid
No other concurrent investigational drugs
No other concurrent anticancer therapy
Patients with known brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

Arm && Interventions

Group	Intervention	Description
Arm I	vorinostat	Patients receive oral vorinostat (SAHA) once daily on days 1-14 and gemcitabine IV over 1-2 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of SAHA and gemcitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A minimum of 6 patients are treated at the MTD
Arm I	gemcitabine hydrochloride	Patients receive oral vorinostat (SAHA) once daily on days 1-14 and gemcitabine IV over 1-2 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of SAHA and gemcitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A minimum of 6 patients are treated at the MTD

Primary Outcome Measures

Name	Time	Method
Maximally tolerated dose of a combination of SAHA and gemcitabine determined by dose-limiting toxicity as measured by NCI CTCAE v3.0 continuously	21 days
Pharmacokinetics of SAHA	-0.5, 0.5, 1, 2, 2.5, 3, 4, 6 and 8 hours after day 1 dose; -0.5 hours day 2; and -0.5, 0.5, 1, 2, 2.5, 3, 4, 6 and 8 hours day 3

Secondary Outcome Measures

Name	Time	Method
Best overall response (complete + partial response rate) as measured radiologically by RECIST	Up to 6 years