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A Phase I Study of the mTOR Inhibitor Temsirolimus in Combination With the HDAC Inhibitor Vorinostat in Patients With Metastatic Prostate Cancer

Phase 1
18 Years
Open (Enrolling)
Prostate Cancer, Adenocarcinoma of the Prostate, Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer

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Trial Information

A Phase I Study of the mTOR Inhibitor Temsirolimus in Combination With the HDAC Inhibitor Vorinostat in Patients With Metastatic Prostate Cancer

PRIMARY OBJECTIVES: I. To determine the safety, tolerability and recommended Phase II dose
of temsirolimus in combination with vorinostat in patients with metastatic, hormone
refractory, chemoresistant prostate cancer. II. To obtain preliminary evidence of response
in prostate cancer patients treated with temsirolimus and vorinostat. SECONDARY OBJECTIVES:
I. To determine the partial and complete objective response rates in metastatic
hormone-refractory, chemo-resistant prostate cancer patients with measurable disease treated
with temsirolimus and vorinostat. II. To determine the progression free survival and overall
survival in patients with metastatic hormone refractory, chemo-resistant prostate cancer.
III. To determine the PSA response, the duration of PSA response, time to PSA progression,
PSA doubling time and PSA slope in metastatic hormone refractory, chemo-resistant prostate
cancer patients treated with temsirolimus and vorinostat. IV. To assess changes in
expression levels of bone remodeling markers (N telopeptides and bone alkaline phosphatase)
and angiogenesis-related gene and protein expression (VEGF/HIF1-alpha) in blood and
circulating tumor cells, and when available, in tissue, and correlate them with cancer and
treatment related outcomes. V. To assess the changes in tumor metabolism with
FDG/IIC-Choline PET/CT scan. OUTLINE: Patients receive oral vorinostat once daily on days
1-14 and temsirolimus IV on days 1, 8, and 15. Courses repeat every 21 days in the absence
of disease progression or unacceptable toxicity. After completion of study treatment,
patients are followed at 30 days and then every 3 months thereafter.

Inclusion Criteria


- Patients must have a histologically confirmed diagnosis of adenocarcinoma of the
prostate that is hormone refractory and with evidence of progressive metastatic
disease following docetaxel treatment by any of the following:

- Increased serum prostate-specific antigen (PSA) levels confirmed by 3
consecutive PSA measurements (at least 2 weeks apart), the first sample to be
taken at least 6 weeks after bicalutamide or megestrol acetate withdrawal AND/OR

- Progression of bidimensionally measurable soft tissue (nodal) metastasis by CT
scan or MRI within the past 4 weeks AND/OR

- Progression of bone disease by at least two new bone lesions on bone scan
confirmed by a second bone scan

- Patients should be without persisting >= grade 2 hematological/non-hematological
toxicities from previous treatments that would preclude evaluation of toxic effects
of study treatment.Grade 1 residual toxicity will be acceptable. Patients should be
off prior therapies at least 4 weeks before starting study treatment

- Prior palliative radiation to metastatic lesion(s) is permitted, provided there is at
least one measurable and/or evaluable lesion(s) that has not been radiated

- Castrate levels of serum testosterone (=< 50 ng/dL or 1.0 mmol/L) confirmed within
two weeks prior to Day 1 of treatment. Testosterone levels will not be required for
patients who have had bilateral orchiectomy

- ECOG performance status 0-1

- Life expectancy of greater than 6 months

- Absolute neutrophil count >= 1,500/mm^3

- Platelets >= 100,000/mm^3

- Hgb >= 9g/L

- Total bilirubin =< 1.5 x laboratory upper limit of normal (ULN)

- AST(SGOT)/ALT(SGPT) <= 2.5 x laboratory ULN

- Creatinine =< 1.5 x laboratory ULN or calculated creatinine clearance >= 50 ml/min

- Serum amylase =< ULN (If > ULN, confirm pancreatic amylase < 1.1 ukat/L and serum
lipase < ULN)

- PT/INR <= 1.5

- Urine protein < 1+ or if >= 1 then 24-hour urine protein should be obtained and
should be < 1000 mg

- Serum cholesterol < ULN (230 mg/dL or 5.3 mmol/L) with or without treatment for
hyperlipidemia; if > 230 mg/dL and untreated, may be rescreened for eligibility after

- Eligibility of patients receiving any medications or substances known to affect or
with the potential to affect the activity or pharmacokinetics of temsirolimus will be
determined following review of their case by the Principal Investigator

- Patients, if sexually active, will agree to use adequate contraceptive methods
(barrier contraceptive with spermicide, vasectomy, abstinence) prior to study entry
and for the duration of study participation

- Ability to understand and the willingness to sign a written informed consent document

- No evidence (>= 5 years) of prior malignancies except successfully treated basal cell
or squamous cell carcinoma of the skin


- Prior use of HDAC or mTOR inhibitors

- Patients with known brain metastases

- Any medical condition, including the presence of laboratory abnormalities, which
confounds the ability to interpret data from the study or places the patient at
unacceptable risk if he participates in the study

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat or temsirolimus

- Concurrent use of other anticancer agents or treatments except LHRH antagonists

- Uncontrolled intercurrent illness including, but not limited to the
following:(a)Ongoing or active infection including viral hepatitis,(b)Symptomatic
congestive heart failure (New York Association Class II, III, or IV),(c) unstable
angina pectoris requiring nitrate therapy,(d) prior myocardial infarction,(e)severe
uncontrolled ventricular cardiac arrhythmias,(f) uncontrolled hypertension (defined
as blood pressure of > 160 mmHg systolic and/or > 90 mmHg diastolic on
medication),(g)electrocardiographic evidence of acute ischemia(h)Psychiatric
illness/social situations that would limit compliance with study requirements

- Known positive serology for HIV and known history of HIV because of the potential for
pharmacokinetic unforeseen toxicity and morbidity in an immunocompromised patient

- Any treatment modalities, including radiation and surgery, not discontinued at least
4 weeks prior to treatment in this study

- Chronic Hepatitis with advanced, decompensated hepatic disease or cirrhosis of the
liver or history of chronic virus hepatitis or known viral hepatitis carrier (patient
recovered from Hepatitis A will be allowed to enter the study)

- Simultaneous participation in any other study involving investigational drugs or
having participated in a study less than 4 weeks prior to treatment in this study

- No investigational or commercial agents or therapies other than those described in
the study may be administered with the intent to treat the patient's malignancy

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Frequencies of DLT and toxicity

Outcome Time Frame:

4 yrs

Safety Issue:


Principal Investigator

Roberto Pili

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute


United States: Institutional Review Board

Study ID:

RPCI I 150709



Start Date:

February 2012

Completion Date:

Related Keywords:

  • Prostate Cancer
  • Adenocarcinoma of the Prostate
  • Hormone-resistant Prostate Cancer
  • Recurrent Prostate Cancer
  • Stage IV Prostate Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Prostatic Neoplasms



Roswell Park Cancer InstituteBuffalo, New York  14263
Sibley Memorial HospitalWashington, District of Columbia  20016
The Sydney Kimmel Comprehensive Center at John HopkinsBaltimore, Maryland  21287