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A Phase I Safety and Tolerability Study of Vorinostat in Combination With Sorafenib in Patients With Advanced Solid Tumors, With Exploration of Two Tumor-type Specific Expanded Cohorts at the Recommended Phase 2 Dose

Phase 1
18 Years
Not Enrolling
Malignant Solid Tumour, Renal Cell Carcinoma, Non Small Cell Lung Carcinoma

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Trial Information

A Phase I Safety and Tolerability Study of Vorinostat in Combination With Sorafenib in Patients With Advanced Solid Tumors, With Exploration of Two Tumor-type Specific Expanded Cohorts at the Recommended Phase 2 Dose

The main purpose of this study is to:

- Evaluate the safety of vorinostat in combination with sorafenib.

- Determine the largest dose of vorinostat + sorafenib that can be given safely to

- Determine if vorinostat + sorafenib are effective in stopping tumors from growing or in
decreasing their size.

- Study the side effects of vorinostat + sorafenib.

Inclusion Criteria:

- Parts A: Histologically or cytologically documented solid tumor malignancy or
non-Hodgkin's lymphoma (Part B: renal cell carcinoma, Part C: non-small cell lung
carcinoma) with clinical evidence of advanced and/or metastatic disease, which is
refractory to established forms of therapy or for which no effective therapy exists,
or for which sorafenib alone would be considered by the investigator as an
appropriate therapy; patients who have refused available standard therapies would
also be deemed eligible

- In Part A, evaluable disease by radiology and/or a recognized serum tumor marker is
required; in Parts B and C, measurable disease by Response Evaluation Criteria in
Solid Tumors (RECIST) is required

- Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2

- Predicted life expectancy ≥ 12 weeks

- Patients may have had prior therapy, providing the following conditions are met:

- Patients must have recovered from any treatment related toxicities (with the
exception of alopecia) to ≤ CTC grade 1 (fatigue, and neurotoxicity at grade 2
are permissible if stable for > 3 months) prior to registration

- Chemotherapy: A minimum of 5 predicted half-lives of the agent must have elapsed
between the end of treatment and registration on to the study; when half-lives
are not available the principle of 2 weeks for once daily medications and 3
weeks for agents given less frequently will be adopted, but discussion with the
principal investigator is recommended

- Hormonal therapy: Patients may have had prior anticancer hormonal therapy
provided it is discontinued > 4 weeks prior to registration into the study;
however, patients with prostate cancer with evidence of progressive disease may
continue on therapy which produces medical castration (eg, goserelin or
leuprorelin) provided this was commenced at least three months earlier

- Radiation: Patients may have had prior radiation therapy that has not exceeded
25% of bone marrow reserve provided that they have recovered from the acute,
toxic effects of radiotherapy prior to registration; a minimum of 7 days must
have elapsed between the end of radiotherapy to non-target lesions and
registration into the study (minimum of 28 days for target lesions)

- Surgery: Previous surgery is permitted provided that wound healing has occurred
prior to registration

- Supportive therapy including bisphosphonates is permissible; previous use of myeloid
and erythroid growth factor support is permissible, but not within 2 weeks of
commencement of study; primary prophylactic use of myeloid and erythroid growth
factors is not permitted within the study, but intervention or secondary prophylaxis
is permitted if instituted following the documentation of ≥ grade 3 neutropenia or ≥
grade 2 anemia (hemoglobin)

- International Normalized Ratio (INR) < 1.5 or a prothrombin time (PT)/partial
thromboplastin time (PTT) within normal limits; patients receiving anticoagulation
treatment with an agent such as warfarin or heparin may be allowed to participate;
for patients on warfarin, the INR should be measured prior to initiation of
sorafenib/vorinostat and monitored at least weekly, or as defined by the local
standard of care, until INR is stable; vorinostat and sorafenib have both been
reported to elevate INR in those on coumadin derivatives

- Neutrophil count ≥ 1.5 x 10^9/L

- Platelet count ≥ 75 x 10^9/L

- Bilirubin ≤ 1.5 x Upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and/or alanine transaminase (ALT) ≤ 2.5 x ULN (ie, ≤
CTC grade 1) or ≤ 5 x Upper limit of normal (UNL) if patient has documented liver
metastases (ie, ≤ CTC grade 2)

- Serum creatinine ≤ 1.5 x ULN

- Patient must be accessible for repeat dosing and follow-up

- Patients - both males and females - with reproductive potential (ie, menopausal for
less than 1 year and not surgically sterilized) must practice effective contraceptive
measures throughout the study; women of childbearing potential must provide a
negative pregnancy test (serum or urine) within 14 days prior to registration

- Patients must provide verbal and written informed consent to participate in the
study, including pharmacokinetic sampling

Exclusion Criteria:

- Active or uncontrolled infections or serious illnesses or medical conditions that
could interfere with the patient's ongoing participation in the study

- History of any psychiatric condition that might impair the patient's ability to
understand or to comply with the requirements of the study or to provide informed

- Concurrent anticancer therapy (with the exception of hormonal therapies as discussed

- Pregnant or breast-feeding females (documented methods of birth control are required
in those with reproductive potential)

- Symptomatic brain metastases which are not stable, require steroids, or
anti-epileptic medication

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to the study drugs

- History of grade 3 or greater toxicities with vorinostat or sorafenib previously at
equivalent daily doses or lower than those planned on being administered within this

- Exposure to other histone deacetylase (HDAC) inhibitors (e.g. sodium valproate)
within 30 days of planned commencement of study drugs, other exposures to HDAC
inhibitor and sorafenib in combination

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management

- Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Pulmonary hemorrhage/bleeding event >= Common Toxicity Criteria for Adverse EffectS
(CTCAE) grade 2 within 4 weeks of first dose of study drug

- Any other hemorrhage/bleeding event >= CTCAE grade 3 within 4 weeks of first dose of
study drug

- Serious non-healing wound, ulcer, or bone fracture

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
study drug

- Use of St. John's Wort or rifampin (rifampicin)

- Known or suspected allergy to sorafenib, vorinostat or any planned agent given in the
course of this trial

- Any condition that impairs patient's ability to swallow whole pills

- Any clinically significant malabsorption problem

- Clinically significant, in the investigator's opinion, pre-existing cardiac
dysfunction or myocardial infarction within 6 months prior to planned commencement of
study drugs

- Any other condition, which in the investigator's opinion, would compromise the safety
of the patient or the feasibility of completing the study objectives through the use
of this patient

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose (MTD)

Outcome Description:

The primary objective of this study is to determine the MTD for vorinostat in combination with the recommended dose of sorafenib 400 mg when given daily in a 21-day cycle and thereby establish a recommended Phase 2 dose of the combinations when administered daily in patients with advanced solid tumors

Outcome Time Frame:

Up to 21 days

Safety Issue:


Principal Investigator

David R Camidge, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Colorado, Denver


United States: Institutional Review Board

Study ID:



Start Date:

March 2008

Completion Date:

March 2012

Related Keywords:

  • Malignant Solid Tumour
  • Renal Cell Carcinoma
  • Non Small Cell Lung Carcinoma
  • Malignant Solid Tumour
  • Renal cell carcinoma
  • Non small cell lung carcinoma
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Carcinoma, Renal Cell
  • Lung Neoplasms
  • Neoplasms



University of Colorado Cancer Center Denver, Colorado  80262