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Phase I/II Study of a Combination of Suberoylanilide Hydroxyamic Acid (Vorinostat) Plus Paclitaxel and Bevacizumab in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Breast Cancer


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Male Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

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Trial Information

Phase I/II Study of a Combination of Suberoylanilide Hydroxyamic Acid (Vorinostat) Plus Paclitaxel and Bevacizumab in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Breast Cancer


PRYMARY OBJECTIVES:

I. To determine the recommended phase II dose of oral suberoylanilide hydroxyamic acid
(vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest
wall recurrent or metastatic breast cancer. (Phase I) II. To determine the efficacy
(response rate, response duration, time to disease progression, time to treatment failure,
and overall survival) and toxicity of oral suberoylanilide hydroxyamic acid (vorinostat) in
combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or
metastatic breast cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins
including histone H3 and H4, b) ubiquitylation of proteins, and c) the levels of p21 and p27
levels in the peripheral blood mononuclear cells (pre treatment vs. cycle 1 day 2 after 3
VORINOSTAT doses but prior to paclitaxel.

II. To determine whether in vivo treatment with vorinostat induces a) acetylation of
proteins including histone H3 and H4, ubiquitylation of proteins, and c) the levels of Bim,
Bak, tBID, p21 and p27 levels, as well as down regulate Bcl-2, Bcl-xL and survivin in chest
wall recurrent or metastatic breast cancer cells (pre treatment vs. cycle 1 day 2 after 3
vorinostat doses but prior to paclitaxel).

III. To determine whether in the primary breast cancer (and metastatic cancer if available)
pretreatment levels of Her-2, Estrogen Receptor (ER)-alpha, Progesterone Receptor (PR), p21,
p27, p-AKT, p-ERK1/2, HDAC1, 2, 3, 4, 6, 10 and SIRT2 levels predict for the response to
treatment with VORINOSTAT plus paclitaxel.

OUTLINE: This is a phase I, multicenter, dose-escalation study of vorinostat (SAHA) followed
by a phase II, open-label study.

Phase I: Patients receive oral SAHA twice daily on days 1-3, 8-10, and 15-17, paclitaxel IV
over 1 hour on days 2, 9, and 16, and bevacizumab IV over 30-90 minutes on days 2 and 16.
Treatment repeats every 28 days in the absence of disease progression or unacceptable
toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA 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. The recommended phase II dose is defined as one
dose level below the MTD.

Phase II: Patients receive SAHA at the recommended phase II dose and paclitaxel and
bevacizumab as in phase I.


Inclusion Criteria:



- Patients must have histologically or cytologically confirmed adenocarcinoma of the
breast; effective with version 2.2 (1/26/09), only patients with disease that is
accessible to biopsy and consent to serial biopsy are eligible

- Patient must have stage IV disease, locally recurrent inoperable chest wall disease;
at least one bidimensional and/or unidimensional, measurable indicator lesion must be
present (patients with only non-measurable disease are eligible for the phase I trial
only); all sites of disease should be noted and followed

- PRIOR CHEMOTHERAPY: Patients are eligible if they have received no prior chemotherapy
for metastatic disease; patients previously treated with a taxane (docetaxel or
paclitaxel) are eligible if they received taxanes as a component of adjuvant and/or
neoadjuvant therapy, and have relapsed at least 12 months after completion of the
taxane; (NOTE: effective with version 2.5 dated 9/15/09 patients are eligible if they
have received 0-2 prior chemotherapy regimens for metastatic disease; patients
previously treated with a taxane (docetaxel or paclitaxel) are eligible if they
received taxanes as a component of adjuvant and/or neoadjuvant therapy, or for
metastatic disease, and have not experienced progressive disease during or within 3
months of completing taxane therapy)

- PRIOR HORMONAL THERAPY, TRASTUZUMAB (HERCEPTIN), OR BEVACIZUMAB (AVASTIN): Patients
may have received any prior number of hormonal therapies; hormonal therapy should be
discontinued at least 1 week before the patient is enrolled on this study; patients
previously treated with Herceptin are eligible if Herceptin is discontinued, and
there is at least a 4 week interval between the last Herceptin dose and registration,
and the left ventricular ejection fraction is performed within 4 weeks prior to
registration and demonstrates an LVEF that is at or above the lower institutional
limit of normal range; patient who have received prior bevacizumab are ineligible

- ECOG performance status =< 1 (Karnofsky >= 70%)

- Absolute neutrophil count >= 1,500/ul

- Platelets >= 100,000/ul

- Total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal

- PTT and either INR or PT < 1.5 x normal

- Creatinine within normal institutional limits OR

- Creatinine clearance >= mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

- Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC)
ratio; for UPC ratio > 0.5, 24-hour urine protein should be obtained and the level
should be < 1000 mg for patient enrollment; Note: UPC ratio of spot urine is an
estimation of the 24 urine protein excretion - a UPC ratio of 1 is roughly equivalent
to a 24-hour urine protein of 1 gm; UPC ratio is calculated using on of the following
formula: [urine protein]/[urine creatinine] - if both protein and creatinine are
reported in mg/dL [(urine protein) x 0.088]/[urine creatinine] - if urine creatinine
is reported in mmol/L

- Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are eligible
provided that both of the following criteria are met: (a) The patient has an in-range
INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable
dose of low molecular weight heparin; (b) the patient has no active bleeding or
pathological condition that carries a high risk of bleeding (e.g., tumor involving
major vessels or known varices)

- LVEF must be at or above the lower institutional limit of the normal range (on MUGA
or Echo obtained within 12 weeks of registration, or within 4 weeks of prior
Herceptin)

- The effects of vorinostat on the developing human fetus at the recommended
therapeutic dose are unknown; women of childbearing potential must agree to use
adequate contraceptive measures during study therapy and for at least 6 months after
the completion of bevacizumab therapy; should a woman become pregnant or suspect she
is pregnant while participating in this study, she should inform her treating
physician immediately; a negative serum or urine pregnancy test is required within 2
weeks of registration for women of childbearing potential

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

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier;
other exclusions for prior therapy include prior hormonal therapy within one week of
registration, prior trastuzumab within 4 weeks of registration, or prior bevacizumab
at any time

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat or other agents used in the study (e.g., paclitaxel,
bevacizumab)

- 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 women are excluded from this study the effects of vorinostat on the
developing human fetus at the recommended therapeutic dose are unknown; breastfeeding
should be discontinued if the mother is treated with vorinostat; these potential
risks may also apply to other agents used in this study; women must agree to use
adequate contraceptive measures during study therapy and for at least 6 months after
the completion of bevacizumab therapy

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible pharmacokinetic interactions with vorinostat or other
agents administered during the study

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

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 28 days

- Invasive procedures defined as follows: (a) major surgical procedure, open biopsy or
significant traumatic injury within 28 days prior to Day 1 therapy, (b) anticipation
of need for major surgical procedures during the course of the study, (c) core biopsy
within 7 days prior to D1 therapy

- NOTE: Patients who undergo the pretreatment core biopsy for optional correlative
studies may be enrolled within 7 days prior to the planned day 1 if delaying
therapy to meet this criterion is not feasible, and if there are no bleeding
complications as a consequence of the biopsy; in addition, patients may also
undergo the second post-treatment core biopsy (ie, this would not be regarded as
an eligibility or protocol violation)

- Evidence of CNS metastases; all patients are required to undergo a CT scan or MRI of
the brain with contrast within 4 weeks of registration

- Patients with clinically significant cardiovascular disease: (a) History of CVA
within 6 months, (b) uncontrolled hypertension, (c) myocardial infarction or unstable
angina within 6 months, (d) New York heart association grade II or greater congestive
heart failure, serious cardiac arrhythmia requiring medication, unstable angina
pectoris, (e) clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy; PT INR > 1.5, unless the patient is
on full dose warfarin

- Patients with known hypersensitivity of Chinese hamster ovary cell products or other
recombinant human antibodies

- Patients may not be receiving any other investigational agents nor had prior
treatment with histone deacetylase (HDAC) inhibitors (i.e. Valproic acid, PXD-001,
Depsipeptide, MS-275 and LAQ-824); patients who have received such agents for other
indications, (i.e. epilepsy) may enroll in the trial after a 30 day washout period)

- Inability to take oral medications on a continuous basis, or history of GI surgery or
other procedures that might, in the opinion of the investigator, interfere with the
absorption or swallowing of the study drugs

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Recommended phase II dose as assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I)

Outcome Description:

Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Joseph Sparano

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03012

NCT ID:

NCT00368875

Start Date:

July 2006

Completion Date:

Related Keywords:

  • Male Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male

Name

Location

Montefiore Medical CenterBronx, New York  10467-2490