Carboplatin, Gemcitabine Hydrochloride, and Stereotactic Body Radiation Therapy in Gynecological Cancer

PRIMARY OBJECTIVES:

I. Determine maximum tolerated carboplatin/gemcitabine dose administered with SBRT as
measured by < 30‐day acute toxicity defined by Common Terminology Criteria for Adverse
Events (CTCAE) v4.0.

SECONDARY OBJECTIVES:

I. Off-study SBRT target local control assessment: 6-week post-trial fludeoxyglucose F 18
(18F-FDG) positron emission tomography (PET)/computed tomography (CT) or other imaging
response by European Organisation for Research and Treatment of Cancer (EORTC) PET criteria
as listed and National Cancer Institute (NCI) guidelines.

II. Off-treatment late toxicity assessment: record 3-month and 6-month radiation-related
toxicity defined by CTCAE v4.0.

III. Off‐study global clinical benefit assessment: 6‐month post-therapy clinical benefit
(defined as percentage of patients who had complete, partial, or stable disease for at least
6 months).

TERTIARY OBJECTIVES:

I. Associate pretherapy tumor biopsy ribonucleotide reductase (R1, R2, p53R2), Tip60 and
Poly(ADP‐ribose) polymerase 1/2 expression with 6‐week therapy response.

OUTLINE: This is a dose-escalation study of carboplatin and gemcitabine hydrochloride.

Patients also receive carboplatin intravenously (IV) over 30 minutes and gemcitabine
hydrochloride IV over 30 minutes on day 1 and undergo SBRT on days 2-4.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 1 year, and then yearly for 2 years.

Inclusion Criteria:

- Patient has diagnosis of a persistent or recurrent gynecologic cancer

- Patient age is > 18 years.

- Patient must have at least one abdominopelvic measurable site of disease as defined
by 9.1.3;. A treatment planning 18F‐FDG positron emission tomography and computed
tomography scan (PET/CT; whole body) may be used to complement assessment, & if done
must be completed prior to first dose of carboplatin / gemcitabine and within 35 days
of first day of SBRT. There MUST BE no more than four (4) intended radiosurgical
target lesions. An individual (one of up to four) radiosurgical target lesion MUST
NOT EXCEED a volume of no greater than 160 cubic centimeters (cc).

- No prior cryosurgery or radiofrequency ablation in SBRT‐target lesion. Patients with
prior cryoablation and radiofrequency ablation are excluded as these treatments are
designed to destroy tissue with freezing or heat. Radiation treatments given by SBRT
may not work biologically or may cause excessive tissue injury in patients who have
had prior cryoablation and radiofrequency ablation.

- Patient has no major medical illnesses or psychiatric illnesses:

1. New York Heart Association (NYHA) class 3 or 4 congestive heart failure;

2. unstable angina pectoris;

3. symptomatic cardiac arrhythmia;

4. hypertension with diastolic blood pressure greater than 110 mmHg;

5. pulmonary disease consisting of dyspnea at rest requiring oxygen
supplementation;

6. renal function impairment (defined here as baseline serum creatinine >2.0
mg/dL);

7. psychiatric illness/social situations that would limit compliance.

- Patient must have no known brain metastases. These patients are excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurological dysfunction that would confound neurological and other
adverse event evaluation.

- Patient must demonstrate adequate organ function (< 35 days from enrollment):

- Bone marrow: absolute neutrophil count (ANC) ≥ 1500/mcl, platelets ≥ 100,000,
hemoglobin ≥ 10 mg/dL.

- Renal function: creatinine ≤ 2.0 mg/dL.

- Hepatic function: bilirubin ≤ 1.5X institutional upper limit of normal (ULN);
AST, ALT, alkaline phosphatase ≤ 2.5X ULN

- Patient MUST have had prior chemotherapy or radiation for a gynecologic cancer.
Patient is > 28 days from previous treatment (chemotherapy or radiation) and
toxicities related to the previous treatment must have resolved to grade 1 or
baseline.

- Patient has Gynecologic Oncology Group performance status score of 0 or 1.

- Patient is able to give study‐specific informed consent

Exclusion Criteria:

- Any patient NOT meeting the above criteria

- Any patient with active connective tissue disease such as lupus or dermatomyositis is
excluded; patients with active connective tissue disease are at an excessive risk of
organ function‐impairing fibrosis

- Any patient with active Crohn's disease or active ulcerative colitis is excluded;
patients having these conditions are at an excessive risk of organ function‐impairing
fibrosis

- Any patient with known anaphylaxis to carboplatin or gemcitabine is excluded

- Pregnant women are excluded from this study because radiation has the potential for
teratogenic or abortifacient effects; screening beta‐human chorionic gonadotropin
(hcg) levels (urine or blood) and diagnostic tests will be used to determine
eligibility in women of childbearing potential; women of child‐bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study
participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately;
these potential risks may also apply to carboplatin/gemcitabine chemotherapy agents
used in this study

- Human immunodeficiency virus (HIV)‐positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
carboplatin or gemcitabine; in addition, patients known to be HIV‐positive patient
are excluded due to an increased risk of lethal infections when treated with
marrow‐suppressive therapy such as carboplatin/gemcitabine; HIV testing is not
mandatory for eligibility evaluation

- Due to a perceived increased risk to transplanted organ for lethal dysfunction or
lethal infection, patients with visceral organ transplants are not eligible

- Patients with other active non‐gynecologic invasive malignancies are excluded;
patients with other invasive malignancies who had (or have) cancer present within the
last two years are excluded