Brief Title
Effect of Acetylcysteine With Topotecan Hydrochloride on the Tumor Microenvironment in Patients With Persistent or Recurrent High Grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Official Title
Evaluation of the Addition of N-Acetylcysteine to Topotecan in the Tumor Microenvironment of Persistent or Recurrent High Grade Endometrioid or Serous Ovarian Carcinoma
Brief Summary
This randomized phase II trial studies the effects of acetylcysteine and topotecan
hydrochloride on the tumor microenvironment, or cells that make up a tumor, compared to
topotecan hydrochloride alone in patients with ovarian, fallopian tube, or primary peritoneal
cancer that has not responded to treatment (persistent) or has returned after a period of
improvement (recurrent) and is high grade (likely to grow and spread quickly). Research has
shown that cancer cells may be able to convert nearby normal cells into cancer cells.
Acetylcysteine may stop this from happening. Topotecan hydrochloride is a chemotherapy drug
used to treat ovarian cancer, and may help acetylcysteine work better. This trial studies the
effect of acetylcysteine and topotecan hydrochloride on the tumor microenvironment to see if
they can help make it more difficult for tumor cells to grow.
Detailed Description
PRIMARY OBJECTIVES:
I. To estimate the proportion of subjects with persistent or recurrent high grade
endometrioid or serous ovarian carcinoma who demonstrate a downregulation of monocarboxylate
transporter 4 (MCT4) in the ovarian stroma in response to exposure to topotecan (topotecan
hydrochloride) and N-acetylcysteine (NAC) (acetylcysteine) as compared to topotecan alone.
SECONDARY OBJECTIVES:
I. To determine the expression levels of caveolin 1 (Cav-1), solute carrier family 16
(monocarboxylate transporter), member 1 (MCT1), translocase of outer mitochondrial membrane
20 homolog (yeast) (TOMM20), fatty acid binding protein 4, adipocyte (FABP4), hypoxia
inducible factor 1, alpha subunit (HIF-1 alpha) and NF kappaB activating protein (NFκB) in
pathological samples of tumors after therapy with NAC relative to samples taken at time of
initial diagnosis.
II. To assess the potential impact of NAC on progression free survival, overall survival,
objective tumor response- complete or partial, and duration of response.
III. To estimate the proportion of subjects who survive progression free for at least 6
months and the proportion of patients who have objective tumor response, complete or partial
in response to therapy IV. To assess safety and tolerability of NAC plus topotecan treatment
in subjects with endometrioid or serous ovarian carcinoma by Common Terminology Criteria for
Adverse Events (CTCAE) version (v)4.0 criteria.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive topotecan hydrochloride intravenously (IV) over 30 minutes on days 1,
8, and 15 (+/- 1 day window for each treatment day). Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
ARM II: Patients receive topotecan hydrochloride as in Arm I. Patients also receive
acetylcysteine IV over 60 minutes on days 1, 8, 15, and 22 (+/- 1 day window for each
treatment day) and acetylcysteine orally (PO) twice daily (BID) on days 2-7, 9-14, 16-21, and
23-28, unless administration window was utilized. Courses repeat every 28 days in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 24 months.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Proportion of Patients Who Demonstrate a Downregulation of MCT4
Secondary Outcome
Change in Expression Levels of Cav-1 in Tissue Samples
Condition
Malignant Ovarian Endometrioid Tumor
Intervention
Topotecan Hydrochloride
Study Arms / Comparison Groups
Arm I (topotecan hydrochloride)
Description: Patients receive topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15 (+/- 1 day window for each treatment day). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
1
Start Date
October 2, 2015
Completion Date
October 12, 2017
Primary Completion Date
June 10, 2016
Eligibility Criteria
Inclusion Criteria:
1. Patient must have persistent or recurrent high grade endometrioid or serous ovarian,
primary peritoneal or fallopian tube carcinoma. Histologic documentation of the
original primary tumor is required via the pathology report.
2. All patients must have measurable disease that is amenable to biopsy. Measurable
disease is defined as at least one lesion that can be accurately measured in at least
one dimension (longest dimension to be recorded). Each lesion must be ≥20 mm when
measured by conventional techniques including palpation, plain film x-ray, CT, and
MRI, or ≥ 10 mm when measured by high resolution CT.
3. Patient must have at least one target lesion to be used to assess response on this
protocol as defined by RECIST 1.1. Tumors within a previously irradiated field will be
designated as non-target lesions unless progression is documented or a biopsy is
obtained to confirm persistent disease at least 90 days following completion of
radiation therapy.
4. Patients must have a GOG performance status of 0, 1, or 2.
5. Patients must be free of active infections requiring antibiotics, with the exception
of uncomplicated urinary tract infections (UTIs).
6. Any hormonal therapy directed at the tumor must be discontinued at least one week
prior to initiation of therapy. Continuation of hormone replacement therapies is
permitted.
7. Any other prior therapy directed at the tumor, including immunologic agents, must be
discontinued at least 3 weeks prior to initiation of therapy.
8. Patients must have had at least one prior platinum/taxane combination chemotherapeutic
regimen for management of primary disease containing carboplatin, cisplatin, or
another organoplatin compound. This initial treatment may include intraperitoneal
therapy, high dose therapy, consolidation, noncytotoxic agents, or extended therapy.
9. Patients must be platinum resistant- defined as progressive disease while receiving
platinum therapy or within 6 months of completing first line platinum therapy or
patients who have progressive disease after two lines of platinum based treatment.
1. Cytotoxic regimens are any that include agents that target the genetic and/or
mitotic apparatus of the dividing cells, resulting in dose limiting toxicity to
the bone marrow or gastrointestinal mucosa
2. Patients are allowed to receive, but not required to receive biologic
(noncytotoxic) therapy as part of their treatment regimen, e.g. bevacizumab.
10. Patients Must Have Adequate:
1. Bone Marrow Function: Absolute Neutrophil Count greater than or equal to
1000/mcl. Platelets greater than or equal to 100,000/mcl. Hemoglobin greater than
10 g/dl. (Patients may be transfused to achieve this hemoglobin.)
2. Renal Function: creatinine less than or equal to 1.5 x upper limit of normal,
CTCAE v 4.0 grade 1.
3. Hepatic Function: bilirubin less than or equal to 1.5 x upper limit of normal,
CTCAE v 4.0 grade 1. Asparate transaminase (AST) and alkaline phosphatase less
than or equal to 2.5 x upper limit of normal, CTCAE v 4.0 grade 1.
4. Coagulation: PT, PTT less than or equal to 1 to 1.5 x upper limit of normal CTCAE
v 4.0 grade 1 except for patients on therapeutic anticoagulation.
5. Neurologic Function: neuropathy (sensory and motor) less than or equal to CTCAE v
4.0 grade 1.
11. Patients must have signed an approved informed consent and authorization permitting
release of personal health information.
12. Patients must meet pre-entry requirements as specified.
13. In the unlikely event that patients are still of childbearing potential, these
patients must have a negative serum pregnancy test within 72 hours prior to initiating
protocol therapy and be practicing an effective form of contraception during protocol
therapy and for at least 4 weeks following completion of protocol therapy.
14. Patients must be 18 years of age or older.
15. Patients must not be receiving any other investigational agent.
16. Patients must be able to swallow whole pills. -
Exclusion Criteria:
1. Patients who have had previous treatment with topotecan.
2. Patients who have had more than 4 prior chemotherapy regimens.
3. Patients who have received radiation to more than 25% of marrow-bearing areas.
4. Patients with a history of other invasive malignancies are excluded if there is any
evidence of other malignancy being present within the last 3 years.
5. Patients who have received prior chemotherapy for any abdominal or pelvic tumor other
than for treatment of ovarian carcinoma within the last 3 years are excluded. Patients
may have received prior chemotherapy for localized breast cancer, provided that it was
completed more than three years prior to registration and the patient remains free of
recurrent of metastatic disease.
6. Pregnant or nursing women or women of childbearing potential unless using effective
contraception as determined by the investigator. -
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Russell Schilder, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT02569957
Organization ID
15P.404
Responsible Party
Sponsor
Study Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
National Institutes of Health (NIH)
Study Sponsor
Russell Schilder, MD, Principal Investigator, Thomas Jefferson University
Verification Date
December 2017