PTC596 in Treating Patients with Newly Diagnosed Unresectable Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Receiving Chemotherapy
- Patients with newly diagnosed epithelial ovarian, fallopian tube or primary peritoneal cancer and be previously untreated
- Patients with bulky disease that is considered by the clinician to be unresectable via primary debulking surgery and needs neoadjuvant chemotherapy prior to debulking surgery. This assessment of unresectability can be made via imaging or laparoscopic scoring
- Patients must have histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma per pre-treatment biopsies by laparoscopy, or interventional radiology or computed tomography (CT) guided core biopsy. Histologic documentation of the original primary tumor is required via the pathology report
- Patients with the following histologic epithelial cell types are eligible: high grade serous adenocarcinoma, endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, or adenocarcinoma not otherwise specified (N.O.S.)
- Absolute neutrophil count (ANC) greater than or to 1,500/mcl. This ANC cannot have been induced or supported by granulocyte colony stimulating factors
- Platelets greater than or equal to 100,000/mcl
- Creatinine =< 1.5 x institutional upper limit normal (ULN)
- Bilirubin =< 1.5 x ULN
- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x ULN
- Alkaline phosphatase =< 2.5 x ULN
- Neuropathy (sensory and motor) less than or equal to grade 1
- Patients should be free of active infection requiring parenteral antibiotics or a serious uncontrolled medical illness or disorder within four weeks of study entry
- Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration. Continuation of hormone replacement therapy is permitted
- Patients must have a performance status score of 0, 1, or 2 by Eastern Cooperative Group (ECOG) criteria
- Patients of childbearing potential must have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception. If applicable, patients must discontinue breastfeeding prior to study entry
- Patients must have satisfactory results for the baseline laboratory analyses and diagnostic procedures as specified in the protocol
- Patients must have signed an Institutional Review Board (IRB)-approved informed consent and authorization permitting release of personal health information
- Patients must have pre-treatment tumor tissue available or agree for tissue collection from interventional radiology (IR) guided biopsy
- Life expectancy of at least 3 months
- Patients who have received prior treatment with PTC596 or standard of care drugs (cis- or carboplatin or paclitaxel)
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to PTC596 or other agents used in this study
- Patients who have a clinical requirement for ongoing systemic immunosuppressive therapy such as chronic steroid use not related to chemotherapy administration
- Patients receiving treatment for active autoimmune disease. “Active” refers to any condition currently requiring therapy. Examples of autoimmune disease include systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis
- Patients with other invasive malignancies, with the exception of nonmelanoma skin cancer and other specific malignancies as noted in the protocol are excluded if there is any evidence of other malignancy being present within the last three years. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy. Patients with concomitant endometrial cancer diagnosed at the time of their ovarian cancer are allowed to participate if the endometrial cancer is Federation of Gynecology and Obstetrics (FIGO) stage IB or less
- Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded. Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
- Patients who have received prior chemotherapy for any abdominal or pelvic tumor are excluded. Patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
- Patients with known active hepatitis, ongoing systemic bacterial, fungal, or viral infection; known human immunodeficiency virus (HIV) infection or acquired-immunodeficiency syndrome (AIDS)-related illness
- Patients with concurrent severe medical problems unrelated to the malignancy that would significantly limit full compliance with the study or expose the patient to extreme risk or decreased life expectancy
- Patients of childbearing potential, not practicing adequate contraception, patients who are pregnant, or patients who are breastfeeding are not eligible for this trial
- Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study
- Patients take concomitant therapy with any of the following: other non-study cytotoxic chemotherapy; other investigational therapies
- Prior bone marrow/hematopoietic stem cell transplantation
- History of solid organ, bone marrow, or progenitor cell transplantation
- History of major surgical procedure within 28 days prior to start of study treatment
- Presence or history of moderate to severe pulmonary dysfunction (e.g., moderate/severe chronic obstructive pulmonary disease, post-pneumonectomy, shortness of breath with limited exertion)
- Use of an investigational drug within 4 weeks of dosing in the current study
I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of BMI1 inhibitor PTC596 (PTC596) in combination with and following conventional chemotherapy and as maintenance as a capsule (weight based dosing) and a tablet (fixed dosing).
II. To examine the tolerability of the combination at the MTD of PTC596 assessed in combination with standard neoadjuvant chemotherapy.
III. To determine the recommended phase II dose (RP2D) of PTC596 in combination with standard neoadjuvant chemotherapy.
MAJOR SECONDARY OBJECTIVES:
I. To assess the objective clinical response (cOR), pathological complete response (pCR) at time of interval debulking surgery, and then evaluate progression free survival (PFS) at years 1 and 2 after debulking surgery and overall survival by long term follow up.
II. To evaluate plasma exposures of PTC596 at selected time points in patients with stage III or IV epithelial ovarian, primary peritoneal or fallopian tube cancer receiving neoadjuvant chemotherapy with carboplatin/paclitaxel.
III. Assess the general safety of PTC596 as a tablet in combination with standard chemotherapy (carboplatin and paclitaxel).
TRANSLATIONAL RESEARCH OBJECTIVES:
I. Determine the impact of PTC596 in combination with conventional chemotherapy on the stem cell markers of treated tumors and correlate treatment effects with improvement in progression-free survival.
II. Investigate the underline mechanisms of PTC596 combined with conventional chemotherapy on outcome improvement by performing the following: compare expression of BMI1, Ki67 and TdT-mediated dUTP nick end labeling (TUNEL) by immunohistochemistry (IHC) in pre and post tissues; compare expression of stem-cell markers by quantitative real time polymerase chain reaction (RT-qPCR) in pre and post tissues; correlate if PTC596 can reduce BMI1 expression and if this BMI1 reduction is associated with better prognosis in patients with advanced gynecologic (GYN) cancer; perform ribonucleic acid (RNA) sequencing to compare a larger set of regulated genes between patients treated with conventional chemotherapy (C/T) and C/T plus PTC596.
OUTLINE: This is a dose-escalation study of BMI1 inhibitor PTC596.
Patients receive BMI1 inhibitor PTC596 orally (PO) on days 1, 4, 8, 11, 15, and 18. Patients also receive standard of care carboplatin intravenously (IV) over 30 minutes and paclitaxel (docetaxel can be substituted if there is a paclitaxel allergic reaction) IV over 3 hours on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Within 6 weeks, patients undergo interval cytoreduction surgery (iCRS). Patients then continue treatment with BMI1 inhibitor PTC596, carboplatin, and paclitaxel for an additional 3-7 cycles in the absence of disease progression or unacceptable toxicity. Patients may then receive BMI1 inhibitor PTC596 for up to 2 years as maintenance per investigator discretion.
After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, and then annually thereafter.
Trial Phase Phase I
Trial Type Treatment
University of Oklahoma Health Sciences Center
Kathleen N. Moore
- Primary ID OU-SCC-PTC-001
- Secondary IDs NCI-2018-03753
- Clinicaltrials.gov ID NCT03206645