Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Digestive System Diseases

Rare Diseases

Carcinoma

Adenocarcinoma

Breast Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Gastrointestinal Neoplasms

Cystadenocarcinoma, Serous

Carcinosarcoma

Mixed Tumor, Mullerian

Digestive System Neoplasms

Ovarian Cancer

Ovarian Epithelial Cancer

Malignant Mixed Mullerian Tumor

Uterine Carcinosarcoma

INCB123667 will be administered at a protocol defined starting regimen once daily (QD) orally in 28-day cycles.

Subsequent dose regimens will be determined during study conduct.

INCB123667 will be administered at the recommended dose or doses for expansion (RDE\[s\]) for advanced or metastatic solid tumors. Participants with gynecologic tumors (epithelial ovarian/fallopian/primary peritoneal carcinoma ) will enroll in this group.

INCB123667 will be administered at the recommended dose or doses for expansion (RDE\[s\]) for advanced or metastatic solid tumors. Participants with Endometrial/Uterine cancer will enroll in this group.

INCB123667 will be administered at the recommended dose or doses for expansion (RDE\[s\]) for advanced or metastatic solid tumors. Participants with gastric, Gastro Esophageal Junction (GEJ), and esophageal adenocarcinomas will enroll in this group.

INCB123667 will be administered at the recommended dose or doses for expansion (RDE\[s\]) for advanced or metastatic solid tumors. Participants with Triple Negative Breast Cancer(TNBC) will enroll in this group.

INCB123667 will be administered at the recommended dose or doses for expansion (RDE\[s\]) for advanced or metastatic solid tumors. Participants with HR+/HER2- breast cancer who have had disease progression on or been intolerant of a CDK4/6 inhibitor will enroll in this group.

INCB123667 will be administered at the recommended dose or doses for expansion (RDE\[s\]) for advanced or metastatic solid tumors. Participants with other tumor indications with CCNE1 amplification or cyclin E1 over-expression will enroll in this group.

INCB0123667

Incyte Corporation Call Center (US)

Incyte Corporation Call Center (ex-US)

Liz Croft Richards

This is an open-label, dose-escalation and dose-expansion study to determine the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of INCB123667 when administered as monotherapy at the RDE(s) in participants with selected advanced or metastatic solid tumors. Part 1A (dose escalation) will determine the recommended dose of INCB123667 for expansion (RDE) and the maximum tolerated dose (MTD). Part 1B (cohort dose expansion phase) will further explore antitumor activity of INCB123667 as a monotherapy in 6 tumor-specific cohorts at the RDE(s) defined in Part 1A.

Part 1a will be dose escalation using a statistical hybrid design to identify the RDE(s), and the starting dose of INCB123667 will be 50mg QD. Part 1B is a dose expansion portion during which drug will be administered at the RDE(s) defined in Part 1A to 6 Disease Groups.

Study of INCB123667 in Subjects With Advanced Solid Tumors

A Phase 1, Open-Label, Multicenter Study of INCB123667 as Monotherapy in Participants With Selected Advanced Solid Tumors

Toxicities occurring during the first treatment cycle, Part 1a, will define tolerability. DLTs will be assessed for severity by the investigator using CTCAE v5.0 criteria.

TEAE is any Adverse Event (AE) either reported for the first time or worsening of a pre-existing event after first dose of study drug.

Participants will receive dose reductions of INCB123667 according to lab guidelines. Treatment may be delayed for up to 2 weeks to allow for resolution of toxicity.

Participants will receive dose reductions according to lab guidelines. Treatment may be delayed for up to 2 weeks to allow for resolution of toxicity.

TEAE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Defines as the maximum (peak) plasma drug concentration

Defined as the time to reach maximum (peak) plasma concentration following drug administration

Ctau is defined as concentration at the end of the dosing interval

Defined as the area under the plasma concentration-time curve

Defined as the apparent total body clearance of the drug from plasma

Defined as apparent volume of distribution during terminal phase

Defined as Elimination half-life (to be used in one-or noncompartmental model)

Defined as having a best overall Complete Response (CR) or Partial Response (PR), as determined by the investigator by radiographic disease assessment according to RECIST v1.1.

Defined as having a best overall response of CR, PR, or Stable Disease (SD) as determined by the investigator by radiographic disease assessment according to RECIST v1.1.

Defined as the time from earliest date of disease response (Completed Rresponse or Partial Response) until earliest date of disease progression as determined by the investigator by radiographic disease assessment according to RECIST v1.1 or death due to any cause if occurring sooner than progression.

Incyte Corporation

Uterine Neoplasms

Adenocarcinoma, Clear Cell

Adenomyoepithelioma

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Epithelial-myoepithelial Carcinoma

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

All Drugs and Chemicals

Celecoxib

Cyclooxygenase 2 Inhibitors

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase Inhibitors

Enzyme Inhibitors

Mark H Einstein, M.D., M.S.

Expression of COX-II has been identified in many types of human cancers. Uterine cancer is the most common gynecologic cancer in the US and there has been an increase in uterine cancer deaths over the past decade mainly due to the difficulty in treating recurrences in the more aggressive histologic types. The study co-investigators have also identified COX-II expression in grade 2 and 3 endometrioid-type, clear cell, and papillary serous types of uterine cancers. Upregulation of COX-II may control the cell cycle by regulating the proliferative capacity of neoplastic endometrial cells. This is a Phase II pre-post intervention comparison study in eligible patients looking at the effects of a COX-II inhibitor on uterine cancer. The patients whose endometrial biopsy shows grade 2 or 3 endometrioid-type, clear cell, and papillary serous types of uterine cancers will be put on a selective COX-II inhibitor, Celebrex (Celecoxib) until the day of their surgery. We hypothesize that Celecoxib will downregulate the expression of COX-II in these tumor types as it does in other similar tumors. We also hypothesize that apoptosis, as measured with the TUNEL assay, will be increased in areas with less COX-II expression and should be inversely proportional to cellular p21 expression. We hypothesize COX-related gene expression will be altered thus suggesting an up- or down-regulation of these genes in the end-organ tissue. Documenting downregulation of COX-II enzyme and altered gene expression in endometrial carcinoma after treatment with Celecoxib may result in further prospective studies using selective COX-II inhibitors as effective, well-tolerated chemotherapeutic agents in these uterine cancers that are resistant to many current therapies.

Endometrial cancer is the most common gynecologic cancer in the United States. The number of deaths from endometrial cancer has risen 128% since 1987. In 2001, an estimated 38,300 women will develop endometrial cancer (ACS Facts and Figures) and an estimated 6,600 women will die from endometrial cancer. Preinvasive and well-differentiated endometrial cancers are hormonally driven and often cured with surgery alone. Higher-grade tumors are usually not hormonally driven and proliferate via unknown mechanisms. These tumors are largely responsible for the rising death rate. Responses to toxic treatment protocols for recurrent endometrial cancer are dismal. Unfortunately, these post-menopausal women also often have comorbidities, which limit their eligibility for current chemotherapy and radiotherapy treatments.

Expression of COX-II has been identified in many human cancers including: colon cancer, gastric cancer, esophogeal cancer, bladder cancer, head and neck cancer, liver cancer, pancreatic cancer, prostate cancer and breast cancer. COX-II expression is also strongly expressed in the primary tumor and metastasic site in human cervical cancer. COX-II may influence cell cycle control by upregulating the proliferative capacity of neoplastic endometrial cells. Furthermore, COX-II inhibitors inhibit tumor proliferation even in cells that do not express COX. This suggests an alternative mechanism of action not yet defined that may play a role in inhibiting the growth of cancer tissue.

The enhanced expression of COX-II has led investigators to use COX-II inhibitors in the prevention and/or treatment of colon and prostate cancers both in vivo and in vitro. Celecoxib is now FDA approved for chemoprevention of colon cancer in familial adenomatous polyposis patients. If it can be shown that COX-II is downregulated by COX-II inhibitors in endometrial cancer, they may offer similar chemopreventative or chemotherapeutic potentials that have already been proven in colon cancer.

COX-II enzyme activity may not always correlate with end organ gene expression. Multiple genes have been implicated in apoptotic pathways and are affected by COX-II inhibitors. NS-398, a selective COX-II inhibitor causes elevations in APC expression and downregulation of c-myc. Prostate apoptosis response 4 (Par-4) levels are increased in cells treated with COX inhibitors. PTEN and hMLH1 are genes which are implicated in malignant transformation of endometrial tissue. 5-Lipooxygenase (5-LOX) is often correlated with COX-I and COX-II. Thus, in addition to COX-I and COX-II, these are good candidate genes to study the effects of COX-II inhibitors on uterine cancers.

Preliminary Data Since COX-II expression is seen in the endometrium and in other hormonally-dependent tumors, we have investigated the expression of COX-II in endometrial cancer. Our preliminary studies on 41 fixed samples of benign and neoplastic endometrium revealed that COX-II was not expressed in benign endometrial tissue, stains minimally (\~1% of tumor cells) in well-differentiated endometrial carcinomas, and stains most strongly in poorly-differentiated carcinomas (\~12% of tumor cells, most staining strongly). COX-II is expressed in all poorly differentiated uterine cancers. Our study also demonstrated that COX-II was also strongly expressed in uterine papillary serous carcinomas (UPSC) as well as clear cell carcinomas of the uterus. These findings were confirmed by Ferrandina, et al. A small percent of our patients as well as the patients in the Ferrandina study have only 1+ or 1-5% staining. These 'low-expressers' only made up 1/13 (7.7%) of our patients.

COX-II expression in endometrial carcinoma has a slight inverse correlation with apoptosis (r=-0.534). However, COX-II expression in endometrial carcinoma correlated with lymphovascular invasion (r=0.69) and depth of invasion (r=0.68). There was no correlation between COX-II expression and ER (r=0.03) or PR (r=-0.02). The presence of a poorly-differentiated tumor may imply a hormonally-independent pathway resulting in de-differentiation. In summary, our preliminary data reveals that COX-II expression is high in grade 2 and 3 endometrioid-type endometrial cancers, as well as UPSC and clear cell subtypes and is correlated with known clinical prognostic factors.

Expression of COX-II has been identified in many types of human cancers. Uterine cancer is the most common gynecologic cancer in the US and there has been an increase in uterine cancer deaths over the past decade mainly due to the difficulty in treating recurrences in the more aggressive histologic types. The study co-investigators have also identified COX-II expression in grade 2 and 3 endometrioid-type, clear cell, and papillary serous types of uterine cancers. Upregulation of COX-II may control the cell cycle by regulating the proliferative capacity of neoplastic endometrial cells. This is a Phase II pre-post intervention comparison study in eligible patients looking at the effects of a COX-II inhibitor on uterine cancer. The patients whose endometrial biopsy shows grade 2 or 3 endometrioid-type, clear cell, and papillary serous types of uterine cancers will be put on a selective COX-II inhibitor, Celebrex (Celecoxib) until the day of their surgery. The expression of COX-II and p21 will be quantified after treatment with Celecoxib in eligible patients. This expression will be evaluated by performing immunohistochemical staining on the endometrial biopsy (pre-intervention) and the hysterectomy specimen (post-intervention). Apoptosis, evaluated by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP- digoxigenin nick end-labeling (TUNEL) assay, will also be evaluated and compared to COX-II expression in endometrial cancer in the two specimens, endometrial biopsy (pre-intervention) and uterus (post-intervention). In addition to IHC analysis and apoptosis, gene expression of COX-related genes in the post-intervention uterine specimens will. This gene expression will be compared to matched controls who were not treated with a COX-II inhibitor. COX-II expression will be correlated with established clinical prognostic factors including lymphovascular invasion, depth of myometrial invasion and lymph node involvement. We hypothesize that Celecoxib will downregulate the expression of COX-II in these tumor types as it does in other similar tumors. We also hypothesize that apoptosis, as measured with the TUNEL assay, will be increased in areas with less COX-II expression and should be inversely proportional to cellular p21 expression. Additionally, COX-II inhibitors affect apoptotic pathways even in cells that do not express COX-II. For low expressing cells, COX-II inhibitor activity may be better documented with apoptosis. We hypothesize COX-related gene expression will be altered thus suggesting an up- or down-regulation of these genes in the end-organ tissue. Documenting downregulation of COX-II enzyme and altered gene expression in endometrial carcinoma after treatment with Celecoxib may result in further prospective studies using selective COX-II inhibitors as effective, well-tolerated chemotherapeutic agents in these uterine cancers that are resistant to many current therapies.

A Pilot Study of Celecoxib in Patients With Grade 2 or 3 Uterine Cancers

A Pilot Phase II Trial of Celecoxib in Patients With Grade 2 or 3 Endometrioid-type, Clear Cell, and Papillary Serous Uterine Cancers

Pharmacia

Mark H. Einstein

Director, Clinical Research for Women's Health

Symptoms and General Pathology

Recurrence

Cystadenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Cystic, Mucinous, and Serous

Adenocarcinoma of the Appendix

Antineoplastic Agents

Amino Acids

Paclitaxel

Albumin-Bound Paclitaxel

Imatinib Mesylate

Tubulin Modulators

Antimitotic Agents

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Phase I MTD using oral dose Imatinib Mesylate escalation 400, 500, 600 mg daily; Paclitaxel 175 mg/m\^2 every 21 days

Intended randomization of Paclitaxel alone or Paclitaxel + Imatinib Mesylate; the study was terminated early due to poor enrollment and all patients are no longer being treated or followed. Single treatment arm MTD using oral dose Imatinib Mesylate escalation = 500 mg daily; Paclitaxel 175 mg/m\^2 every 21 days

Phase II, (Arm 1) = Paclitaxel 175 mg/m\^2 every 21 days Phase II, (Arm 2) Paclitaxel 175 mg/m\^2 every 21 days+ Imatinib Mesylate MTD using oral dose Imatinib Mesylate escalation = 500 mg daily

Phase I = Maximum tolerated dose (MTD) derived from dose escalation of 400, 500, 600 mg by mouth daily

175 mg/m\^2 by vein over 3 Hours every 21 Days

Objectives:

* To determine the maximum tolerated dose (MTD) of imatinib mesylate in combination with fixed dose paclitaxel in patients with stage IIIC, IV or recurrent uterine papillary serous carcinoma.
* To determine the nature and degree of toxicity of imatinib mesylate and paclitaxel in this cohort of patients.
* To determine the efficacy of imatinib mesylate and paclitaxel in patients with stage IIIC, IV or recurrent uterine papillary serous carcinoma whose tumor expresses either c-Kit, PDGFR or abl.

Before possible study participants can receive treatment with imatinib mesylate and paclitaxel, their tumor tissue that was previously collected (at the surgery to diagnose your tumor) will be tested for the following three biomarkers: c-Kit, PDGFR-B, and Abl. Those participants who have at least one positive biomarker will be eligible for treatment on this study.

Paclitaxel is a chemotherapy drug used in the treatment of ovarian cancer. Imatinib mesylate is a medication that blocks several proteins that are important in the development of cancer.

Before treatment starts, you will have a complete physical exam, routine blood tests (about 2-3 teaspoons), an electrocardiogram (ECG--a test to measure the electrical activity of the heart). You will have an echocardiogram (an ultrasound test used to visualize the structures of the heart), a chest x-ray, and a CT scan or MRI of the abdomen and pelvis. Women who are able to have children must have a negative blood pregnancy test.

Routine blood tests (about 2 teaspoons) will be done weekly during treatment, and before each course of therapy, which is every 3 weeks. A complete checkup including evaluation of side effects, will also be done before each course of therapy and at the end of therapy (3 weeks after treatment ends).

There are two phases to this study, Phase I and Phase II. If you are assigned to Phase 1, you will receive treatment with imatinib mesylate and paclitaxel. Phase 1 will study 3 different doses of imatinib mesylate in combination with a fixed dose of paclitaxel. The Phase I part of the study will help researchers learn the most effective dose of imatinib mesylate to be used in combination with paclitaxel. All participants in Phase 1 will receive one of three doses of imatinib mesylate to be given with a standard dose of paclitaxel. You will be assigned to a specific dose level based on the number of participants treated at the time of your enrollment.

The Phase II portion of the study will begin only after the most effective dose of imatinib mesylate has been determined.

If you are assigned to Phase II, you will be randomly assigned (as in the toss of a coin) to one of two treatment groups. Participants in one group will receive treatment with paclitaxel only (every 21 days). Participants in the second group will receive treatment with paclitaxel (every 21 days) along with imatinib mesylate (every day). The dose level of imatinib mesylate that you receive will be the same as the dose used during Phase I. The computer-generated assignment will favor the treatment group which is more effective. For example, if the combination of paclitaxel and imatinib mesylate is more effective than paclitaxel alone, then more patients will be selected to receive the combination therapy.

You will receive paclitaxel by vein over 3 hours every 21 days. Those participants who are assigned treatment with both paclitaxel and imatinib mesylate will begin taking imatinib mesylate the day after the first dose of paclitaxel. A single dose of imatinib mesylate will be taken by mouth every day.

Evaluation of tumor response (for participants who already have the disease) will be determined by CT scan or MRI and chest x-ray (patients with chest disease). These scans will be taken after Courses 2 and 4 , then after every 3 courses until the therapy is finished, and once more at the end of therapy. Patients who show no signs of the disease will be given a total of up to 6 courses. Patients who have the disease may continue treatment until the disease gets worse. You will be taken off study if the disease gets worse or intolerable side effects occur. If you are removed from the study, you will be asked to have a follow-up CT scan or MRI and chest x-ray to evaluate the tumor.

THIS IS AN INVESTIGATIONAL STUDY. Paclitaxel is commercially available and approved for use in the treatment of ovarian cancer. Gleevec® is also commercially available and approved for use in the treatment of certain types of adult leukemias and stomach cancers. The combination of paclitaxel and imatinib mesylate is still investigational and has been approved for use in research only.

At least 51 and as many as 65 participants will take part in this study. All participants will be enrolled and treated at M. D. Anderson.

Gleevec/Taxol for Patients With Uterine Papillary Serous Carcinoma

A Phase I/II Study of Gleevec/Taxol in Patients With Newly Diagnosed Stage IIIC or IV or Recurrent (Any Stage) Uterine Papillary Serous Carcinoma (UPSC)

Maximum Tolerated Dose (MTD) of Oral Imatinib Mesylate in Combination with Fixed Dose Paclitaxel where MTD of Imatinib Mesylate (mg/m\^2 daily) to be determined with conventional 3+3 design, MTD is highest dose level in which 6 participants treated with at most 2 experiencing dose limiting toxicity (DLT). Study utilizes Common Terminology for Adverse Events Criteria (CTCAE) version 3.0 for adverse event reporting.

Following cohorts of 3 at lower dose levels until 1 of 3 patients experiences DLT; if 1 of 3 patients experiences DLT at dose level, enter 3 additional patients at dose level, if only 1 of 6 patients experiences DLT at dose level, proceed to next higher dose level with cohort of 3; If 2 of 3 or 3 of 6 patients experience DLT, MTD has exceeded. Once DLT exceeded, treat another 3 patients at previous dose if there were only 3 patients treated at that dose level. MTD is highest dose level in which treated 6 patients with at most 2 experiencing the DLT.

Complete Response (CR): Disappearance lesions, no evidence new lesions documented by 2 disease assessments\> 4 weeks apart. Partial Response (PR):\>30% decrease in sum longest dimensions (LD) all target measurable lesions reference baseline sum of LD; No progression non-target lesions \& no new lesions; Documentation by 2 disease assessments \>4 weeks apart; Progressive Disease (PD) (ANY of following): \>20% increase in sum LD of target lesions reference smallest sum LD or appearance of new lesions within 8 weeks of study entry; Unequivocal progression on existing non-target lesions, other than pleural effusions without cytological proof of neoplastic origin, within 8 weeks of study entry also considered increasing disease. Death due to disease without prior objective documentation of progression; Global deterioration in health attributable to disease requiring change in therapy without objective evidence of progression. Stable disease: Any condition not meeting above criteria.

Efficacy of Gleevec and Taxol in Participants defined by tumor progression for participants with measurable disease or recurrent non-measurable disease. Time to tumor progression defined as the time from date of initial treatment to first objective documentation of disease progression. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). After two cycles (6 weeks), participants will undergo clinical and radiographic (participants with measurable disease) tumor restaging or confirmation recurrent non-measurable disease. Evaluation of tumor response (for participants who already have the disease) determined by CT scan or MRI and chest x-ray (participants with chest disease).

M.D. Anderson Cancer Center

Cohort One = Paclitaxel (Taxol) 175 mg/m\^2 intravenous (IV) every 21 days + Imatinib Mesylate (Gleevec). Phase I Maximum Tolerated Dose (MTD) to be determined from escalating doses in subsequent cohorts: 400 (this arm, Cohort One), 500 (Cohort Two) or 600 mg (Cohort Three) orally daily.

Phase I: Imatinib Mesylate 400mg

Paclitaxel 175 mg/m\^2 IV every 21 days + Imatinib Mesylate 500 mg orally daily

Phase II: Imatinib Mesylate 500 mg

Paclitaxel 175 mg/m\^2 IV every 21 days + Imatinib Mesylate 600 mg orally daily

Phase 1: Imatinib Mesylate 600 mg

Paclitaxel 175 mg/m\^2 IV every 21 days + Imatinib Mesylate at MTD 500 mg orally

Phase II: Imatinib Mesylate MTD 500 mg

Phase I = Paclitaxel (Taxol) 175 mg/m\^2 intravenous (IV) every 21 days + Imatinib Mesylate (Gleevec) 400, 500 or 600 mg orally daily

Phase I: Paclitaxel + Imatinib Mesylate

Phase II = Paclitaxel 175 mg/m\^2 IV every 21 days + Imatinib Mesylate at MTD 500 mg orally daily

Phase II: Paclitaxel + Imatinib Mesylate MTD 500 mg

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

David Gershenson, MD

Cohort One = Paclitaxel 175 mg/m\^2 IV every 21 days + Imatinib Mesylate 400 mg orally daily

Imatinib Mesylate 400 mg

Cohort Two = Paclitaxel 175 mg/m\^2 IV every 21 days + Imatinib Mesylate 500 mg orally daily

Imatinib Mesylate 500 mg

Cohort Three = Paclitaxel 175 mg/m\^2 IV every 21 days + Imatinib Mesylate 600 mg orally daily

Imatinib Mesylate 600 mg

One participant of 12 registered withdrew prior to receiving treatment.

Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)

Paclitaxel (Taxol) 175 mg/m\^2 intravenous (IV) every 21 days + Imatinib Mesylate (Gleevec) 400, 500 or 600 mg orally daily or Phase II MTD 500 mg

Participants With Measurable Disease

Participants With Non-Measurable Disease

Number of Participants With Complete Response

Due to poor enrollment, the study was terminated early and no data collected for the Time to tumor progression outcome measure.

Time to Tumor Progression

Phase I: Imatinib Mesylate 400 mg

Phase I: Imatinib Mesylate 500 mg

Phase I: Imatinib Mesylate 600 mg

Phase II, Cohort 4 = Paclitaxel 175 mg/m\^2 IV every 21 days + Imatinib Mesylate at MTD 500 mg orally daily

Overall Study

Carboplatin

Drug:Carboplatin and Paclitaxel and Radiation: Pelvic Radiation Therapy

Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=6.5) Repeat q 21 days x 3 cycles followed by RT followed by Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=5.0)Repeat q 21 days x 3 cycles

Carboplatin and Paclitaxel and Pelvic Radiation Therapy

Carboplatin and Paclitaxel and Radiation Therapy

Combination chemo/radiotherapy trials in advanced/recurrent endometrial cancer are ongoing. The optimal radiation modality, chemotherapeutic agents, and sequence of these regimens for the treatment of UPSC are yet to be established. A retrospective review of 16 patients treated at our institution with the sequential use of radiation "sandwiched" between paclitaxel/platinum chemotherapy found only one patient to have recurred at 16 months with a median follow-up of 15 months (range 6-33 months). The regimen was well tolerated. Eight of the sixteen patients (50%) developed grade 3 neutropenia following cycle 4 of chemotherapy, two of which required a 1 week treatment delay. There were no cases of grade 3 or 4 thrombocytopenia noted. There was no febrile neutropenia and no hospital admissions for toxicity. There were no observed grade 3 or 4 non-hematologic toxicities. With the median follow up of 15 months, we have not observed late toxicities.

Given these favorable preliminary findings, supported by recently published data documenting efficacy of the "sandwich" multimodality technique in other difficult uterine malignancies (malignant mixed mullerian tumors), we propose to study this combination of chemotherapy and radiation prospectively. Our aim is to better evaluate patterns of recurrence and possible benefits in progression-free and overall survival.

Uterine papillary serous carcinoma (UPSC) is an uncommon, but aggressive variant of endometrial carcinoma that has a high recurrence rate and poor response to therapy. It has a propensity to metastasize throughout the abdomen, similar to serous carcinoma of the ovary. In fact, many patients with disease apparently confined to the uterus have microscopic intra-abdominal spread at the time of diagnosis. Recurrences are common both in the pelvis as well as in the upper abdomen.

After staging and debulking of gross disease, adjuvant radiation therapy is recommended to treat patients with endometrial carcinoma at high risk for recurrent disease. High-risk features include histologic cell type, grade, depth of myometrial invasion, cervical extension, lymph-vascular invasion, adnexal involvement, intraperitoneal spread, positive peritoneal cytology, and positive lymph nodes. Pelvic radiation can limit local recurrences to less than 6.5%. However, approximately 25-30% of patients with high-risk features who receive radiation recur with distant metastases. Even patients treated with whole abdominal irradiation are at risk for extra-abdominal recurrences with progression-free intervals of 7 to 8 months.

Adjuvant chemotherapeutic regimens have been studied in high-risk endometrial cancers, but none have demonstrated a survival advantage. Doxorubicin, in combination with platinum, has a reported 42% response rate, but a high toxicity profile. Paclitaxel has an overall response rate of 36% in patients with advanced and recurrent endometrial cancer. Platinum-based chemotherapies have a 28-42% response rate.

Retrospective studies in patients with UPSC have demonstrated response rates of up to 35% in patients with multiagent chemotherapy. In one study, a median progression-free interval of 30 months was observed in patients treated with paclitaxel and platinum in the adjuvant and recurrent settings. Based on these findings and the similarities and clinical success of paclitaxel/platinum therapy in patients with ovarian serous carcinoma, this combination warrants further investigation in a prospective manner in patients with UPSC.

Combination chemo/radiotherapy trials in advanced/recurrent endometrial cancer are ongoing. The optimal radiation modality, chemotherapeutic agents, and sequence of these regimens for the treatment of UPSC are yet to be established. A retrospective review of 16 patients treated at our institution with the sequential use of radiation "sandwiched" between paclitaxel/platinum chemotherapy found only one patient to have recurred at 16 months with a median follow-up of 15 months (range 6-33 months). The regimen was well tolerated. Eight of the sixteen patients (50%) developed grade 3 neutropenia following cycle 4 of chemotherapy, two of which required a 1 week treatment delay. There were no cases of grade 3 or 4 thrombocytopenia noted. There was no febrile neutropenia and no hospital admissions for toxicity. There were no observed grade 3 or 4 non-hematologic toxicities. With the median follow up of 15 months, we have not observed late toxicities.

Given these favorable preliminary findings, supported by recently published data documenting efficacy of the "sandwich" multimodality technique in other difficult uterine malignancies (malignant mixed mullerian tumors), we propose to study this combination of chemotherapy and radiation prospectively. Our aim is to better evaluate patterns of recurrence and possible benefits in progression-free and overall survival.

Surrogate endpoint biomarkers such as ER/PR, HER2/Neu and p53 will be correlated with prognosis. In addition, fresh frozen tissue will be banked for future cDNA microarray analyses of UPSC tumors.

A Study of Radiation Therapy and Paclitaxel and Carboplatin in Patients With Uterine Papillary Serous Carcinoma

A Pilot Phase II Trial of Radiation Therapy "Sandwiched" Between Paclitaxel and Carboplatin in Patients With Uterine Papillary Serous Carcinoma

Overall survival analysis of early stage (stage 1 \& 2) and late stage (stage 3 \& 4)UPSC patients who were prescribed radiation "sanwhiched" between three cycles of paclitaxel/platinum chemotherapy before and after RT. Outcome measures were Progression Free Survival (PFS) and Overall Survival (OS).

Montefiore Medical Center

Attending

There is no difference in the reporting of adverse events. Adverse even data is not available. Only the toxicity data are available.

Drug:Carboplatin and Paclitaxel and Radiation: Pelvic Radiation Therapy

Carboplatin and Paclitaxel and Pelvic Radiation Therapy : Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=6.5) Repeat q 21 days x 3 cycles followed by RT followed by Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=5.0)Repeat q 21 days x 3 cycles

Note: The original PI has left the institution, therefore Dr. Kuo inherited the study. Efforts were made to contact the PI/study team members to locate the raw data, but were unsuccessful. No AE data are available at this time.

Carboplatin & Paclitaxel & Radiation: Pelvic Radiation Therapy

Drug:Carboplatin and Paclitaxel and Radiation: Pelvic Radiation Therapy

Carboplatin and Paclitaxel and Pelvic Radiation Therapy : Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=6.5) Repeat q 21 days x 3 cycles followed by RT followed by Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=5.0)Repeat q 21 days x 3 cycles

Carboplatin and Paclitaxel and Radiation Therapy : Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=6.5) Repeat q 21 days x 3 cycles followed by RT followed by Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=5.0)Repeat q 21 days x 3 cycles

Drug:Carboplatin, Paclitaxel & Radiation

We considered 72 patients as baseline participants because they are the ones who completed the first three cycles of chemotherapy followed by at least partial RT. Of the 72 patients, 65 of them completed all prescribed regimen of treatment. This was the reason for the discrepancy.

There are minor differences in the carboplatin doses between the current trial and our pilot study.

This is a single institution trial. A limited number of advanced stage patients was accrued.

Dr. Dennis Yi-Shin Kuo

Early stage (PFS)

Late stage (PFS)

Early stage (OS)

Late stage (OS)

Drug:Carboplatin and Paclitaxel and Radiation: Pelvic Radiation Therapy

Carboplatin and Paclitaxel and Pelvic Radiation Therapy: Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=6.5) Repeat q 21 days x 3 cycles followed by RT followed by Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=5.0)Repeat q 21 days x 3 cycles

Carboplatin and Paclitaxel and Radiation Therapy: Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=6.5) Repeat q 21 days x 3 cycles followed by RT followed by Paclitaxel 175 mg/m2/3 hour \& Carboplatin (AUC=5.0)Repeat q 21 days x 3 cycles

Kaplan-Meier survival analysis of Progression Free Survival (PFS) and Overall Survival (OS).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of INCB123667 in Subjects With Advanced Solid Tumors	NCT05238922	Solid Tumors	INCB0123667	18 Years -	Incyte Corporation
A Pilot Study of Celecoxib in Patients With Grade 2 or 3 Uterine Cancers	NCT00231829	Uterine Cancer	Celecoxib	18 Years -	Montefiore Medical Center
Study of INCB123667 in Subjects With Advanced Solid Tumors	NCT05238922	Solid Tumors	INCB0123667	18 Years -	Incyte Corporation
Gleevec/Taxol for Patients With Uterine Papillary Serous Carcinoma	NCT00506779	Uterine Cancer	Imatinib Mesyla... Paclitaxel	-	M.D. Anderson Cancer Center
Study of INCB123667 in Subjects With Advanced Solid Tumors	NCT05238922	Solid Tumors	INCB0123667	18 Years -	Incyte Corporation
A Study of Radiation Therapy and Paclitaxel and Carboplatin in Patients With Uterine Papillary Serous Carcinoma	NCT00231868	Uterine Cancer	Carboplatin and... Carboplatin and... Carboplatin and...	18 Years -	Montefiore Medical Center
A Pilot Study of Celecoxib in Patients With Grade 2 or 3 Uterine Cancers	NCT00231829	Uterine Cancer	Celecoxib	18 Years -	Montefiore Medical Center

Spots Global Cancer Trial Database for uterine papillary serous carcinoma