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Transitional Cell Carcinoma

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Patients receive dalantercept SC on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Dalantercept

Laboratory Biomarker Analysis

Vicky Makker

This phase II trial studies how well dalantercept works in treating patients with endometrial cancer that has come back or is persistent. Dalantercept may stop the growth of endometrial cancer by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. To estimate the proportion of patients with persistent or recurrent endometrial cancer who survive progression-free for at least 6 months and the proportion of patients who have objective tumor response (complete or partial), treated with dalantercept (ACE-041).

II. To determine the nature and degree of toxicity of dalantercept in this cohort of patients.

SECONDARY OBJECTIVES:

I. To estimate progression-free survival (PFS) and overall survival (OS) of patients with persistent or recurrent endometrial cancer treated with dalantercept.

TERTIARY OBJECTIVES:

I. To measure the expression of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), activin receptor-like kinase 1 (ALK1), endoglin (CD105), and other markers via immunohistochemistry (IHC) and determine if there is correlation between expression and clinical response to treatment.

II. To determine the correlation between ALK1 gene expression, other markers, and clinical response to treatment.

III. To determine the correlation between concentration of VEGF, bone morphogenetic protein 9 (BMP9), bone morphogenetic protein 10 (BMP10), and ALK1 in pre-cycle 1 plasma using an enzyme-linked immunosorbent assay (ELISA), and clinical response to treatment.

IV. To correlate somatic mutations in candidate genes with response to therapy.

OUTLINE:

Patients receive dalantercept subcutaneously (SC) on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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

Dalantercept in Treating Patients With Recurrent or Persistent Endometrial Cancer

A Phase II Evaluation of Dalantercept, a Novel Soluble Recombinant Activin Receptor-Like Kinase 1 (ALK-1) Inhibitor Receptor-Fusion Protein, in the Treatment of Recurrent or Persistent Endometrial Carcinoma

Response was defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and based on imaging done every other cycle. Responses can be either partial or complete. Per RECIST v1.1 target and non-target lesions are assessed by MRI or CT scan: Complete Response (CR), Disappearance of all target and non-target lesions and all lymph nodes must be \< 10 mm in short axis; Partial Response (PR), \>=30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD.

Treatment and Progression-free Survival is defined as the duration alive from study entry until progression is documented, death or non-protocol treatment is initiated; whichever comes sooner. Progressive disease is defined as at least a 5 mm absolute increase and a 20% relative increase in the sum of measurable target lesions' longest dimensions relative to the smallest sum at baseline or on study or the appearance of new lesions or unequivocal progression of existing non-target lesions.

Non-protocol treatment initiation prior to disease progression and prior to 6 months from study entry was counted as an event for treatment and progression-free survival at 6 months. Disease progression within 6 months of study entry or death within 6 months of study entry and prior to disease progression counts as an event for treatment and progression-free survival at 6 months.

Progression-free survival is defined as the duration alive from study entry until progression is documented or death, whichever comes sooner. Progressive disease is defined as at least a 5 mm absolute increase and a 20% relative increase in the sum of measurable target lesions' longest dimensions relative to the smallest sum at baseline or on study or the appearance of new lesions or unequivocal progression of existing non-target lesions.

Disease progression within 6 months of study entry or death within 6 months of study entry and prior to disease progression counts as an event for progression-free survival at 6 months.

Progression-free survival is defined as the duration alive from study entry until progression is documented or death, whichever comes sooner. Progressive disease is defined as at least a 5 mm absolute increase and a 20% relative increase in the sum of measurable target lesions' longest dimensions relative to the smallest sum at baseline or on study or the appearance of new lesions or unequivocal progression of existing non-target lesions.

Duration of survival is defined as the duration alive from study entry until death or last contact.

The frequencies of the maximum grade of any acute adverse event, regardless of attribution are reported during treatment and up to 30 days after stopping the study treatment are reported.

National Cancer Institute (NCI)

Gynecologic Oncology Group

The frequencies of the maximum grade of any serious adverse event or all other adverse events by category or specific term occurring during treatment and up to 30 days after stopping the study treatment are reported

Dalantercept 1.2 mg/kg (maximum starting dose of 120 mg) subcutaneously once every three weeks. One cycle is defined as three weeks.

Patients weighing more than 100 kg start treatment at 120 mg, and if dalantercept is tolerated for 2 cycles (i.e. toxicities are tolerable, less than grade 2 and resolved), the patient can be dose escalated to dosing based on actual body weight.

A CT of the chest, abdomen and pelvis to assess response by RECIST 1.1 is required every two cycles. Treatment was to continue until disease progression or adverse effects prohibit further therapy.

Patients receive dalantercept SC on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Dalantercept: Given SC

Laboratory Biomarker Analysis: Correlative studies

Treatment (Dalantercept)

40-49

50-59

60-69

70-79

Age, Customized

Sex: Female, Male

United States

Region of Enrollment

Linda Gedeon, BA, CCRP Clinical Research Coordinator

Response

Treatment and Progression-free Survival at 6 Months

Progression-free Survival at 6 Months

Duration of Progression-free Survival

Duration of Survival

Anemia

Abdominal Distention

Abdominal Pain

Ascites

Constipation

Diarrhea

Gastric Hemorrhage

Nausea

Rectal Fistula

Rectal Hemorrhage

Vomiting

Edema Face

Edema Limbs

Fatigue

Prolonged activated partial thromboplastin time

Alkaline Phosphatase Increased

Creatinine Increased

Lymphocyte Count Decreased

Weight Loss

Anorexia

Dehydration

Hyperglycemia

Hypoalbuminemia

Hypoglycemia

Hypokalemia

Arthralgia

Back Pain

Myalgia

Dizziness

Headache

Neuralgia

Urinary Tract Obstruction

Dyspnea

Epistaxis

Pleural Effusion

Hypertension

Thromboembolic Event

Number of patients who did not experience the specified AE.

Grade 0

Number of patients who experienced a grade 1 event using Common Terminology Criteria version 4.0

Grade 1 (CTCAE v4.0)

Number of patients who experienced a grade 2 event using Common Terminology Criteria version 4.0

Grade 2 (CTCAE v4.0)

Number of patients who experienced a grade 3 event using Common Terminology version 4.0

Grade 3 (CTCAE v 4.0)

Number of patients who experienced a grade 4 event using Common Terminology Criteria version 4.0

Grade 4 (CTCAE v 4.0)

Number of patients who experienced a grade 5 event using Common Terminology Criteria version 4.0

Grade 5 (CTCAE v 4.0)

Adverse Events (Primary Serious and All Other AEs)

Overall Study

Amino Acids

Mitogens

Tyrosine Kinase Inhibitors

Tyrosine

Patients receive brivanib alaninate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Brivanib Alaninate

Matthew Powell

This phase II trial is studying how well brivanib alaninate works in treating patients with endometrial cancer that has come back (recurred) or is persistent. Brivanib alaninate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. To assess the activity of brivanib (brivanib alaninate) for patients with recurrent or persistent endometrial cancer with the frequency of patients who survive progression-free for at least 6 months after initiating therapy or have objective tumor response..

SECONDARY OBJECTIVES:

I. To determine the duration of progression-free survival and overall survival. II. To determine the nature and degree of toxicity of brivanib as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)3.0 in this cohort of patients.

TERTIARY OBJECTIVES:

I. To determine whether activating mutations in fibroblast growth factor receptor 2 (FGFR2) are associated with progression-free survival status \> 6 months following brivanib treatment, objective tumor response following brivanib treatment, or endometrioid histology.

II. To explore the associations between select biomarkers and response to brivanib (progression-free survival status \> 6 months and objective tumor response), measures of clinical outcome (progression-free survival and overall survival) or disease status including histologic cell type: i) mutations in FGFR2 or phosphatase and tensin homolog (PTEN) in deoxyribonucleic acid (DNA) from formalin-fixed and paraffin-embedded (FFPE) tumor or normal blood cells; ii) immunohistochemical (IHC) expression of the FGFR family and ligands, steroid receptor isoforms or phosphorylated (p) v-akt murine thymoma viral oncogene homolog 1 (AKT) in FFPE tumor; iii) concentration or the change in the concentration of vascular endothelial growth factor (VEGF) or type IV collagen in pre-cycle 1, pre-cycle 2 and/or pre-cycle 3 plasma.

III. To explore the relationship among the panel of biomarkers evaluated in this cohort: i) mutations in FGFR2 or PTEN; ii) IHC expression of the FGFR family and ligands, steroid receptor isoforms or pAKT; iii) concentration or the change in the concentration of VEGF or type IV collagen.

OUTLINE:

Patients receive brivanib alaninate orally (PO) once daily (QD) on days 1-28. 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 2 years and then every 6 months for 3 years.

Brivanib Alaninate in Treating Patients With Recurrent or Persistent Endometrial Cancer

A Phase II Evaluation of Brivanib (BMS582664), an Oral, Multitargeted Growth Factor Tyrosine Kinase Inhibitor in the Treatment of Recurrent or Persistent Endometrial Carcinoma

Will be correlated with clinical measures of outcome such as tumor response, progression-free survival (PFS), and endometrioid histology.

Will be correlated with PFS, OS, tumor response, and histologic cell type.

Will be correlated with PFS, overall survival (OS), tumor response, and histologic cell type.

Whether or not the patient survived progression-free for at least 6 months.

Per response evaluation criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>= 30 % decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR.

Characterized graphically with Kaplan-Meier estimates and using descriptive statistics. The effect of cell type (type I versus type II endometrial cancers) on overall survival will be examined.

Characterized graphically with Kaplan-Meier estimates and using descriptive statistics. The effect of cell type (type I versus type II endometrial cancers) on progression-free survival will be examined.

Brivanib 800 mg orally every day (one cycle = 28 days) until disease progression or adverse effects prohibit further therapy.

Brivanib

Age, Continuous

20-29 years

30-39 years

40-49 years

50-59 years

60-69 years

70-79 years

80-89 years

Linda Gedeon For Michael Sill, PhD.

Progression-free Survival > 6 Months

Tumor Response

Duration of Overall Survival

Leukopenia

Cardiac

Coagulation

Constitutional

Dermatologic

Gastrointestinal

Genitourinary/Renal

Infection

Lymphatics

Metabolic

Musculoskeletal

Other Neurological

Pain

Vascular

Death, Not CTC coded

Severity of Adverse Events as Assessed by CTCAE v3.0 Criteria

Activating Mutation in FGFR2

Change in Concentration of VEGF and Type IV Collagen

IHC Expression of FGFR Family and Ligands, Steroid Receptor Isoforms, and pAKT

Mutations in FGFR2 and PTEN

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma, Adenosquamous

Endometrial Neoplasms

Uterine Neoplasms

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

Adenosquamous Carcinoma of the Endometrium

Antineoplastic Agents

Anti-Infective Agents

Paclitaxel

Albumin-Bound Paclitaxel

Doxorubicin

Liposomal doxorubicin

Cisplatin

Lenograstim

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Patients receive doxorubicin hydrochloride IV over 30 minutes followed by cisplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on day 2, and filgrastim SC on days 3-12 or pegfilgrastim SC on day 3. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Patients then receive doxorubicin hydrochloride IV and cisplatin IV or IP on day 1, and paclitaxel IP on days 1 or 8. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Doxorubicin Hydrochloride

Filgrastim

Pegfilgrastim

D. McMeekin

This phase I trial studies the side effects and best dose of intraperitoneal paclitaxel when given together with doxorubicin hydrochloride and cisplatin in treating patients with stage III-IV endometrial cancer. Drugs used in chemotherapy, such as paclitaxel, doxorubicin hydrochloride, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving them in different ways may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of intraperitoneal (IP) paclitaxel when given concurrently with fixed dose intravenous (IV) doxorubicin (doxorubicin hydrochloride) and IV cisplatin.

II. To determine the maximum tolerated dose of IP paclitaxel when given concurrently with fixed dose IV doxorubicin hydrochloride and IP cisplatin.

III. To determine the feasibility of an IV/IP based doxorubicin hydrochloride, paclitaxel, and cisplatin chemotherapy regimen in patients with advanced endometrial cancer.

OUTLINE: This is a dose-escalation study of paclitaxel.

Patients receive doxorubicin hydrochloride IV over 30 minutes followed by cisplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on day 2, and filgrastim subcutaneously (SC) on days 3-12 or pegfilgrastim SC on day 3. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Patients then receive doxorubicin hydrochloride IV and cisplatin IV or IP on day 1, and paclitaxel IP on days 1 or 8. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Intraperitoneal Paclitaxel, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Stage III-IV Endometrial Cancer

A Phase I Study of IV Doxorubicin Plus Intraperitoneal (IP) Paclitaxel and IV or IP Cisplatin in Endometrial Cancer Patients at High Risk for Peritoneal Failure

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dalantercept in Treating Patients With Recurrent or Persistent Endometrial Cancer	NCT01642082	Endometrial Ade... Endometrial Cle... Endometrial Mix... Endometrial Muc... Endometrial Ser... Endometrial Squ... Endometrial Tra... Endometrial Und... Recurrent Uteri...	Dalantercept Laboratory Biom...	18 Years -	GOG Foundation
Brivanib Alaninate in Treating Patients With Recurrent or Persistent Endometrial Cancer	NCT00888173	Endometrial Ade... Endometrial Cle... Endometrial Mix... Endometrial Muc... Endometrial Ser... Endometrial Squ... Endometrial Tra... Endometrial Und... Recurrent Uteri...	Brivanib Alanin... Laboratory Biom...	18 Years -	GOG Foundation
Intraperitoneal Paclitaxel, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Stage III-IV Endometrial Cancer	NCT00575952	Endometrial Ade... Endometrial Cle... Endometrial Mix... Endometrial Ser... Endometrial Squ... Endometrial Und... Recurrent Uteri... Stage IIIA Uter... Stage IIIC Uter... Stage IVA Uteri... Stage IVB Uteri...	Cisplatin Doxorubicin Hyd... Filgrastim Paclitaxel Pegfilgrastim	-	GOG Foundation

Spots Global Cancer Trial Database for endometrial mixed adenocarcinoma