Temsirolimus, Carboplatin, and Paclitaxel as First-Line Therapy in Treating Patients With Newly Diagnosed Stage III-IV Clear Cell Ovarian Cancer

Stage IV Ovarian Cancer Clinical Trial

Official title:

A Phase II Evaluation of Temsirolimus (CCI-779) (NCI Supplied Agent: NSC# 683864,) in Combination With Carboplatin and Paclitaxel Followed by Temsirolimus Consolidation as First-Line Therapy in the Treatment of Clear Cell Carcinoma of the Ovary

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01196429
• Other study ID #: NCI-2011-02653
• Secondary ID: NCI-2011-02653CD
• Status: Completed
• Phase: Phase 2
• Start date: August 2010
• Est. completion date: January 2015

Study information

• Verified date: August 2019
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well temsirolimus, carboplatin, and paclitaxel as first-line therapy works in treating patients with newly diagnosed stage III-IV clear cell ovarian cancer. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving temsirolimus with combination chemotherapy may be an effective treatment for ovarian cancer.

Description:

PRIMARY OBJECTIVES:

I. To assess the activity of the study regimen as measured by the proportion of patients who are alive and progression-free for at least 12 months after study entry in patients with newly diagnosed stage III or IV clear cell ovarian cancer in the following populations: patients in the United States (U.S.) and worldwide (outside of Japan) and patients in Japan.

II. To compare progression-free survival in newly diagnosed stage III or IV clear cell ovarian cancer patients in patients in the U.S. and worldwide (outside of Japan) versus patients in Japan.

SECONDARY OBJECTIVES:

I. To characterize the duration of overall survival and progression-free survival in each population.

II. To examine the frequency and severity of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4 in each population.

III. To estimate the rate of objective tumor response in patients with measurable disease.

TERTIARY OBJECTIVES:

I. To explore whether immunohistochemical (IHC) expression of components of the mammalian target of rapamycin (mTOR) signaling pathway (phosphatase and tensin homolog [PTEN], total and phosphorylated protein kinase B [Akt], as well as, ATP-binding cassette, sub-family C [CFTR/MRP], member 3 [ABCC3] [MRP3], ATPase, H+ transporting, lysosomal accessory protein 1 [AB CF2], cyclin E, and vascular endothelial growth factor [VEGF]) are associated with outcome, nationality or clinical characteristics.

II. To explore whether there is any differences in differential gene expression profiles between U.S. and worldwide (outside of Japan) versus Japanese patients.

OUTLINE:

Patients receive paclitaxel* intravenously (IV) over 3 hours and carboplatin IV over 30 minutes on day 1 and temsirolimus IV on days 1 and 8. Treatment repeats every 3 weeks for 6 courses. Patients then receive consolidation therapy comprising temsirolimus IV on days 1, 8, and 15. Treatment repeats every 3 weeks for 11 courses in the absence of disease progression or unacceptable toxicity.

NOTE: * For circumstances in which docetaxel should be substituted for paclitaxel, docetaxel is given IV over 1 hour.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have stage III or IV clear cell ovarian cancer; primary tumors must be at least 50% clear cell histomorphology in order to be eligible; in addition, the tumors should be negative for expression of Wilms tumor 1 (WT-1) antigen and estrogen receptor (ER) antigen by immunohistochemistry; appropriate tissue sections to confirm stage and histologic classification of cell type must be sent to Gynecologic Oncology Group (GOG) for central pathology review; immunohistochemical stained slides for ER and WT-1 antigen must be also be submitted to GOG for pathology review

• Patients who have met the pre-entry requirements

• Patients must have signed an approved informed consent and authorization permitting release of personal health information

• Patients with a GOG performance status of 0, 1, or 2

• Patients must be entered between 2 and 12 weeks after initial surgery; performed for the combined purpose of diagnosis, staging and cytoreduction

• Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection [UTI])

• Absolute neutrophil count >= 1,500/mcl

• Platelets >= 100,000/mcl

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 times institutional upper limit of normal (< 5 times upper limit of normal [ULN] for subjects with liver metastases)

• Alkaline phosphatase =< 2.5 times institutional upper limit of normal (< 5 times ULN for subjects with liver metastases)

• Creatinine =< 1.5 x institutional upper limit of normal, grade 1 per CTCAE v. 4.0

• Cholesterol =< 350 mg/dL (fasting)

• Triglycerides =< 400 mg/dL (fasting)

• Albumin >= 3.0 g/dL

• Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of venous thrombosis including pulmonary thrombo-embolus)

• Partial thromboplastin time (PTT) < 1.2 times the upper limit of normal

• Neurologic function (sensory and motor) =< CTCAE grade 1

Exclusion Criteria:

• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy

• 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 five 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 including neo-adjuvant chemotherapy for their clear cell ovarian cancer

• Patients with primary peritoneal and fallopian tube carcinoma are not eligible

• Previous treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus), paclitaxel, or carboplatin

• Patients cannot be receiving enzyme-inducing antiepileptic drugs (enzyme-inducing antiepileptic drugs [EIAEDs]; e.g., phenytoin, carbamazepine, phenobarbital) nor any other cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer such as rifampin or St. John's Wort; use of agents that potently inhibit CYP3A4 (and hence may raise temsirolimus levels), such as ketoconazole, is discouraged, but not specifically prohibited; the appropriateness of use of such agents is left to physician discretion; strong CYP3A4 inhibitors are prohibited

• Patients receiving any investigational agents

• Patients with severely impaired lung function defined as a diffusion lung capacity for carbon monoxide (DLCO) =< 50% of the normal predicted value and/or oxygen (O2) saturation =< 88% at rest on room air

• Patients with symptomatic congestive heart failure of New York Heart Association class III or IV, unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant disease

• Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels

• Patients on maintenance corticosteroids are ineligible with the exception of short term use (fewer than 5 days)

• Patients with baseline requirement for oxygen

• Patients with serious concomitant illness which, in the opinion of the treating physician, will place patient at unreasonable risk from therapy on this protocol

• Patients who are pregnant or nursing; patients of childbearing potential must agree to use contraceptive measures during study therapy and for at least six months after completion of study therapies

• Patients with poorly controlled diabetes

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Cystadenocarcinoma
• Ovarian Clear Cell Cystadenocarcinoma
• Ovarian Neoplasms
• Stage III Ovarian Cancer
• Stage IV Ovarian Cancer

Intervention

Drug:
• Carboplatin
Given IV
• Docetaxel
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Paclitaxel
Given IV
• Temsirolimus
Given IV

Locations

Country	Name	City	State
Japan	Hyogo Cancer Center	Akashi-city	Hyogo
Japan	Kagoshima City Hospital	Kagoshima City	Kagoshima
Japan	Kure National Hospital	Kure	Hiroshima
Japan	Shikoku Cancer Center	Matsuyama
Japan	National Kyushu Cancer Center	Minami-ku
Japan	Jikei University School of Medicine	Minato-ku, Tokyo
Japan	Iwate Medical University School of Medicine	Morioka	Iwate
Japan	University of the Ryukyus Hospital-Col Health Scnc	Nakagami-gun	Okinawa
Japan	Niigata University Medical and Dental Hospital	Niigata City	Niigata
Japan	Kinki University	Osaka, Osaka
Japan	Saitama Medical University International Medical Center	Saitama
Japan	Hokkaido University Hospital	Sapporo	Hokkaido
Japan	Tohoku University School of Medicine	Sendai	Aoba-ku
Japan	Keio University	Shinjuku-ku	Tokyo
Japan	Shizuoka Cancer Center	Shizuoka City	Suntou
Japan	National Cancer Center Hospital	Tokyo
Japan	Tottori University	Tottori
Korea, Republic of	National Cancer Center-Korea	Goyang-si	Gyeonggi-do
Korea, Republic of	Keimyung University-Dongsan Medical Center	Jung-Ku	Daegu
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Gangnam Severance Hospital	Seoul
Korea, Republic of	Korea Cancer Center Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul	Korea
Korea, Republic of	Seoul National University Hospital	Seoul
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio
United States	Michigan Cancer Research Consortium CCOP	Ann Arbor	Michigan
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado
United States	PeaceHealth Medical Group PC	Bellingham	Washington
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington
United States	Harrison Medical Center	Bremerton	Washington
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	Cooper Hospital University Medical Center	Camden	New Jersey
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Oakwood Hospital and Medical Center	Dearborn	Michigan
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Iowa Oncology Research Association CCOP	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Elkhart Clinic	Elkhart	Indiana
United States	Elkhart General Hospital	Elkhart	Indiana
United States	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Hurley Medical Center	Flint	Michigan
United States	Genesys Regional Medical Center	Grand Blanc	Michigan
United States	Gynecologic Oncology of West Michigan PLLC	Grand Rapids	Michigan
United States	Hartford Hospital	Hartford	Connecticut
United States	Saint Francis Hospital and Medical Center	Hartford	Connecticut
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Sudarshan K Sharma MD Limted-Gynecologic Oncology	Hinsdale	Illinois
United States	M D Anderson Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center CCOP Research Base	Houston	Texas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Saint Vincent Oncology Center	Indianapolis	Indiana
United States	Allegiance Health	Jackson	Michigan
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Mercy Hospital-Joplin	Joplin	Missouri
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Kettering Medical Center	Kettering	Ohio
United States	Community Howard Regional Health	Kokomo	Indiana
United States	IU Health La Porte Hospital	La Porte	Indiana
United States	Sparrow Hospital	Lansing	Michigan
United States	Women's Cancer Center of Nevada	Las Vegas	Nevada
United States	Saint Mary Mercy Hospital	Livonia	Michigan
United States	Los Angeles County-USC Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Lake University Ireland Cancer Center	Mentor	Ohio
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Winthrop University Hospital	Mineola	New York
United States	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana
United States	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Skagit Valley Hospital Regional Cancer Care Center	Mount Vernon	Washington
United States	Palo Alto Medical Foundation-Gynecologic Oncology	Mountain View	California
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	Michiana Hematology Oncology PC-Niles	Niles	Michigan
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Walter Reed Army Medical Center-Olney	Olney	Maryland
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Florida Hospital Orlando	Orlando	Florida
United States	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Saint Joseph Mercy Port Huron	Port Huron	Michigan
United States	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Saint Mary's of Michigan	Saginaw	Michigan
United States	Lakeland Hospital	Saint Joseph	Michigan
United States	Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Memorial University Medical Center	Savannah	Georgia
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Group Health Cooperative-Seattle	Seattle	Washington
United States	Northwest Hospital	Seattle	Washington
United States	Pacific Gynecology Specialists	Seattle	Washington
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Olympic Medical Cancer Care Center	Sequim	Washington
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana
United States	Northern Indiana Cancer Research Consortium CCOP	South Bend	Indiana
United States	South Bend Clinic	South Bend	Indiana
United States	Cancer Care Northwest - Spokane South	Spokane	Washington
United States	Rockwood Cancer Treatment Center-DHEC-Downtown	Spokane	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Cancer Research for the Ozarks NCORP	Springfield	Missouri
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	MultiCare Tacoma General Hospital	Tacoma	Washington
United States	Saint Joseph Medical Center	Tacoma	Washington
United States	Tulsa Cancer Institute	Tulsa	Oklahoma
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Cadence Cancer Center in Warrenville	Warrenville	Illinois
United States	Wenatchee Valley Hospital and Clinics	Wenatchee	Washington
United States	Michiana Hematology Oncology PC-Westville	Westville	Indiana
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Countries where clinical trial is conducted

United States,  Japan,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Patients Who Are Alive and Progression-free for at Least 12 Months After Study Entry in Patients With Newly Diagnosed Stage III or IV Clear Cell Ovarian Cancer in the Following Populations: Patients in the U.S./Worldwide and Japan	Progression of target lesions (TL) was a >=20% increase in the sum of the diameters of TL, taking as reference the smallest sum on study (including the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must demonstrate an absolute increase >=5 mm. Progression of non-target lesions (NTL) as defined as appearance of >=1 new lesions or unequivocal progression of existing NTL. Unequivocal progression should not normally trump target lesion status; it must be representative of overall disease status change, not a single lesion increase. Clear progression of only NTL is exceptional, but the opinion of the treating physician should prevail in such circumstances, and the progression status should be later confirmed by a review panel (or Principal Investigator). Progression of TL, unequivocal progression of NTL, or new lesions constitutes progression. This description is abbreviated; see the RECIST 1.1 manuscript for further details.	Tumor scans were done every other cycle for the first 6 months; then every 3 months x2; then every 6 months thereafter; and at any other time if clinically indicated or signs suggestive of progressive disease or rising levels; for up to 5 years.
Primary	Compare Progression-free Survival in Newly Diagnosed Stage III or IV Clear Cell Ovarian Cancer Patients in Patients in the U.S. and Worldwide (Outside of Japan) Versus Patients in Japan.	Progression-free survival (PFS) was defined s the period from study entry until disease progression, death, or the last date of contact. Progression was based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Outcome measure data not reported because protocol stated "If the combination is declared active (i.e. HO is rejected) in one or both of the populations, the two populations will be compared with respect to PFS using a logrank test stratified by optimal/suboptimal disease status." The combination was not declared active in either population.	Tumor scans were done every other cycle for the first 6 months;then every 3 mnths x2;then every 6 mnths thereafter; and at any other time if clinically indicated based on symptoms or physical signs suggesting progressive dx or rising serum tumor marker le
Primary	Frequency and Severity of Toxicity	Grade 3 or higher adverse events were graded by CTC AE v4	Each cycle while on treatment
Secondary	Progression-free Survival	Progression-free survival (PFS) was defined as the period from study entry until disease progression, death, or the last date of contact. Progression was based on RECIST 1.1	Tumor scans were done every other cycle for the first 6 months; then every 3 months x 2; then every 6 mths thereafter; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease or rising tumor mark
Secondary	Overall Survival	Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.	Every cycle during treatment, then every 3 months for the first 2 years, then every six months for the next three years and then annually for the next 5 years.
Secondary	Objective Tumor Response	Complete and Partial Tumor Response by RECIST 1.1. RECIST1.1 is a multi-page paper, and response is defined in the protocol across multiple pages, so it is not practical to define response here.	Every other cycle for first 6 months; then every 3 months for two years; then every six months for the next three years; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease or rising serum tu