Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Temsirolimus and Bevacizumab in Treating Patients With Locally Advanced, Recurrent, Metastatic, or Progressive Endometrial Cancer, Ovarian Epithelial Cancer, Liver Cancer, Islet Cell Cancer, or Carcinoid Tumor

Basic Trial Information

Special Category: CTSU trial

Objectives

Primary

1. To determine the response rate and progression-free survival at 6 months in patients with locally advanced, recurrent, metastatic, or progressive endometrial cancer, ovarian epithelial cancer, hepatocellular carcinoma, islet cell cancer, or carcinoid tumor treated with temsirolimus and bevacizumab.
2. To determine the toxicity of this regimen in these patients.

Secondary

1. To collect blood and tumor specimens from all patients for possible future laboratory correlative studies.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed diagnosis of 1 of the following:
  • Endometrial cancer (endometrioid only), meeting the following criteria:
    • Recurrent or persistent endometrial adenocarcinoma, uterine papillary serous carcinoma, or carcinosarcoma that is refractory to curative therapy or established treatments
    • Histologic or cytologic confirmation of original primary tumor is required
  • Hepatocellular carcinoma (HCC), meeting the following criteria:
    • Biopsy-confirmed disease OR diagnosed by clinical and radiologic criteria as indicated by all of the following:
      • Known cirrhosis or chronic hepatitis B or C infection
      • Hypervascular liver masses > 2 cm
      • Serum alpha-fetoprotein (AFP) > 400 ng/dL OR AFP > 3 times normal and doubling in value within the past 3 months
    • Liver status: Child-Pugh score A (≤ 6 points) or better
    • Not on an active liver transplant list and considered likely to receive a liver transplant within the next 6 months
  • Carcinoid tumor or islet cell (well-or moderately-differentiated neuroendocrine) cancer
    • On a stable dose of long-acting somatostatin analogue for ≥ 2 months before study entry for patients with carcinoid tumor
    • Stable dose of long-acting somatostatin analogue for ≥ 2 months before study entry for patients with islet cells cancer allowed but not required
  • Ovarian epithelial cancer, meeting the following criteria:
    • Primary peritoneal/fallopian tube, serous, endometrioid, mixed, or poorly differentiated histology
    • No evidence of free abdominal air not explained by paracentesis or recent surgical procedures

• Locally advanced, recurrent, or metastatic disease

• Measurable disease
  • Patients with only lesions measuring ≥ 1 cm to < 2 cm must undergo spiral CT imaging for both pre- and post-treatment tumor assessments
  • Patients who have had prior palliative radiotherapy to metastatic lesion(s) must have ≥ 1 measurable lesion that has not been previously irradiated

• Tissue (from the primary tumor or metastases) available for tumor studies

• No untreated CNS metastases
  • Brain metastases that have been adequately treated are allowed provided there is no evidence of progression or hemorrhage after treatment as ascertained by clinical examination and brain imaging (MRI or CT scan) within the past 12 weeks AND there is no ongoing requirement for steroids
    • Stable doses of anticonvulsants allowed

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior localized therapy (for patients with HCC)
• No prior VEGF or VEGFR-targeting agents (including sorafenib for patients with HCC), or mTOR inhibitors
• More than 3 months since prior surgical resection of CNS metastases or brain biopsy
• More than 4 weeks since prior major surgical procedure or open biopsy
• At least 4 weeks since prior adjuvant or palliative radiotherapy
• More than 7 days since prior core biopsy
• Prior systemic therapy for metastatic disease allowed, including targeted therapies, biologic-response modifiers, chemotherapy, hormonal therapy, or investigational therapy
• No prior chemotherapy for metastatic or recurrent endometrial cancer
• At least 1 week since prior hormonal therapy for endometrial cancer
• At least 3 weeks since prior systemic therapy for endometrial cancer, including biological or immunologic agents as adjuvant therapy
• No prior radiotherapy to any portion of the abdominal cavity or pelvis other than for the treatment of endometrial cancer
• No prior radiotherapy to > 25% of marrow-bearing areas (for patients with endometrial cancer)
• Prior specific therapy (e.g., banding and/or sclerotherapy) for varices allowed provided there has been no bleeding within the past 6 months (for patients with HCC)
• No prior liver transplant with evidence of recurrent or metastatic disease (for patients with HCC)
• At least 4 weeks since prior regional therapy for liver metastasis in patients with HCC (12 weeks for patients with islet cell cancer or carcinoid tumor)*, including any of the following:
  • Selective internal radiotherapy (e.g., brachytherapy, cyberknife, or radiolabeled microsphere embolization)
  • Hepatic artery chemoembolization
  • Hepatic artery embolization
  • Hepatic artery infusional chemotherapy
  • Radiofrequency ablation
• No more than 2 prior cytotoxic chemotherapy regimens for persistent or recurrent ovarian cancer
• No more than 2 prior cytotoxic chemotherapy regimens for islet cell cancer or carcinoid tumor
• At least 4 weeks since prior interferon for islet cell cancer or carcinoid tumor
• Prior radiolabeled octreotide for islet cell cancer or carcinoid tumor allowed
  • Patients should have progressive disease after radiolabeled octreotide
• Prior investigational therapy for islet cell cancer or carcinoid tumor allowed
• At least 2 months since prior and concurrent
• No concurrent major surgical procedures
• No concurrent radiotherapy
• No concurrent angiotensin-converting enzyme (ACE) inhibitors (e.g., benazapril, captopril, enalopril, fosonopril, lisinopril, moexipril, perindopril, quinopril, ramipril, or trandolapril)
  • Alternate antihypertensives allowed
• No concurrent CYP3A4 inhibitors or inducers
• Concurrent full-dose anticoagulants allowed (except for patients with carcinoid tumors) provided the INR is in-range (between 2 and 3) AND patient is on a stable dose of warfarin or low molecular weight heparin
• Concurrent zoledronic acid allowed for patients with bone metastases and/or hypercalcemia provided it was started before initiation of study treatment
• Concurrent antiviral therapy allowed (for patients with HCC)

 [Note: *Patients must show progressive disease in the liver after regional therapy OR have measurable disease outside the liver.]

Patient Characteristics:

• ECOG performance status 0-1
• ANC ≥ 1,500/mm³
• Platelet count ≥ 75,000/mm³
• Hemoglobin ≥ 9.0 g/dL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)*
• Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases or for patients with HCC)
• AST ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases or for patients with HCC)
• Creatinine ≤ 1.5 times ULN
• Urine protein < 2+ by urinalysis or dipstick OR urine protein < 2 g by 24-hour urine collection
• Fasting serum cholesterol ≤ 350 mg/dL
• Triglycerides ≤ 1.5 times ULN (lipid-lowering agents allowed)
• INR ≤ 1.5 (unless receiving full-dose anticoagulants)*
• LVEF normal by MUGA or ECHO within the past 4 weeks (for patients who have had prior anthracyclines)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 3 months after completion of study therapy
• Willing to donate blood for biomarker studies
• No significant traumatic injury within the past 4 weeks
• No serious non-healing wound, ulcer, or bone fracture
• No abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within the past 6 months
• No clinical signs and symptoms of GI obstruction (for patients with ovarian cancer)
• No requirement for parenteral hydration/nutrition or tube feeding (for patients with ovarian cancer)
• No evidence of bleeding diathesis or coagulopathy in the absence of therapeutic anticoagulation
• No evidence of a history of bleeding within the past 6 months, including any of the following:
  • Hemoptysis
  • Cerebrovascular accident within the past 6 months
  • Peripheral vascular disease with claudication on < 1 block
  • History of clinically significant bleeding
• No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
• No hemorrhage ≥ grade 3 within the past 4 weeks (for patients with HCC)
• No significant cardiovascular disease, defined as any of the following:
  • NYHA class II-IV congestive heart failure
  • Angina pectoris requiring nitrate therapy
  • Myocardial infarction within the past 6 months
• No uncontrolled hypertension, defined as systolic BP ≥ 150 mm Hg and/or diastolic BP ≥ 90 mm Hg
• No active infection requiring antibiotics
• No known HIV-positivity
• No currently active second malignancy other than nonmelanoma skin cancer
  • Patients are not considered to have a 'currently active' malignancy if they have completed anticancer therapy and are considered by their physician to be at < 30% risk of relapse
• No known hypersensitivity to other recombinant human antibodies or Chinese hamster ovary cell products
• No other uncontrolled serious medical or psychiatric condition (e.g., cardiac arrhythmias or diabetes)
• No clinical evidence of encephalopathy (for patients with HCC)

 [Note: *Direct bilirubin and INR for patients with HCC may be per Child-Turcotte-Pugh scoring.]

Expected Enrollment

Outcomes

Tumor response rate as assessed by RECIST criteria
6-month progression-free survival rate

Overall survival
Duration of response
Time to disease progression
Time to treatment failure

Outline

This is a multicenter study. Patients are stratified according to type of cancer (endometrial vs ovarian vs hepatocellular vs carcinoid vs islet cell).

Patients receive temsirolimus IV on days 1, 8, 15, and 22 and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood and tumor tissue samples are collected periodically for future biomarker and other laboratory correlative studies.

After completion of study treatment, patients are followed up periodically for up to 3 years.

Trial Contact Information

Trial Lead Organizations

Mayo Clinic Cancer Center

Charles Erlichman, MD, Principal investigator		Ph: 507-284-2511 Email: erlichman.charles@mayo.edu

U.S.A.
Arizona
	Scottsdale
	Mayo Clinic Scottsdale
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
California
	Duarte
	City of Hope Comprehensive Cancer Center
		Clinical Trials Office - City of Hope Comprehensive Cancer Center	Ph:  800-826-4673
			Email: becomingapatient@coh.org
Florida
	Jacksonville
	Mayo Clinic - Jacksonville
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
New York
	Bronx
	Albert Einstein Cancer Center at Albert Einstein College of Medicine
		Clinical Trials Office - Albert Einstein Cancer Center at Albert Einstein College of Medicine	Ph:  718-904-2730
			Email: aecc@aecom.yu.edu
Ohio
	Columbus
	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
		Ohio State University Cancer Clinical Trial Matching Service	Ph:  866-627-7616
			Email: osu@emergingmed.com
Canada
Ontario
	Toronto
	Princess Margaret Hospital
		Jennifer Knox, MD	Ph:  416-946-2399

Registry Information
Official Title		A Phase II Trial of Temsirolimus and Bevacizumab in Patients with Endometrial, Ovarian, Hepatocellular Carcinoma, Carcinoid and Islet Cell Cancer
Trial Start Date		2009-09-08
Trial Completion Date		2012-12-01 (estimated)
Registered in ClinicalTrials.gov		NCT01010126
Date Submitted to PDQ		2009-10-26
Information Last Verified		2012-02-14
NCI Grant/Contract Number		CA15083, CM62205

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