Official Title: “A Phase II Trial of Temsirolimus and Bevacizumab in Patients With Endometrial, Ovarian, Hepatocellular Carcinoma, Carcinoid and Islet Cell Cancer”

RATIONALE: Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving temsirolimus together with bevacizumab may kill more tumor cells.

PURPOSE: This phase II trial is studying the side effects of giving temsirolimus together with bevacizumab and to see how well it works in treating patients with locally advanced, recurrent, metastatic, or progressive endometrial cancer, ovarian epithelial cancer, liver cancer, islet cell cancer, or carcinoid tumor.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: December 2012

OBJECTIVES:

Primary - 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. - To determine the toxicity of this regimen in these patients.

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

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.

Intervention(s) in this Clinical Trial

• Biological: bevacizumab
• Drug: temsirolimus
• Other: laboratory biomarker analysis

Primary Measures

• Tumor response rate as assessed by RECIST criteria
  • Safety Issue?: No
• 6-month progression-free survival rate
  • Safety Issue?: No

Secondary Measures

• Overall survival
  • Safety Issue?: No
• Duration of response
  • Safety Issue?: No
• Time to disease progression
  • Safety Issue?: No
• Time to treatment failure
  • Safety Issue?: No

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 (neuroendocrine) cancer
• On a stable dose of octreotide for ≥ 2 months before study entry
• Ovarian epithelial cancer, meeting the following criteria:
• Serous, endometrioid, mixed, or poorly differentiated histology
• No evidence of free abdominal air not explained by paracentesis or recent surgical procedures
• Locally advanced, recurrent, metastatic, or progressive 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

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 75,000/mm^3
• Hemoglobin ≥ 9.0 g/dL
• Direct 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 < 1+ by urinalysis or dipstick OR urine protein < 1,000 mg 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 correlative marker 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 ongoing hemoptysis
• No 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 cerebrovascular accident within the past 6 months
• No peripheral vascular disease with claudication on < 1 block
• 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 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.

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from prior localized therapy (for patients with HCC)
• No prior VEGF or VEGFR-targeting agents 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 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
• No concurrent major surgical procedures
• No concurrent radiotherapy
• No concurrent angiotensin-converting enzyme (ACE) inhibitors (alternate antihypertensives allowed)
• No concurrent CYP3A4 inhibitors or inducers
• Concurrent full-dose anticoagulants allowed 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Mayo Clinic

Overall Clinical Trial Officials and Contacts

Charles Erlichman, MD Principal Investigator Mayo Clinic  

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01010126

Study ID Number: CDR0000653790

ClinicalTrials.gov Identifier: NCT01010126

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database