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A Phase II Trial of Temsirolimus and Bevacizumab in Patients With Endometrial, Ovarian, Hepatocellular Carcinoma, Carcinoid or Islet Cell Cancer

Phase 2
18 Years
Open (Enrolling)
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Endometrial Papillary Serous Carcinoma, Localized Unresectable Adult Primary Liver Cancer, Metastatic Gastrointestinal Carcinoid Tumor, Ovarian Carcinosarcoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Mixed Epithelial Carcinoma, Ovarian Papillary Serous Carcinoma, Pancreatic Alpha Cell Adenoma, Pancreatic Alpha Cell Carcinoma, Pancreatic Beta Islet Cell Adenoma, Pancreatic Beta Islet Cell Carcinoma, Pancreatic Delta Cell Adenoma, Pancreatic Delta Cell Carcinoma, Pancreatic G-cell Adenoma, Pancreatic G-cell Carcinoma, Pancreatic Polypeptide Tumor, Pulmonary Carcinoid Tumor, Recurrent Adult Primary Liver Cancer, Recurrent Endometrial Carcinoma, Recurrent Fallopian Tube Cancer, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Islet Cell Carcinoma, Recurrent Ovarian Epithelial Cancer, Recurrent Primary Peritoneal Cavity Cancer, Regional Gastrointestinal Carcinoid Tumor, Stage IIIA Endometrial Carcinoma, Stage IIIA Fallopian Tube Cancer, Stage IIIA Ovarian Epithelial Cancer, Stage IIIA Primary Peritoneal Cavity Cancer, Stage IIIB Endometrial Carcinoma, Stage IIIB Fallopian Tube Cancer, Stage IIIB Ovarian Epithelial Cancer, Stage IIIB Primary Peritoneal Cavity Cancer, Stage IIIC Endometrial Carcinoma, Stage IIIC Fallopian Tube Cancer, Stage IIIC Ovarian Epithelial Cancer, Stage IIIC Primary Peritoneal Cavity Cancer, Stage IV Fallopian Tube Cancer, Stage IV Ovarian Epithelial Cancer, Stage IV Primary Peritoneal Cavity Cancer, Stage IVA Endometrial Carcinoma, Stage IVB Endometrial Carcinoma, Uterine Carcinosarcoma

Thank you

Trial Information

A Phase II Trial of Temsirolimus and Bevacizumab in Patients With Endometrial, Ovarian, Hepatocellular Carcinoma, Carcinoid or Islet Cell Cancer


I. To determine the response rate and progression-free survival at 6 months in patients with
endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer.

II. To determine the toxicity of the combination of temsirolimus and bevacizumab in patients
with endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer.


I. To collect blood and tumor specimens from all patients entered on the trial for possible
future analysis.


Patients receive temsirolimus intravenously (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.

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

Inclusion Criteria:

- Histologically or cytologically confirmed endometrial (endometrioid, uterine,
papillary serous carcinoma, and carcinosarcoma), ovarian (primary
peritoneal/fallopian tube, serous, endometrioid, mixed, and poorly differentiated
epithelial ovarian cancers [for purposes of eligibility, carcinosarcoma is considered
a poorly differentiated carcinoma]), hepatocellular carcinoma , carcinoid or islet
cell (neuroendocrine: well- or moderately-differentiated neuroendocrine) cancer which
are locally advanced, recurrent, or metastatic

- Patients must have measurable disease; patients having only lesions measuring >= 1 cm
to < 2 cm must use spiral computed tomography (CT) imaging for both pre- and
post-treatment tumor assessments; patients who have had prior palliative radiotherapy
to metastatic lesion(s) must have at least one measurable lesion(s) that have not
been previously irradiated

- Radiation therapy (adjuvant or palliative) must be completed >= 4 weeks prior to
registration, if applicable

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelets >= 75,000/mm^3

- Hemoglobin >= 9.0 g/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN); Note: direct bilirubin and
international normalized ratio (INR) for hepatocellular carcinoma (HCC) patients
allowed as per Child-Turcotte-Pugh scoring

- Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN if liver metastasis is present or
patient is in HCC cohort)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
2.5 x ULN (=< 5 x ULN if liver metastasis is present or patient is in HCC cohort)

- Creatinine =<1.5 x ULN

- Urinalysis < 2+ protein; urine protein should be screened by dipstick or urine
analysis; for proteinuria >= 2+, 24-hour urine protein should be obtained and the
level should be < 2 g for patient enrollment

- Fasting serum cholesterol =< 350mg/dL (=< 9.0 mmol/L)

- Triglycerides =< 1.5 x ULN (mg/dL or mmol/L); patients with triglyceride levels > 1.5
x ULN can be started on lipid lowering agents and reevaluated within 1 week; if
levels go to =< 1.5 x ULN, they can be considered for the trial and continue the
lipid lowering agents; NOTE: cholesterol and triglyceride measurement and management
are not required for single-agent bevacizumab cohort with islet cell carcinoma

- International normalized ratio (INR) =< 1.5 (unless the patient is on full dose

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

- Capable of understanding the investigational nature, potential risks and benefits of
the study and able to provide valid informed consent

- Negative serum pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only; NOTE: patients and their partners should be practicing
an effective form of contraception during the study and for at least 3 months
following the last dose of this combined therapy

- Full-dose anticoagulants, if a patient is receiving full-dose anticoagulants (except
carcinoid tumors), the following criteria should be met for enrollment: the subject
must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin or
on stable dose of low molecular weight (LMW) heparin

- Prior systemic treatments for metastatic disease are permitted, including targeted
therapies, biologic response modifiers, chemotherapy, hormonal therapy, or
investigational therapy; exception: in the case of endometrial cancer no prior
chemotherapy for metastatic or recurrent disease is allowed; prior planned adjuvant
chemotherapy is allowed

- Patients who have had prior anthracycline must have a normal ejection fraction on
left ventricular ejection fraction (LVEF) assessment by multigated acquisition scan
(MUGA) or echocardiogram (Echo) =< 4 weeks prior to registration

- Availability of tissue if applicable (from the primary tumor or metastases) for tumor
studies for banking; Note: in the case of hepatocellular cancer if diagnosed by
clinical and radiologic criteria only, availability of tissue not applicable

- Willingness to donate blood for biomarker studies related to the type of therapies
used in this trial and the tumor types being treated


- Any hormonal therapy directed at the malignant tumor is allowed; NOTE: therapy must
be discontinued at least one week prior to registration

- Prior systemic therapy including biologic and immunologic agents as adjuvant
treatment, must be discontinued at least 3 weeks prior to registration

- Recurrent or persistent endometrial adenocarcinoma, uterine papillary serous
carcinoma and carcinosarcoma which is refractory to curative therapy or established
treatments; NOTE: histologic or cytologic confirmation of original primary tumor is


- HCC confirmed by biopsy OR diagnosed by clinical and radiologic criteria; all of the
following criteria must be met or a biopsy is required:

- Known cirrhosis or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV)

- Hypervascular liver masses > 2 cm, and either serum alpha-fetoprotein (AFP) >
400 ng/ml, or

- AFP > three times normal and doubling in value in the antecedent 3 months

- Child-Pugh A (=< 6 points) or better liver status

- Prior regional treatments for liver metastasis are permitted including:

- Selective internal radiation therapy such as brachytherapy, cyberknife,
radiolabeled microsphere embolization, etc.

- Hepatic artery chemoembolization

- Hepatic artery embolization

- Hepatic artery infusional chemotherapy

- Radiofrequency ablation NOTE: patients must be >= 4 weeks from treatment and
show progressive disease in the liver after regional therapy or must have
measurable disease outside the liver

- Concomitant anti-viral therapy is allowed

- History of prior varices or evidence of varices on pre-study CT/magnetic resonance
imaging (MRI) imaging are required to undergo endoscopy =< 4 weeks prior to
registration; those who had received specific therapy (banding and/or sclerotherapy)
and had not bled within the prior 6 months are eligible

- Suitably recovered from prior localized therapy, in the opinion of the investigator


- Patient has evidence of progressive disease as documented by Response Evaluation
Criteria in Solid Tumors (RECIST) =< 7 months prior to study entry

- Carcinoid tumor cohort: prior and concurrent long-acting somatostatin analogue
therapy is required; patient has to be on a stable dose of a long-acting somatostatin
analogue >- 2 months prior to study entry with documentation of progressive disease
on current dose

- Islet cell tumor cohort: prior and/or concurrent long-acting somatostatin analogue
therapy is allowed, but not required; if patient is continued on a long-acting
somatostatin analogue, a stable dose for >= 2 months prior to study entry is required
with documentation of progressive disease on current dose

- Prior therapies allowed include:

- =< 2 prior chemotherapy regimens

- Prior interferon >= 4 weeks prior to registration

- Radiolabeled octreotide therapy (patients with prior radiolabeled octreotide
therapy should have progressive disease after such therapy)

- Other investigational therapy NOTE: islet Cell Single Agent Bevacuzumab Cohort:
Prior mammalian target of rapamycin (mTOR) inhibitor is allowed

- Prior regional treatments for liver metastasis are permitted including:

- Selective internal radiation therapy such as brachytherapy, cyberknife,
radiolabeled microsphere embolization, etc.

- Hepatic artery chemoembolization

- Hepatic artery embolization

- Hepatic artery infusional chemotherapy

- Radiofrequency ablation NOTE: patients must be >= 12 weeks from treatment and
show progressive disease in the liver after regional therapy or must have
measurable disease outside the liver

Exclusion Criteria:

- Prior therapy with vascular endothelial growth factor receptor (VEGFR) targeting
agents or mammalian target of rapamycin (mTOR) inhibitors (except as in HCC and in
the Islet cell single agent bevacizumab alone cohort where prior mTOR inhibitor is
allowed); Note: prior use of bevacizumab is not allowed in any cohort

- Invasive procedures defined as follows:

- Major surgical procedure, open biopsy or significant traumatic injury =< 4 weeks
prior to registration

- Anticipation of need for major surgical procedures during the course of the

- Core biopsy =< 7 days prior to registration

- Serious or non-healing wound, ulcer or bone fracture

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
=< 180 days prior to first date of bevacizumab therapy

- Evidence of bleeding diathesis or coagulopathy in the absence of therapeutic

- Evidence of a history bleeding =< 6 months such as hemoptysis, or cerebrovascular
accident =< previous 6 months, or peripheral vascular disease with claudication on <
1 block, or history of clinically significant bleeding, because of the potential
bleeding and/or clotting risk with bevacizumab

- Untreated central nervous system (CNS) metastases; exceptions: patients with known
CNS metastases can be enrolled if the brain metastases have been adequately treated
and there is no evidence of progression or hemorrhage after treatment as ascertained
by clinical examination and brain imaging (MRI or CT) =< 12 weeks prior to
registration and no ongoing requirement for steroids

- Anticonvulsants (stable dose) are allowed

- Patients who had surgical resection of CNS metastases or brain biopsy =< 3
months prior to registration will be excluded

- Significant cardiovascular disease defined as congestive heart failure (New York
Heart Association class II, III or IV), angina pectoris requiring nitrate therapy, or
recent myocardial infarction (=< 6 months prior to registration)

- Uncontrolled hypertension (defined as a blood pressure of >= 150 mmHg systolic and/or
>= 90 mmHg diastolic)

- Patient is on angiotensin-converting-enzyme (ACE) inhibitors (benazapril, captopril,
enalopril, fosonopril, lisinopril, moexipril, perindopril, quinopril, ramipril, and
trandolapril); (patients may have an alternate antihypertensive substituted); NOTE:
ACE inhibitors are allowed in single agent bevacizumab cohort

- Currently active, second malignancy other than non-melanoma skin cancers; NOTE:
patients are not considered to have a 'currently active' malignancy if they have
completed anti-cancer therapy and are considered by their physician to be at less
than 30% risk of relapse

- Any of the following, as this regimen may be harmful to a developing fetus or nursing

- Pregnant women

- Breastfeeding women

- Men or women of childbearing potential or their sexual partners who are
unwilling to employ adequate contraception (diaphragm, birth control pills,
injections, intrauterine device [IUD], surgical sterilization, subcutaneous
implants, or abstinence, etc.) NOTE: the effects of the agent(s) on the
developing human fetus at the recommended therapeutic dose are unknown

- Known hypersensitivity to other recombinant human antibodies or Chinese hamster ovary
cell products

- Other uncontrolled serious medical or psychiatric condition (e.g. cardiac
arrhythmias, diabetes, etc.)

- Current therapy with a cytochrome P450 3A4 (CYP3A4) inhibitor or inducer; NOTE: these
agents are allowed in the single-agent bevacizumab islet cell carcinoma cohort

- Active infection requiring antibiotics

- Active bleeding or pathological conditions that carry high risk of bleeding (e.g.
tumor involving major vessels, known varices)

- Known human immunodeficiency virus (HIV)-positive


- Received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER
THAN for the treatment of endometrial cancer

- Any chemotherapy for metastatic or recurrent cancer

- Radiation therapy to > 25% of marrow bearing areas


- Child-Pugh B or C classification

- Grade >= 3 hemorrhage =< 4 weeks prior to registration

- Prior liver transplant with evidence of recurrent or metastatic disease

- Patients on an active liver transplant list and considered likely to receive a liver
transplant =< 6 months following registration

- Clinical evidence of encephalopathy


- Clinical signs and symptoms of gastrointestinal (GI) obstruction and require parental
hydration/nutrition or tube feeding

- Evidence of free abdominal air not explained by paracentesis or recent surgical

- Received more than two prior cytotoxic chemotherapy regimens for persistent or
recurrent disease


- Patients on anticoagulant therapy

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Tumor response rate defined as the total number of efficacy-evaluable patients who achieved a complete or partial response according to the RECIST criteria divided by the total number of efficacy evaluable patients enrolled on study

Outcome Description:

A 95% confidence interval for the true response rate will be constructed using the Duffy-Santner approach.

Outcome Time Frame:

Up to 3 years

Safety Issue:


Principal Investigator

Charles Erlichman

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

September 2009

Completion Date:

Related Keywords:

  • Adult Primary Hepatocellular Carcinoma
  • Advanced Adult Primary Liver Cancer
  • Endometrial Papillary Serous Carcinoma
  • Localized Unresectable Adult Primary Liver Cancer
  • Metastatic Gastrointestinal Carcinoid Tumor
  • Ovarian Carcinosarcoma
  • Ovarian Endometrioid Adenocarcinoma
  • Ovarian Mixed Epithelial Carcinoma
  • Ovarian Papillary Serous Carcinoma
  • Pancreatic Alpha Cell Adenoma
  • Pancreatic Alpha Cell Carcinoma
  • Pancreatic Beta Islet Cell Adenoma
  • Pancreatic Beta Islet Cell Carcinoma
  • Pancreatic Delta Cell Adenoma
  • Pancreatic Delta Cell Carcinoma
  • Pancreatic G-cell Adenoma
  • Pancreatic G-cell Carcinoma
  • Pancreatic Polypeptide Tumor
  • Pulmonary Carcinoid Tumor
  • Recurrent Adult Primary Liver Cancer
  • Recurrent Endometrial Carcinoma
  • Recurrent Fallopian Tube Cancer
  • Recurrent Gastrointestinal Carcinoid Tumor
  • Recurrent Islet Cell Carcinoma
  • Recurrent Ovarian Epithelial Cancer
  • Recurrent Primary Peritoneal Cavity Cancer
  • Regional Gastrointestinal Carcinoid Tumor
  • Stage IIIA Endometrial Carcinoma
  • Stage IIIA Fallopian Tube Cancer
  • Stage IIIA Ovarian Epithelial Cancer
  • Stage IIIA Primary Peritoneal Cavity Cancer
  • Stage IIIB Endometrial Carcinoma
  • Stage IIIB Fallopian Tube Cancer
  • Stage IIIB Ovarian Epithelial Cancer
  • Stage IIIB Primary Peritoneal Cavity Cancer
  • Stage IIIC Endometrial Carcinoma
  • Stage IIIC Fallopian Tube Cancer
  • Stage IIIC Ovarian Epithelial Cancer
  • Stage IIIC Primary Peritoneal Cavity Cancer
  • Stage IV Fallopian Tube Cancer
  • Stage IV Ovarian Epithelial Cancer
  • Stage IV Primary Peritoneal Cavity Cancer
  • Stage IVA Endometrial Carcinoma
  • Stage IVB Endometrial Carcinoma
  • Uterine Carcinosarcoma
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Adenoma
  • Carcinoid Tumor
  • Carcinoma
  • Carcinosarcoma
  • Mixed Tumor, Mullerian
  • Glucagonoma
  • Adenoma, Islet Cell
  • Liver Neoplasms
  • Peritoneal Neoplasms
  • Fallopian Tube Neoplasms
  • Carcinoma, Endometrioid
  • Cystadenocarcinoma, Serous
  • Malignant Carcinoid Syndrome
  • Gastrointestinal Neoplasms
  • Uterine Neoplasms
  • Ovarian Neoplasms
  • Endometrial Neoplasms
  • Neoplasms, Glandular and Epithelial
  • Carcinoma, Islet Cell
  • Carcinoma, Hepatocellular



Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Cleveland Clinic FoundationCleveland, Ohio  44195
Mayo ClinicRochester, Minnesota  55905
H. Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612
University of Iowa Hospitals and ClinicsIowa City, Iowa  52242
Washington University School of MedicineSaint Louis, Missouri  63110
Fox Chase Cancer CenterPhiladelphia, Pennsylvania  19111
Fairview Ridges HospitalBurnsville, Minnesota  55337
Hutchinson Area Health CareHutchinson, Minnesota  55350
United HospitalSt. Paul, Minnesota  55102
Ridgeview Medical CenterWaconia, Minnesota  55387
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Ingalls Memorial HospitalHarvey, Illinois  60426
Hartford HospitalHartford, Connecticut  06102-5037
Weill Medical College of Cornell UniversityNew York, New York  10021
Montefiore Medical CenterBronx, New York  10467-2490
Mercy HospitalCoon Rapids, Minnesota  55433
Fairview-Southdale HospitalEdina, Minnesota  55435
Abbott-Northwestern HospitalMinneapolis, Minnesota  55407
Regions HospitalSaint Paul, Minnesota  55101
Saint Francis Regional Medical CenterShakopee, Minnesota  55379
Rice Memorial HospitalWillmar, Minnesota  56201
Crossroads Cancer CenterEffingham, Illinois  62401
Mayo Clinic in ArizonaScottsdale, Arizona  85259-5404
Mayo Clinic in FloridaJacksonville, Florida  32224
Memorial Medical CenterSpringfield, Illinois  62781
City of HopeDuarte, California  91010
University of PittsburghPittsburgh, Pennsylvania  15261
University of North CarolinaChapel Hill, North Carolina  27599
Hennepin County Medical CenterMinneapolis, Minnesota  
Tower Cancer Research FoundationBeverly Hills, California  90211
University of ConnecticutFarmington, Connecticut  06032
Case Western Reserve UniversityCleveland, Ohio  44106
Emory UniversityAtlanta, Georgia  30322
Ohio State University Medical CenterColumbus, Ohio  43210
Metro-Minnesota CCOPSt. Louis Park, Minnesota  
UC Davis Comprehensive Cancer CenterSacramento, California  95817
Lakeview HospitalStillwater, Minnesota  55082
Decatur Memorial HospitalDecatur, Illinois  62526
Virginia Commonwealth UniversityRichmond, Virginia  
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
M D Anderson Cancer CenterHouston, Texas  77030
University of Southern CaliforniaLos Angeles, California  90033
Evanston CCOP-NorthShore University HealthSystemEvanston, Illinois  60201
Fort Wayne Medical Oncology and Hematology Inc - State BoulevardFort Wayne, Indiana  46845
Unity HospitalFridley, Minnesota  55432
Saint John's Hospital - HealtheastMaplewood, Minnesota  55109
Minnesota Oncology Hematology PA-MaplewoodMaplewood, Minnesota  55109
North Memorial Medical Health CenterRobbinsdale, Minnesota  55422
Park Nicollet Clinic - Saint Louis ParkSaint Louis Park, Minnesota  55416
Minnesota Oncology and Hematology PA-WoodburyWoodbury, Minnesota  55125
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Billings ClinicBillings, Montana  59107-7000
New York University Langone Medical CenterNew York, New York  10016
City of Hope Medical Group IncPasadena, California  91105
Cancer Care Center of DecaturDecatur, Illinois  62526
Los Angeles County-USC Medical CenterLos Angeles, California  90033
Memorial Sloan Kettering Cancer Center at Basking RidgeBasking Ridge, New Jersey  07920
University of Maryland Saint Joseph Medical CenterTowson, Maryland  21204