Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer
Condition: Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Endometrial Serous Adenocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Lung Carcinoid Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Metastatic Digestive System Neuroendocrine Tumor G1; Ovarian Carcinosarcoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Polypeptide Tumor; Recurrent Adult Liver Carcinoma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IIIC Uterine Corpus Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma
MeSH terms: Carcinoma; Adenocarcinoma; Carcinoma, Hepatocellular; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Adenoma; Neuroendocrine Tumors; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Carcinoid Tumor; Carcinoma, Neuroendocrine; Cystadenocarcinoma, Serous; Carcinoma, Endometrioid; Carcinosarcoma; Mixed Tumor, Mullerian; Insulinoma; Gastrinoma; Glucagonoma; Somatostatinoma; Liver Neoplasms; Intestinal Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms; Malignant Carcinoid Syndrome; Gastrointestinal Neoplasms; Carcinoma, Islet Cell; Adenocarcinoma, Papillary; Recurrence
Intervention: Bevacizumab; Temsirolimus
Intervention description: Given IV; Given IV
Intervention MeSH terms: Sirolimus; Bevacizumab; Antineoplastic Agents, Immunological; Temsirolimus; MTOR Inhibitors; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 252.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well temsirolimus and bevacizumab work in treating patients
      with advanced endometrial, ovarian, liver, carcinoid, or islet cell cancer. 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
      cancer by blocking blood flow to the tumor. Giving temsirolimus together with bevacizumab may
      kill more tumor cells.
    

Eligibility criteria:

        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 =< 350 mg/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
             warfarin)

          -  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

          -  ENDOMETRIAL CANCER (PERMANENTLY CLOSED TO ENROLLMENT)

          -  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 required

          -  HEPATOCELLULAR CANCER (PERMANENTLY CLOSED TO ENROLLMENT)

          -  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)
                  infection

               -  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

          -  ISLET CELL CANCER AND CARCINOID TUMOR (PERMANENTLY CLOSED TO ENROLLMENT)

          -  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 Bevacizumab 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 study

               -  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
             anticoagulation

          -  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
             child:

               -  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

          -  ENDOMETRIAL CANCER (PERAMANENTLY CLOSED TO ENROLLMENT)

          -  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

          -  HEPATOCELLULAR CANCER EXCLUSION (PERMANENTLY CLOSED TO ENROLLMENT)

          -  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

          -  Prior treatment with sorafenib or other vascular endothelial growth factor (VEGF)
             inhibitors; NOTE: Exceptions allowed for patients unable to tolerate the agent;
             intolerance is defined in this protocol as a discontinued agent due to side effects
             with an exposure < to 4 weeks of drug, at any dose level

          -  OVARIAN CANCER (PERMANENTLY CLOSED TO ENROLLMENT)

          -  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
             procedures

          -  Received more than two prior cytotoxic chemotherapy regimens for persistent or
             recurrent disease

          -  CARCINOID (PERMANENTLY CLOSED TO ENROLLMENT)

          -  Patients on anticoagulant therapy