Trebananib And Temsirolimus in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
Trebananib And Temsirolimus in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
This phase I trial studies the side effects and the best dose of trebananib and temsirolimus
 when given together in treating patients with solid tumors that are metastatic or cannot be
 removed by surgery. Trebananib may stop the growth of tumor cells by blocking blood flow to
 the tumor. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes
 needed for cell growth. Giving trebananib with temsirolimus may be an effective treatment for
 solid tumors.
PRIMARY OBJECTIVES:

 I. To determine the recommended phase II dose (RP2D) and safety profile of AMG 386
 (trebananib) in combination with temsirolimus in patients with advanced solid tumors.

 SECONDARY OBJECTIVES:

 I. To evaluate pharmacodynamic (PD) effects of both drugs when administered in combination,
 with the goal of identifying potential predictive and PD markers that need further
 exploration and validation in future trials.

 II. To explore preliminary anti-tumor activity of both drugs when administered at the RP2D to
 patients with advanced endometrial cancer, renal cell carcinoma, or carcinoid tumor.

 OUTLINE: This is a dose-escalation study of trebananib.

 Patients receive trebananib intravenously (IV) over 60 minutes and temsirolimus IV over 30-60
 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease
 progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 30 days.
Inclusion Criteria:

 -  DOSE ESCALATION COHORTS: Patients must have histologically or cytologically confirmed
 malignancy that is metastatic or unresectable and for which standard curative or
 palliative measures do not exist or are no longer effective

 -  DOSE EXPANSION COHORTS: Patients must have histologically and/or cytologically
 confirmed uterine cancer, renal cell cancer or carcinoid tumor that is metastatic or
 unresectable and for which standard curative or palliative measures do not exist or
 are no longer effective

 -  Patients must have measurable disease, defined as at least one lesion that can be
 accurately measured in at least one dimension (longest diameter to be recorded for
 non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
 techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic
 resonance imaging (MRI), or calipers by clinical exam

 -  DOSE ESCALATION COHORTS: No limitation on prior therapy; however, there must be at
 least a 4 week interval between initiation of study treatment and any prior
 radiotherapy or systemic therapy, 6 weeks if the last regimen included carmustine
 (BCNU) or mitomycin C; exceptions may be made however, for low dose,
 non-myelosuppressive radiotherapy for symptomatic palliation; please contact the study
 coordinator at the Princess Margaret Hospital (PMH) Phase I Consortium Central Office
 or the principal investigator if any questions arise about interpretation of this
 criterion

 -  EXPANSION COHORTS:

 -  Uterine cancer: Patients diagnosed with uterine cancer will be eligible provided
 they have received at least one prior line of chemotherapy for recurrent or
 metastatic disease unless the investigator feels that cytotoxic chemotherapy is
 contraindicated; prior hormonal treatment will be allowed; prior anti-angiogenic
 agents and prior treatment with agents targeting phosphatidylinositol 3-kinase
 (PI3K)- protein kinase B (AkT)- mammalian target of rapamycin (mTOR) pathway are
 not allowed

 -  Renal cell cancer: Patients diagnosed with renal cell cancer (RCC) will be
 required to have received at least one prior line anti- vascular endothelial
 growth factor (VEGF)/ receptor (R) treatment (i.e. bevacizumab, sunitinib, and/or
 sorafenib); prior treatment with agents targeting PI3K-Akt-mTOR pathway is not
 allowed

 -  Carcinoid tumor: Patients diagnosed with carcinoid tumor must have demonstrated
 radiographic evidence of disease progression within six months prior to
 enrollment; prior and/or concurrent long-acting somatostatin analogue therapy is
 allowed; 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 radiolabeled octreotide therapy is
 allowed; prior regional treatments for liver metastasis are permitted including:

 -  Selective internal radiation therapy (i.e. brachytherapy, radiolabeled
 microsphere embolization, etc)

 -  Hepatic artery chemoembolization

 -  Hepatic artery embolization

 -  Hepatic artery infusional chemotherapy

 -  Radiofrequency ablation

 -  Patients must be > 12 weeks from regional treatments and show progressive disease
 in the liver after regional therapy or must have measurable disease outside the
 liver; patients may have received one prior line of anti-VEGF/R treatment (e.g.
 bevacizumab, sunitinib, and/or sorafenib); prior treatment with agents targeting
 PI3K-Akt-mTOR pathway is not allowed

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

 -  Life expectancy of greater than 12 weeks

 -  Leukocytes >= 3.0 x 10^9/L

 -  Absolute neutrophil count >= 1.5 x 10^9/L

 -  Platelets >= 100 x 10^9/L

 -  Hemoglobin >= 90 g/L (or >= 9 g/dL)

 -  Total bilirubin =< institutional upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 2.5 x institutional upper limit of normal if no known liver metastasis or =< 5 x
 institutional upper limit of normal if known liver metastasis

 -  Partial thromboplastin time (PTT) or activated PTT (aPTT) =< 1.5 x ULN per
 institutional laboratory range and international normalized ratio (INR) =< 1.5

 -  Creatinine =< institutional ULN OR creatinine clearance > 40 mL/min per 24 hours (h)
 urine collection or calculated according to the Cockcroft-Gault formula

 -  Urinary protein =< 30 mg/dL in urinalysis or =< 1 + on dipstick, unless quantitative
 protein is < 1000 mg in a 24 h urine sample

 -  Total cholesterol < 400 mg/dL (or < 10.34 mmol/L)

 -  Serum triglyceride level < 500 mg/dL (or < 5.7 mmol/L)

 -  Generally well-controlled blood pressure with systolic blood pressure =< 140 mm Hg AND
 diastolic blood pressure =< 90 mm Hg prior to enrollment; the use of anti-hypertensive
 medications to control hypertension is permitted

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry and for
 the duration of study participation, and 6 months after completion of AMG386 and/or
 temsirolimus administration; should a woman become pregnant or suspect she is pregnant
 while she or her partner is participating in this study, she should inform her
 treating physician immediately; men treated or enrolled on this protocol must also
 agree to use adequate contraception prior to the study, for the duration of study
 participation, and 6 months after completion of AMG386 and/or temsirolimus
 administration

 -  Ability to understand and the willingness to sign a written informed consent document

 Exclusion Criteria:

 -  History of central nervous system metastases

 -  History of venous or arterial thromboembolism within 12 months prior to
 enrollment/randomization; patients requiring ongoing anticoagulation with therapeutic
 dosages of low molecular weight heparin or warfarin are excluded

 -  History of clinically significant bleeding within 6 months of enrollment/randomization

 -  Unresolved toxicities from prior systemic therapy that are Common Terminology Criteria
 for Adverse Events (CTCAE) version 4.0 >= grade 2 in severity except alopecia

 -  Currently or previously treated with AMG 386, or other molecules that inhibit the
 angiopoietins or TEK tyrosine kinase, endothelial (Tie2) receptor

 -  Clinically significant cardiovascular disease within 12 months prior to
 enrollment/randomization, including myocardial infarction, unstable angina, grade 2 or
 greater peripheral vascular disease, cerebrovascular accident, transient ischemic
 attack, congestive heart failure, or arrhythmias not controlled by outpatient
 medication or placement of percutaneous transluminal coronary angioplasty/stent

 -  Major surgery within 28 days prior to enrollment or still recovering from prior
 surgery

 -  Minor surgical procedures, except placement of tunneled central venous access device
 within 3 days (7 days if with VEGF inhibitor) prior to randomization/enrollment

 -  Treatment within 30 days prior to enrollment with strong immune modulators, including
 but not limited to systemic cyclosporine, tacrolimus, sirolimus, mycophenolate
 mofetil, methotrexate, azathioprine, rapamycin, thalidomide, lenalidomide, and
 targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab, alefacept,
 anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or rituximab

 -  Non-healing wound, ulcer (including gastrointestinal), or fracture

 -  Subject not consenting to the use of highly effective contraceptive precautions (e.g.,
 double barrier method [i.e., condom plus diaphragm]) during the course of the study
 and for 6 months after administration of the last study medication

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to AMG 386 or temsirolimus

 -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
 nitrosoureas or mitomycin C) prior to entering the study or those who have not
 recovered from adverse events due to agents administered more than 4 weeks earlier

 -  Patients who have not yet completed at least 21 days (30 days for prior monoclonal
 antibody therapy) since ending other investigational device or drug trials, or who are
 currently receiving other investigational treatments

 -  Temsirolimus is a cytochrome P450 3A4 (CYP3A4) substrate; patients receiving any
 medications or substances that are strong inhibitors or inducers of CYP3A4 are
 ineligible

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
 the mother is treated with AMG 386; these potential risks may also apply to
 temsirolimus

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are ineligible

 -  Patients with pre-existing clinically significant pulmonary infiltrates of unknown
 origin

 -  Patients with an indwelling peritoneal or pleural catheter that is used to manage
 malignant effusions

 -  Known intra-abdominal inflammatory process or serious gastrointestinal ulceration

 -  No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
 the past 6 months

 -  No gastric or esophageal varices

 -  Patients with primary bowel tumors in situ or recurrent disease at bowel anastomosis