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A Randomized Phase 2 Study of AMG 386 With or Without Continued Anti-Vascular Endothelial Growth Factor (VEGF) Therapy in Patients With Renal Cell Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib

Phase 2
18 Years
Open (Enrolling)
Recurrent Renal Cell Cancer, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer

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Trial Information

A Randomized Phase 2 Study of AMG 386 With or Without Continued Anti-Vascular Endothelial Growth Factor (VEGF) Therapy in Patients With Renal Cell Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib


I. To evaluate the overall response rate (complete response [CR] + partial response [PR]) of
AMG 386 (trebananib) alone and in combination with continuation of previously administered
bevacizumab, pazopanib (pazopanib hydrochloride), sorafenib (sorafenib tosylate), or
sunitinib (sunitinib malate) in advanced renal cell carcinoma.


I. To evaluate progression free survival in each arm. II. To evaluate the tolerance and
toxicity of AMG 386 alone and in combination with continuation of the prior vascular
endothelial growth factor (VEGF) targeted agent.


I. To evaluate the association between pretreatment tumor gene expression levels and
response to AMG 386 in combination with continuation of the prior VEGF targeted agent.

II. To evaluate the association between single nucleotide polymorphisms (SNPs) in angiogenic
genes and response to AMG 386 in combination with continuation of the prior VEGF targeted

III. To compare changes in circulating angiogenic factors in patients treated with AMG 386
monotherapy to those treated with AMG 386 in combination with VEGF-targeted therapy.

IV. To compare expression of angiogenic genes from archival tumor specimens to the
expression in biopsy specimens obtained after progression on anti-VEGF therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive trebananib intravenously (IV) over 30-60 minutes on days 1, 8, 15,
22, 29, and 36. Courses repeat every 42 days in the absence of disease progression or
unacceptable toxicity.

ARM II: Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes
on days 1, 15, and 29; pazopanib hydrochloride orally (PO) once daily (QD) on days 1-42;
sorafenib tosylate PO twice daily (BID) on days 1-42; or sunitinib malate PO QD on days
1-28. Courses repeat every 42 days in the absence of disease progression or unacceptable

After completion of study treatment, patients are followed up for up to 8 weeks.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed renal cell carcinoma
except medullary or collecting duct subtypes; sarcomatoid differentiation will be

- 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

- Patients must have documented radiologic or clinical progressive disease following at
least one prior anti-VEGF regimen administered either as a single agent or in
combination with other agents for at least 8 weeks; the immediate prior treatment
regimen must have included bevacizumab, pazopanib, sorafenib or sunitinib
administered not more than 12 weeks before study entry; note: enrollment not more
than 8 weeks after the last dose of anti-VEGF therapy is encouraged

- Any number of prior regimens is allowed; prior investigational therapy is allowed

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

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =<
upper limit of normal (ULN) per institutional laboratory range and international
normalized ratio (INR) =< 1.5

- Creatinine within normal institutional limits or creatinine clearance > 60 mL/min per
24 h urine collection or calculated according to the Cockcroft-Gault formula

- Urinary protein =< 100 mg/dL in urinalysis or =< 1+ on dipstick, unless quantitative
protein is < 1000 mg in a 24 h urine sample

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

- Patients must have a tumor site amenable to biopsy as determined by the treating
investigator; any questions regarding suitability of a site for biopsy will be
adjudicated by the principal investigator

- Patients must be willing to consent to tumor biopsy for research purposes

- Patients should have archival tumor tissue (either unstained slides or tumor blocks)
available for retrieval

- 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, for
the duration of study participation, and 6 months after completion of AMG 386; 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 AMG 386 and bevacizumab, pazopanib, sunitinib, or
sorafenib administration

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

Exclusion Criteria:

- Intolerance of the immediate prior treatment with bevacizumab, pazopanib, sorafenib,
or sunitinib; note: subjects who required a dose reduction of pazopanib, sorafenib,
or sunitinib during prior therapy MAY be eligible if they tolerated the agent after
dose level reduction (to a minimum of dose level -2 as defined in this protocol)

- Central nervous system metastases unless: (1) metastases have been treated and have
remained controlled for at least two weeks following treatment, AND (2) patient has
no residual neurological dysfunction off corticosteroids for at least one week; a CT
or MRI to evaluate for central nervous system (CNS) disease is required for
symptomatic patients only

- History of venous or arterial thromboembolism within 12 months prior to

- History of clinically significant bleeding within 6 months of

- Unresolved toxicities from prior systemic therapy that are Common Terminology
Criteria in Adverse Events (CTCAE) version 3.0 or 4.0 >= grade 2 in severity except

- Currently or previously treated with AMG 386, or other molecules that inhibit the
angiopoietins or 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

- Minor surgical procedures except placement of tunneled central venous access device
within 3 days prior to enrollment

- 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 the anti-VEGF agent used in study

- History of allergic reactions to bacterially-produced proteins

- Patients who have had anti-VEGFR tyrosine kinase inhibitor within 1 week or anti-VEGF
antibody therapy within 3 weeks prior to entering the study; patients who have had
other forms of 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

- Patients receiving any medications or substances that are strong inhibitors or
inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP450 3A4) are
ineligible; caution is advised for patients requiring weak or moderate CYP450 3A4
inhibitors or inducers; specifically prohibited medicines include indinavir,
nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone,
carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St.
John's wort, and troglitazone

- 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 must be discontinued if
the mother is treated with AMG 386

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated

- Inability to take oral medications on a continuous basis; patients who are to take
pazopanib, sorafenib, or sunitinib and are unable to swallow pills whole are
ineligible (the pills cannot be crushed or broken)

- Any condition which in the investigator's opinion makes the subject unsuitable for
study participation

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall tumor response rate (ORR) defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria

Outcome Description:

Both arms will be evaluated separately using a Simon Optimum design. If trebananib is ineffective (alone or in the presence of an anti-VEGF agent), then we would expect to see no objective responses (by RECIST v1.1), while a 15% response rate would be taken as interesting enough to encourage future study.

Outcome Time Frame:

Up to 8 weeks post-treatment

Safety Issue:


Principal Investigator

Thomas Semrad

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

August 2012

Completion Date:

Related Keywords:

  • Recurrent Renal Cell Cancer
  • Stage III Renal Cell Cancer
  • Stage IV Renal Cell Cancer
  • Carcinoma, Renal Cell



University of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania  15213
Wayne State UniversityDetroit, Michigan  48202
UC Davis Comprehensive Cancer CenterSacramento, California  95817
University of Southern CaliforniaLos Angeles, California  90033
Penn State Milton S Hershey Medical CenterHershey, Pennsylvania  17033
City of Hope- South Pasadena Cancer CenterSouth Pasadena, California  91030