Advanced Renal Cell Carcinoma, Advanced Sarcomatoid Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v7, Stage IV Renal Cell Cancer AJCC v7
Conditions
Brief summary
This randomized phase II trial studies how well trebananib with or without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate works in treating patients with kidney cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Trebananib may stop the growth of tumor cells by blocking blood flow to the tumor. Immunotherapy with monoclonal, such as bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pazopanib hydrochloride, sorafenib tosylate, and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. It is not yet known whether giving trebananib with or without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate is more effective in treating kidney cancer.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate the overall response rate (complete response \[CR\] + partial response \[PR\]) of trebananib (AMG 386) alone and in combination with continuation of previously administered bevacizumab, pazopanib hydrochloride (pazopanib), sorafenib tosylate (sorafenib), or sunitinib malate (sunitinib) in advanced renal cell carcinoma. SECONDARY OBJECTIVES: 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 VEGF targeted agent. CORRELATIVE OBJECTIVES: 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 agent. 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. Cycles 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. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4-8 weeks.
Interventions
DRUGPazopanib Hydrochloride
Given PO
DRUGSorafenib Tosylate
Given PO
DRUGSunitinib Malate
Given PO
BIOLOGICALTrebananib
Given IV
BIOLOGICALBevacizumab
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed renal cell carcinoma except medullary or collecting duct subtypes; sarcomatoid differentiation will be allowed * 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 prior anti-VEGF 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; nevertheless, intercurrent therapy with an mTOR inhibitor (everolimus or temsirolimus) will be allowed if progression on that treatment is observed within 12 weeks of the prior anti-VEGF therapy * 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 =\< institutional upper limits of normal * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate 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 * International normalized ratio (INR) =\< 1.5 * Creatinine within normal institutional limits OR creatinine clearance \> 40 mL/min per 24 hour (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 * The effects of AMG 386 are known to be detrimental to fetal development; for this reason and because inhibitors of angiogenesis as well as other therapeutic agents used in this trial are known to be teratogenic, 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 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 enrollment/randomization * History of clinically significant bleeding within 6 months of enrollment/randomization * 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 alopecia * 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 surgery * 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, mTOR 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 because AMG 386, bevacizumab, pazopanib, sorafenib, and sunitinib are inhibitors of angiogenesis with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AMG 386, breastfeeding must be discontinued if the mother is treated with AMG 386 * Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pazopanib, sorafenib, or sunitinib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Observed Response Rate | Up to 8 weeks | Defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by RECIST version 1.1 criteria, assessed by MRI: Complete Response (CR), Disappearance of all target lesions: any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; Partial Response (PR), \>= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Best response will be listed for each patient and summarized using standard descriptive methods-point estimate and associated confidence intervals. |
| Tumor Response | at 8 weeks | Tumor Response Classification |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From start of treatment to time of progression or death, whichever occurs first, assessed up to 8 weeks | Time to reach Kaplan-Meier median survival (outcome being death or progression) (95% Confidence Interval) is reported. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered a progression.) |
| Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | 8 weeks for adverse events. Until removal from the study or to death for late adverse events, up to 12 weeks | Adverse events were graded using CTCAE version 5.0. Grades 3, 4, 5 (on a scale of 1 to 5, 5 being the worst grade - death) toxicities related ('Possibly', 'Probably', or 'Definitely') to the treatment drugs (AMG 386 alone or in combination with prior VEGF targeted agent). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Circulating Angiogenic Factors | Baseline to up to 8 weeks | Analyzed as continuous variables (most likely after transformation). The gene expression results from the pretreatment tumor biopsies are expressed as ratios between that of the gene of interest and the internal reference gene beta-actin and can be analyzed as continuous variables - generally after log transformation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Trebananib Monotherapy) Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Trebananib: Given IV | 17 |
| Arm II (Trebananib and Anti-VEGF Therapy) Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Bevacizumab: Given IV
Pazopanib Hydrochloride: Given PO
Sorafenib Tosylate: Given PO
Sunitinib Malate: Given PO
Trebananib: Given IV | 18 |
| Total | 35 |
Baseline characteristics
| Characteristic | Total | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|---|
| Age, Continuous | 60 years | 64 years | 59 years |
| ECOG Performance Score 0 | 23 Participants | 12 Participants | 11 Participants |
| ECOG Performance Score 1 | 12 Participants | 5 Participants | 7 Participants |
| Prior Anti-VEGF Agent Bevacizumab | 15 Participants | 5 Participants | 10 Participants |
| Prior Anti-VEGF Agent Pazopanib | 11 Participants | 6 Participants | 5 Participants |
| Prior Anti-VEGF Agent Sorafenib | 4 Participants | 2 Participants | 2 Participants |
| Prior Anti-VEGF Agent Sunitinib | 5 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian/Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 8 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 21 Participants | 9 Participants | 12 Participants |
| Region of Enrollment United States | 35 participants | 17 participants | 18 participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 27 Participants | 13 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 2 / 18 |
| other Total, other adverse events | 16 / 17 | 18 / 18 |
| serious Total, serious adverse events | 10 / 17 | 18 / 18 |
Outcome results
Primary
Observed Response Rate
Defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by RECIST version 1.1 criteria, assessed by MRI: Complete Response (CR), Disappearance of all target lesions: any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; Partial Response (PR), \>= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Best response will be listed for each patient and summarized using standard descriptive methods-point estimate and associated confidence intervals.
Time frame: Up to 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Trebananib Monotherapy) | Observed Response Rate | 0 percentage of patients responding |
| Arm II (Trebananib and Anti-VEGF Therapy) | Observed Response Rate | 11 percentage of patients responding |
Primary
Tumor Response
Tumor Response Classification
Time frame: at 8 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Trebananib Monotherapy) | Tumor Response | Partial Response | 0 Participants |
| Arm I (Trebananib Monotherapy) | Tumor Response | Stable Disease | 5 Participants |
| Arm I (Trebananib Monotherapy) | Tumor Response | Progressive Disease | 11 Participants |
| Arm I (Trebananib Monotherapy) | Tumor Response | Not Evaluable | 1 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Tumor Response | Not Evaluable | 2 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Tumor Response | Partial Response | 2 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Tumor Response | Progressive Disease | 6 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Tumor Response | Stable Disease | 8 Participants |
Secondary
Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs
Adverse events were graded using CTCAE version 5.0. Grades 3, 4, 5 (on a scale of 1 to 5, 5 being the worst grade - death) toxicities related ('Possibly', 'Probably', or 'Definitely') to the treatment drugs (AMG 386 alone or in combination with prior VEGF targeted agent).
Time frame: 8 weeks for adverse events. Until removal from the study or to death for late adverse events, up to 12 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | SAE Respiratory, thoracic and mediastinal disorders: Dyspnea | 1 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Investigations: Weight gain | 0 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Blood and lymphatic system disorders: Anemia | 0 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Metabolism and nutrition disorders: Acidosis | 0 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | SAE Metabolism and nutrition disorders: Hypokalemia | 1 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Metabolism and nutrition disorders: Hyperglycemia | 1 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | General disorders and administrative site conditions: Fatigue | 1 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Metabolism and nutrition disorders: Hyponatremia | 0 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | SAE Respiratory, thoracic and mediastinal disorders: Pleural effusion | 1 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Musculoskeletal and connective tissue disorders: Back pain | 1 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Investigations: Lymphocyte count decreased | 0 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Vascular disorders: Hypertension | 3 Participants |
| Arm I (Trebananib Monotherapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | SAE Cardiac disorders: Cardiac arrest | 0 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Vascular disorders: Hypertension | 3 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | SAE Cardiac disorders: Cardiac arrest | 1 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | SAE Metabolism and nutrition disorders: Hypokalemia | 0 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | SAE Respiratory, thoracic and mediastinal disorders: Dyspnea | 1 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | SAE Respiratory, thoracic and mediastinal disorders: Pleural effusion | 0 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Blood and lymphatic system disorders: Anemia | 1 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | General disorders and administrative site conditions: Fatigue | 3 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Investigations: Lymphocyte count decreased | 1 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Investigations: Weight gain | 1 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Metabolism and nutrition disorders: Acidosis | 1 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Metabolism and nutrition disorders: Hyperglycemia | 0 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Metabolism and nutrition disorders: Hyponatremia | 1 Participants |
| Arm II (Trebananib and Anti-VEGF Therapy) | Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs | Musculoskeletal and connective tissue disorders: Back pain | 1 Participants |
Secondary
Progression Free Survival (PFS)
Time to reach Kaplan-Meier median survival (outcome being death or progression) (95% Confidence Interval) is reported. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered a progression.)
Time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Trebananib Monotherapy) | Progression Free Survival (PFS) | 2.7 months |
| Arm II (Trebananib and Anti-VEGF Therapy) | Progression Free Survival (PFS) | 5.2 months |
Other Pre-specified
Changes in Circulating Angiogenic Factors
Analyzed as continuous variables (most likely after transformation). The gene expression results from the pretreatment tumor biopsies are expressed as ratios between that of the gene of interest and the internal reference gene beta-actin and can be analyzed as continuous variables - generally after log transformation.
Time frame: Baseline to up to 8 weeks
Population: availability of samples. attrition from the study.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | Angiopoietin--2 prior to cycle 2 | 132156 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGF--C prior to cycle 3 | 230 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | PIGF at baseline | 31.1 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | IL--8 at baseline | 0.1 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | Tie--2 prior to cycle 3 | 912 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | IL--8 prior to cycle 2 | 3.6 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | PIGF prior to cycle 2 | 30.5 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | IL--8 prior to cycle 3 | 2.5 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | Tie--2 at baseline | 803 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | ICAM--1 at baseline | 161879 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | PIGF prior to cycle 3 | 31.4 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | ICAM--1 prior to cycle 2 | 193335 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGF--A at baseline | 27.3 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | ICAM--1 prior to cycle 3 | 262636 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGFR--3 at baseline | 873 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VCAM--1 at baseline | 965554 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | Angiopoietin--2 prior to cycle 3 | 125928 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VCAM--1 prior to cycle 2 | 1336300 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGFR--3 prior to cycle 2 | 722 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VCAM--1 prior to cycle 3 | 982488 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGF--A prior to cycle 2 | 21.3 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | FGF2 at baseline | 124 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGFR--3 prior to cycle 3 | 489 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | FGF2 prior to cycle 2 | 112 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | Tie--2 prior to cycle 2 | 783 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | FGF2 prior to cycle 3 | 131 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGF--C at baseline | 255 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | PDGF -- AA at baseline | 351 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGF--A prior to cycle 3 | 20.7 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | PDGF -- AA prior to cycle 2 | 291 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | VEGF--C prior to cycle 2 | 209 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | PDGF -- AA prior to cycle 3 | 264 pg/ml |
| Arm I (Trebananib Monotherapy) | Changes in Circulating Angiogenic Factors | Angiopoietin--2 at baseline | 3909 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | PDGF -- AA prior to cycle 3 | 173 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | Angiopoietin--2 at baseline | 3237 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | Angiopoietin--2 prior to cycle 2 | 120956 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | Angiopoietin--2 prior to cycle 3 | 96075 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | Tie--2 at baseline | 835 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | Tie--2 prior to cycle 2 | 671 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | Tie--2 prior to cycle 3 | 753 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGF--A at baseline | 26.1 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGF--A prior to cycle 2 | 33.4 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGF--A prior to cycle 3 | 41.2 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | PIGF at baseline | 30.7 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | PIGF prior to cycle 2 | 33.6 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | PIGF prior to cycle 3 | 31.5 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGFR--3 at baseline | 489 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGFR--3 prior to cycle 2 | 50 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGFR--3 prior to cycle 3 | 50 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGF--C at baseline | 283 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGF--C prior to cycle 2 | 311 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VEGF--C prior to cycle 3 | 311 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | IL--8 at baseline | 0.1 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | IL--8 prior to cycle 2 | 5.9 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | IL--8 prior to cycle 3 | 0.4 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | ICAM--1 at baseline | 243594 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | ICAM--1 prior to cycle 2 | 239027 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | ICAM--1 prior to cycle 3 | 200959 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VCAM--1 at baseline | 1307900 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VCAM--1 prior to cycle 2 | 1850000 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | VCAM--1 prior to cycle 3 | 1666200 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | FGF2 at baseline | 120 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | FGF2 prior to cycle 2 | 110 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | FGF2 prior to cycle 3 | 120 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | PDGF -- AA at baseline | 478 pg/ml |
| Arm II (Trebananib and Anti-VEGF Therapy) | Changes in Circulating Angiogenic Factors | PDGF -- AA prior to cycle 2 | 262 pg/ml |
Comparison: Arm A vs Arm B shift test on Angiopoietin -- 2 prior to cycle 2. Wilcoxon rank-sum test p-value.p-value: 0.86Wilcoxon (Mann-Whitney)
Comparison: Angiopoietin -- 2 prior to cycle 3p-value: 0.76Wilcoxon (Mann-Whitney)
Comparison: Tie--2 Prior to cycle 2p-value: 0.14Wilcoxon (Mann-Whitney)
Comparison: Tie -- 2 prior to cycle 3p-value: 0.069Wilcoxon (Mann-Whitney)
Comparison: VEGF -- A prior to cycle 2p-value: 0.19Wilcoxon (Mann-Whitney)
Comparison: VEGF--A prior to cycle 3p-value: 0.046Wilcoxon (Mann-Whitney)
Comparison: PIGF Prior to Cycle 2p-value: 0.029Wilcoxon (Mann-Whitney)
Comparison: PIGF prior to cycle 3p-value: 0.2Wilcoxon (Mann-Whitney)
Comparison: VEGFR--3 prior to cycle 2p-value: 0.11Wilcoxon (Mann-Whitney)
Comparison: VEGFR--3 prior to cycle 3p-value: 0.068Wilcoxon (Mann-Whitney)
Comparison: VEGF--C prior to cycle 2p-value: 0.61Wilcoxon (Mann-Whitney)
Comparison: VEGF--C prior to cycle 3p-value: 0.27Wilcoxon (Mann-Whitney)
Comparison: IL--8 prior to cycle 2p-value: 0.61Wilcoxon (Mann-Whitney)
Comparison: IL--8 prior to cycle 3p-value: 0.49Wilcoxon (Mann-Whitney)
Comparison: ICAM--1 prior to cycle 2p-value: 0.82Wilcoxon (Mann-Whitney)
Comparison: ICAM--1 prior to cycle 3p-value: 0.069Wilcoxon (Mann-Whitney)
Comparison: VCAM--1 prior to cycle 2p-value: 0.34Wilcoxon (Mann-Whitney)
Comparison: VCAM--1 prior to cycle 3p-value: 0.046Wilcoxon (Mann-Whitney)
Comparison: FGF2 prior to cycle 2p-value: 0.11Wilcoxon (Mann-Whitney)
Comparison: FGF2 prior to cycle 3p-value: 0.23Wilcoxon (Mann-Whitney)
Comparison: PDGF--AA prior to cycle 2p-value: 0.37Wilcoxon (Mann-Whitney)
Comparison: PDGF--AA prior to cycle 3p-value: 0.35Wilcoxon (Mann-Whitney)