A Phase 2 interventional study of Bevacizumab and Pazopanib Hydrochloride in Advanced Renal Cell Carcinoma, Advanced Sarcomatoid Renal Cell Carcinoma and Stage III Renal Cell Cancer AJCC v7, sponsored by National Cancer Institute (NCI). Completed at 12 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-06-07.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
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.
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.
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Browse Carcinoma studies →National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.
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Exclusion Criteria:
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.
Biological: Trebananib
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.
Biological: Bevacizumab · Drug: Pazopanib Hydrochloride · Drug: Sorafenib Tosylate · Drug: Sunitinib Malate · Biological: Trebananib
Given IV
Also known as: Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab awwb, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar CT-P16, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar GB-222, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar RPH-001, Bevacizumab Biosimilar SCT501, BP102, BP102 Biosimilar, HD204, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501
Given PO
Also known as: GW786034B, Votrient
Given PO
Also known as: BAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenib
Given PO
Also known as: SU011248, SU11248, sunitinib, Sutent
Given IV
Also known as: AMG 386, AMG386, Angiopoietin 1/2-Neutralizing Peptibody AMG 386
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
Tumor Response
Tumor Response Classification
Time frame: at 8 weeks
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
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
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
| Milestone | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|
| Started | 19 | 22 |
| Completed | 17 | 18 |
| Not completed | 2 | 4 |
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.
| percentage of patients responding | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|
| Observed Response Rate | 0 (0 to 20) | 11 (1 to 35) |
Tumor Response Classification
| Participants | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|
| Partial Response | 0 | 2 |
| Stable Disease | 5 | 8 |
| Progressive Disease | 11 | 6 |
| Not Evaluable | 1 | 2 |
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.)
| months | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|
| Progression Free Survival (PFS) | 2.7 (2.3 to 4.7) | 5.2 (2.7 to 10.8) |
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).
| Participants | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|
| SAE Cardiac disorders: Cardiac arrest | 0 | 1 |
| SAE Metabolism and nutrition disorders: Hypokalemia | 1 | 0 |
| SAE Respiratory, thoracic and mediastinal disorders: Dyspnea | 1 | 1 |
| SAE Respiratory, thoracic and mediastinal disorders: Pleural effusion | 1 | 0 |
| Blood and lymphatic system disorders: Anemia | 0 | 1 |
| General disorders and administrative site conditions: Fatigue | 1 | 3 |
| Investigations: Lymphocyte count decreased | 0 | 1 |
| Investigations: Weight gain | 0 | 1 |
| Metabolism and nutrition disorders: Acidosis | 0 | 1 |
| Metabolism and nutrition disorders: Hyperglycemia | 1 | 0 |
| Metabolism and nutrition disorders: Hyponatremia | 0 | 1 |
| Musculoskeletal and connective tissue disorders: Back pain | 1 | 1 |
| Vascular disorders: Hypertension | 3 | 3 |
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.
| pg/ml | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|
| Angiopoietin--2 at baseline | 3909 (3246 to 4863) | 3237 (2424 to 4813) |
| Angiopoietin--2 prior to cycle 2 | 132156 (110775 to 160316) | 120956 (84474 to 131643) |
| Angiopoietin--2 prior to cycle 3 | 125928 (114871 to 141528) | 96075 (84200 to 150486) |
| Tie--2 at baseline | 803 (510 to 1035) | 835 (650 to 1094) |
| Tie--2 prior to cycle 2 | 783 (535 to 1041) | 671 (571 to 856) |
| Tie--2 prior to cycle 3 | 912 (263 to 1232) | 753 (424 to 912) |
| VEGF--A at baseline | 27.3 (10.5 to 48.4) | 26.1 (19.6 to 38.0) |
| VEGF--A prior to cycle 2 | 21.3 (10.5 to 29.0) | 33.4 (13.6 to 48.2) |
| VEGF--A prior to cycle 3 | 20.7 (0.3 to 34.2) | 41.2 (26.1 to 56.7) |
| PIGF at baseline | 31.1 (26.1 to 35.2) | 30.7 (28.3 to 46.7) |
| PIGF prior to cycle 2 | 30.5 (21.8 to 36.0) | 33.6 (29.9 to 39.2) |
| PIGF prior to cycle 3 | 31.4 (30.5 to 34.3) | 31.5 (26.3 to 41.8) |
| VEGFR--3 at baseline | 873 (157 to 1073) | 489 (50 to 898) |
| VEGFR--3 prior to cycle 2 | 722 (117 to 869) | 50 (50 to 321) |
| VEGFR--3 prior to cycle 3 | 489 (362 to 954) | 50 (50 to 416) |
| VEGF--C at baseline | 255 (72 to 425) | 283 (251 to 380) |
| VEGF--C prior to cycle 2 | 209 (67 to 340) | 311 (247 to 357) |
| VEGF--C prior to cycle 3 | 230 (45 to 358) | 311 (154 to 503) |
| IL--8 at baseline | 0.1 (0.1 to 12.6) | 0.1 (0.1 to 4.0) |
| IL--8 prior to cycle 2 | 3.6 (0.1 to 17.5) | 5.9 (0.1 to 13.5) |
| IL--8 prior to cycle 3 | 2.5 (0.1 to 8.1) | 0.4 (0.1 to 17.3) |
| ICAM--1 at baseline | 161879 (103645 to 240620) | 243594 (185653 to 601003) |
| ICAM--1 prior to cycle 2 | 193335 (117584 to 247434) | 239027 (160295 to 318968) |
| ICAM--1 prior to cycle 3 | 262636 (221161 to 266594) | 200959 (150610 to 276615) |
| VCAM--1 at baseline | 965554 (738499 to 1421550) | 1307900 (982643 to 1946700) |
| VCAM--1 prior to cycle 2 | 1336300 (955663 to 1903550) | 1850000 (1327000 to 2555600) |
| VCAM--1 prior to cycle 3 | 982488 (969237 to 1581000) | 1666200 (1351500 to 2091050) |
| FGF2 at baseline | 124 (105 to 136) | 120 (105 to 136) |
| FGF2 prior to cycle 2 | 112 (89 to 131) | 110 (95 to 132) |
| FGF2 prior to cycle 3 | 131 (104 to 136) | 120 (97 to 133) |
| PDGF -- AA at baseline | 351 (237 to 788) | 478 (112 to 647) |
| PDGF -- AA prior to cycle 2 | 291 (190 to 394) | 262 (213 to 829) |
| PDGF -- AA prior to cycle 3 | 264 (119 to 710) | 173 (105 to 777) |
Collected over 8 weeks for adverse events. Until removal from the study or to death for late adverse events, up to 12 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm I (Trebananib Monotherapy) | 0/17 (0%) | 10/17 (58.8%) | 16/17 (94.1%) |
| Arm II (Trebananib and Anti-VEGF Therapy) | 2/18 (11.1%) | 18/18 (100%) | 18/18 (100%) |
| Event | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|
| DyspneaRespiratory, thoracic and mediastinal disorders | 1/17 | 3/18 |
| Myocardial infarctionCardiac disorders | 0/17 | 2/18 |
| Acute kidney injuryRenal and urinary disorders | 0/17 | 2/18 |
| NauseaGastrointestinal disorders | 1/17 | 1/18 |
| Urinary tract infectionInfections and infestations | 1/17 | 0/18 |
| UrosepsisInfections and infestations | 1/17 | 0/18 |
| Lymphocyte count decreasedInvestigations | 1/17 | 1/18 |
| HyperglycemiaMetabolism and nutrition disorders | 1/17 | 0/18 |
| HypokalemiaMetabolism and nutrition disorders | 1/17 | 0/18 |
| Back painMusculoskeletal and connective tissue disorders | 1/17 | 0/18 |
| Event | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) |
|---|---|---|
| HypertensionVascular disorders | 5/17 | 11/18 |
| FatigueGeneral disorders | 9/17 | 10/18 |
| Creatinine increasedInvestigations | 4/17 | 10/18 |
| NauseaGastrointestinal disorders | 7/17 | 8/18 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 7/17 | 3/18 |
| HyponatremiaMetabolism and nutrition disorders | 6/17 | 7/18 |
| ProteinuriaRenal and urinary disorders | 4/17 | 7/18 |
| AnemiaBlood and lymphatic system disorders | 5/17 | 6/18 |
| Weight gainInvestigations | 2/17 | 6/18 |
| HypoalbuminemiaMetabolism and nutrition disorders | 4/17 | 6/18 |
| Age, Continuous(years) | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) | Total |
|---|---|---|---|
| Median | 64 (49 to 76) | 59 (46 to 74) | 60 (46 to 76) |
| Sex: Female, Male(Participants) | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) | Total |
|---|---|---|---|
| Female | 4 | 4 | 8 |
| Male | 13 | 14 | 27 |
| Race/Ethnicity, Customized(Participants) | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) | Total |
|---|---|---|---|
| American Indian/Alaska Native | 2 | 0 | 2 |
| Asian/Pacific Islander | 0 | 1 | 1 |
| Black | 2 | 1 | 3 |
| Hispanic | 4 | 4 | 8 |
| White | 9 | 12 | 21 |
| Region of Enrollment(participants) | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) | Total |
|---|---|---|---|
| United States | 17 | 18 | 35 |
| ECOG Performance Score(Participants) | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) | Total |
|---|---|---|---|
| 0 | 12 | 11 | 23 |
| 1 | 5 | 7 | 12 |
| Prior Anti-VEGF Agent(Participants) | Arm I (Trebananib Monotherapy) | Arm II (Trebananib and Anti-VEGF Therapy) | Total |
|---|---|---|---|
| Bevacizumab | 5 | 10 | 15 |
| Pazopanib | 6 | 5 | 11 |
| Sorafenib | 2 | 2 | 4 |
| Sunitinib | 4 | 1 | 5 |
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