Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Papillary Renal Cell Carcinoma

Chromophil Renal Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive CBM588 PO BID, nivolumab IV over 30 minutes on day 1, and cabozantinib S-malate PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive nivolumab IV over 30 minutes on day 1 and cabozantinib S-malate PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate

Clostridium butyricum CBM 588 Probiotic Strain

Sumanta K Pal

This phase I trial evaluates the effects of CBM588 in combination with standard therapies, nivolumab and cabozantinib, in treating patients with kidney cancer that has spread to other places in the body (advanced/metastatic). The digestive microbiome may have an effect on how patients respond to treatment, and previous research shows that a specific bacteria found in the gut (Bifidobacterium) may predispose participants to a better response to standard therapies. CBM588 is a strain of bacteria that can restore species of Bifidobacterium to the microbiome. The primary aim of this study is to determine how CBM588 changes the microbiome of patients with metastatic renal cell carcinoma. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving CBM588, nivolumab, and cabozantinib may kill more tumor cells.

PRIMARY OBJECTIVE:

I. To determine the effect of clostridium butyricum CBM 588 probiotic strain (CBM588) (in combination with cabozantinib/nivolumab) in modulation of the gut microbiome in patients with metastatic renal cell carcinoma (mRCC).

SECONDARY OBJECTIVES:

I. To evaluate the effect of CBM588 on the clinical efficacy of the cabozantinib/nivolumab combination.

II. To assess the effect of CBM588 on systemic immunodulation of the cabozantinib/nivolumab combination in patients with mRCC.

III. To assess the effect of CBM588 on toxicities such as diarrhea and nausea using Common Terminology Criteria for Adverse Events (CTCAE) version (v)5 criteria with the cabozantinib/nivolumab combination in patients with mRCC.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 and cabozantinib S-malate orally (PO) once daily (QD). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM 2: Patients receive CBM588 PO twice a day (BID), nivolumab IV over 30 minutes on day 1, and cabozantinib S-malate PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

CBM588 in Combination With Nivolumab and Cabozantinib for the Treatment of Advanced or Metastatic Kidney Cancer

Pilot Study to Evaluate the Biologic Effect of CBM588 in Combination With Cabozantinib/Nivolumab for Patients With Metastatic Renal Cell Carcinoma

Will be assessed for patients' stool sample

Using translational methods, will compute the Shannon index at baseline for a comparison of microbial diversity.

Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The association between treatment arm and overall response as per RECIST criteria (response observed versus not observed) will be examined using Fisher's exact test.

The difference in progression free survival across the two groups will be explored graphically using Kaplan-Meier survival plots. Median progression-free survival time for each of the two arms will be reported and Cox Proportional Hazards model will be used to estimate the hazard ratio and its confidence interval.

Using translational methods will estimate the proportion of T-cells in the blood. This will be assessed graphically across serial timepoints of blood collection to ascertain any trends. Will compare the proportion of circulating T-cells with cabozantinib/nivolumab alone versus cabozantinib/nivolumab with CBM 588.

Using translational methods will estimate the proportion of MDSCs in the blood. This will be assessed graphically across serial timepoints of blood collection to ascertain any trends. Will compare the proportion of circulating MDSCs with cabozantinib/nivolumab alone versus cabozantinib/nivolumab with CBM 588.

Using translational methods will estimate the proportion of serum cytokines in the blood. This will be assessed graphically across serial time points of blood collection to ascertain any trends. Will compare the IL-6, IL-8, and other cytokines/chemokines with cabozantinib/nivolumab alone versus cabozantinib/nivolumab with CBM 588.

Will compare toxicities, such as diarrhea and nausea, using Common Terminology Criteria for Adverse Events version 5 with cabozantinib/nivolumab alone versus cabozantinib/nivolumab with CBM 588.

National Cancer Institute (NCI)

City of Hope Medical Center

Antibodies

Antibodies, Monoclonal

Bevacizumab

Immunoglobulins

Immunoglobulin G

Endothelial Growth Factors

Mitogens

Sunitinib

Immunoglobulins, Intravenous

Sorafenib

Trebananib

Angiogenesis Inhibitors

Growth Inhibitors

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

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.

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.

Pazopanib Hydrochloride

Sorafenib Tosylate

Sunitinib Malate

Thomas J Semrad

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.

Trebananib With or Without Bevacizumab, Pazopanib Hydrochloride, Sorafenib Tosylate, or Sunitinib Malate in Treating Patients With Advanced Kidney Cancer

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

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.

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 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.)

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).

CTCAE version 4.0 will be used until March 31, 2018. CTCAE version 5.0 will be used from April 1, 2018.

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

Arm I (Trebananib Monotherapy)

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

Arm II (Trebananib and Anti-VEGF Therapy)

Total

Age, Continuous

Sex: Female, Male

American Indian/Alaska Native

Asian/Pacific Islander

Black

Hispanic

White

Race/Ethnicity, Customized

United States

Region of Enrollment

ECOG (Eastern Cooperative Oncology Group) Performance Score is a measure of patients' ability to tolerate therapies in serious illness, e.g. chemotherapy.

0 = Asymptomatic: Fully active, able to carry on all pre-disease activities without restriction

1. = Restricted in strenuous activity, ambulatory and able to do light work
2. = Capable of all self care, but no work activities; out of bed \> 50% of day
3. = Capable of limited self-care; confined to bed or chair \> 50% of day
4. = Completely disabled; no self-care; confined to bed or chair
5. = Dead

ECOG Performance Score

anti-VEGF agent: anti-Vascular Endothelial Growth Factor receptor agent.

Prior Anti-VEGF Agent

Thomas J Semrad, MD, MAS

Observed Response Rate

Tumor Response

Progression Free Survival (PFS)

SAE Cardiac disorders: Cardiac arrest

SAE Metabolism and nutrition disorders: Hypokalemia

SAE Respiratory, thoracic and mediastinal disorders: Dyspnea

SAE Respiratory, thoracic and mediastinal disorders: Pleural effusion

Blood and lymphatic system disorders: Anemia

General disorders and administrative site conditions: Fatigue

Investigations: Lymphocyte count decreased

Investigations: Weight gain

Metabolism and nutrition disorders: Acidosis

Metabolism and nutrition disorders: Hyperglycemia

Metabolism and nutrition disorders: Hyponatremia

Musculoskeletal and connective tissue disorders: Back pain

Vascular disorders: Hypertension

Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs

Arm A vs Arm B shift test on Angiopoietin -- 2 prior to cycle 2. Wilcoxon rank-sum test p-value.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CBM588 in Combination With Nivolumab and Cabozantinib for the Treatment of Advanced or Metastatic Kidney Cancer	NCT05122546	Advanced Clear ... Advanced Papill... Advanced Renal ... Advanced Sarcom... Metastatic Clea... Metastatic Papi... Metastatic Rena... Metastatic Sarc... Stage III Renal... Stage IV Renal ... Unresectable Cl... Unresectable Re...	Cabozantinib S-... Clostridium but... Nivolumab	18 Years -	City of Hope Medical Center
Trebananib With or Without Bevacizumab, Pazopanib Hydrochloride, Sorafenib Tosylate, or Sunitinib Malate in Treating Patients With Advanced Kidney Cancer	NCT01664182	Advanced Renal ... Advanced Sarcom... Stage III Renal... Stage IV Renal ...	Bevacizumab Pazopanib Hydro... Sorafenib Tosyl... Sunitinib Malat... Trebananib	18 Years -	National Cancer Institute (NCI)
CBM588 in Combination With Nivolumab and Cabozantinib for the Treatment of Advanced or Metastatic Kidney Cancer	NCT05122546	Advanced Clear ... Advanced Papill... Advanced Renal ... Advanced Sarcom... Metastatic Clea... Metastatic Papi... Metastatic Rena... Metastatic Sarc... Stage III Renal... Stage IV Renal ... Unresectable Cl... Unresectable Re...	Cabozantinib S-... Clostridium but... Nivolumab	18 Years -	City of Hope Medical Center
CBM588 in Combination With Nivolumab and Cabozantinib for the Treatment of Advanced or Metastatic Kidney Cancer	NCT05122546	Advanced Clear ... Advanced Papill... Advanced Renal ... Advanced Sarcom... Metastatic Clea... Metastatic Papi... Metastatic Rena... Metastatic Sarc... Stage III Renal... Stage IV Renal ... Unresectable Cl... Unresectable Re...	Cabozantinib S-... Clostridium but... Nivolumab	18 Years -	City of Hope Medical Center

Spots Global Cancer Trial Database for advanced sarcomatoid renal cell carcinoma