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

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 14 days for 2 cycles. Patients then undergo partial or radical nephrectomy 7-28 days later. Patients then receive nivolumab over 30 IV on day 1. Treatment repeats every 14 days for 6 cycles, and then every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients enrolled after Amendment 4 receive nivolumab IV over 30 minutes on day 1. Patients then undergo partial or radical nephrectomy 7-28 days later. Patient then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 9 cycles in the absence of disease progression or unacceptable toxicity.

Patients undergo partial or radical nephrectomy within 8 weeks after registration followed by observation.

Nephrectomy

Patient Observation

Lauren Harshman

This phase III trial compares nephrectomy (surgery to remove a kidney or part of a kidney) with nivolumab to the usual approach of nephrectomy followed by standard post-operative follow-up and monitoring, in treating patients with kidney cancer that is limited to a certain part of the body (localized). Nivolumab is a drug that may help stimulate the immune system to attack any cancer cells that may remain after surgery. The addition of nivolumab to the usual surgery could prevent the cancer from returning. It is not yet known whether nivolumab and nephrectomy is more effective than nephrectomy alone in treating patients with kidney cancer.

PRIMARY OBJECTIVE:

I. To compare recurrence-free survival (RFS) between patients with renal cell carcinoma randomly assigned to perioperative nivolumab in conjunction with radical or partial nephrectomy with patients randomized to surgery alone.

SECONDARY OBJECTIVES:

I. To evaluate for differences in recurrence-free survival associated with perioperative nivolumab compared to surgery alone among the subset of patients with clear cell histology.

II. To compare the overall survival between the two arms. III. To describe the safety and tolerability of perioperative nivolumab.

CORRELATIVE OBJECTIVES:

I. To correlate the primary tumor's expression of PD-L1 with outcome. II. To correlate the expression of PD-L1 on tumor tissue at nephrectomy and recurrence with outcome.

III. To archive images for potential central confirmation of recurrence and for future correlative work with American College of Radiology Imaging Network (ACRIN), including markers predicting outcome or response.

IV. To prospectively collect tumor and biologic specimens (e.g., serum, peripheral blood mononuclear cells \[PBMCs\]) for future correlative studies.

V. To characterize the pharmacokinetics of nivolumab and explore exposure response relationships with respect to safety and efficacy.

VI. To characterize the immunogenicity of nivolumab.

QUALITY OF LIFE OBJECTIVE:

I. To evaluate differences in change from baseline in patient-reported symptoms and toxicities among patients randomized to treatment with nivolumab compared to surgery alone.

OTHER EXPLORATORY OBJECTIVES:

I. To explore descriptively the efficacy of treatment with nivolumab in patients with non-clear cell (including unclassified) histologies.

II. To characterize the effects of nivolumab on bone metabolism and bone density.

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

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 14 days for 2 cycles. Patients then undergo partial or radical nephrectomy 7-28 days later. Patient then receive nivolumab over 30 IV on day 1. Treatment repeats every 14 days for 6 cycles, and then every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients enrolled after Amendment 4 receive nivolumab IV over 30 minutes on day 1. Patients then undergo partial or radical nephrectomy 7-28 days later. Patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 9 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients undergo partial or radical nephrectomy within 8 weeks after registration followed by observation.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and every 12 months for 5 years.

Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy

A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients With Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC)

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

Association between the primary tumor's expression of PD-L1 with outcome

Association between the expression of PD-L1 on tumor tissue at nephrectomy as well as recurrence and outcome

To archive images for potential central confirmation of recurrence and for future correlative work

To collect tumor and biologic specimens for future correlative studies

To characterize the pharmacokinetics of nivolumab and explore exposure response relationships with respect to safety and efficacy

To characterize the immunogenicity of nivolumab

To evaluate differences in change from baseline in patient-reported symptoms and toxicities among patients randomized to treatment with nivolumab compared to surgery alone

To explore descriptively the efficacy of treatment with nivolumab in patients with non-clear cell (including unclassified) histologies.

To characterize the effects of nivolumab on bone metabolism and bone density

RFS is defined as time from randomization to disease recurrence or death from any cause. Patients who did not undergo nephrectomy or were not disease-free following nephrectomy were considered as having an event at day 1. Patients that are alive without an event were censored at the date of last disease evaluation. RFS rate at 5 years was the proportion of patients who are recurrence-free and alive at 5 years based on Kaplan-Meier estimates.

RFS is defined as time from randomization to disease recurrence or death from any cause. Patients who did not undergo nephrectomy or were not disease-free following nephrectomy were considered as having an event at day 1. Patients that are alive without an event were censored at the date of last disease evaluation. RFS rate at 3 years was the proportion of patients who are recurrence-free and alive at 3 years based on Kaplan-Meier estimates.

Overall survival is defined as time from randomization to death from any cause. Overall survival rate at 5 years was the proportion of patients who are alive at 5 years based on Kaplan-Meier estimates.

Canadian Cancer Trials Group

National Cancer Institute (NCI)

All patients registered on this study were included in the all-cause mortality analysis. Patients who received treatment and were assessed for adverse events were included in the analysis of adverse events.

Arm A (Nephrectomy + Nivolumab)

Arm B (Nephrectomy Only)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

All randomized RCC patients are included in this analysis.

Study Statistician

All randomized RCC patients were included in this analysis.

Recurrence-free Survival (RFS) Rate at 5 Years

All randomized RCC patients who had clear cell histology according to surgery or biopsy were included in this analysis.

Recurrence-free Survival (RFS) Rate at 3 Years Among Patients With Clear Cell Histology

All randomized patients were included in this analysis.

Overall Survival Rate at 5 Years

Association Between the Primary Tumor's Expression of PD-L1 With Outcome

Association Between the Expression of PD-L1 on Tumor Tissue at Nephrectomy as Well as Recurrence and Outcome

To Archive Images for Potential Central Confirmation of Recurrence and for Future Correlative Work

To Collect Tumor and Biologic Specimens for Future Correlative Studies

To Characterize the Pharmacokinetics of Nivolumab and Explore Exposure Response Relationships With Respect to Safety and Efficacy

To Characterize the Immunogenicity of Nivolumab

To Evaluate Differences in Change From Baseline in Patient-reported Symptoms and Toxicities Among Patients Randomized to Treatment With Nivolumab Compared to Surgery Alone

To Explore Descriptively the Efficacy of Treatment With Nivolumab in Patients With Non-clear Cell (Including Unclassified) Histologies.

To Characterize the Effects of Nivolumab on Bone Metabolism and Bone Density

Overall Study

Papillary Renal Cell Carcinoma

Chromophil Renal Cell Carcinoma

Chromophobe Renal Cell Carcinoma

Collecting Duct Carcinoma

Dermatologic Agents

Isotretinoin

Cohort 1 is designed as a single stage study with a total sample size of 20. This design discriminates between ORR rates of 10 and 35%.

Cohort 2 is designed as a Simon's optimal two-stage design with a total possible sample size of 17. This design discriminates between ORR rates of 5 and 25%.

Cohort 3 is designed as an expansion cohort of Cohort 1 with 20 additional patients to obtain a more precise estimate of the ORR and clinical outcomes

Cohort 4 is an expansion of Cohorts 1+3, which will accure an additional 40 patients

cabozantinib 40mg, self administered orally once daily on a continuous schedule (days 1-28) Patients will continue to take cabozantinib until disease progression (unless continuing treatment beyond progression), major toxicity, or withdrawal from the study for any reason.

cabozantinib

Patients will receive an intravenous infusion of nivolumab, per institutional standards, at 240 mg on Cycle 1, Day 1 and will return to the center approximately every two weeks (14 ± 3 days) for subsequent infusions until disease progression (unless continuing treatment beyond progression), major toxicity, or withdrawal from the study for any reason.

nivolumab

Darren Feldman, MD

The purpose of this study is to compare any good and bad effects of using a combination of nivolumab (Opdivo®) and cabozantinib (Cabometyx®) in people with metastatic kidney cancer.

This is a single institution open-label phase II trial of cabozantinib and nivolumab in patients with advanced or metastatic non-clear cell Renal Cell Carcinoma (nccRCC), who have not received prior PD-1/PD-L1 directed therapy. This study is designed as separate cohorts defined by histology across three cohorts.

A Study of Nivolumab In Combination With Cabozantinib in Patients With Non-Clear Cell Renal Cell Carcinoma

A Phase 2 Open-Label Study of Nivolumab Combined With Cabozantinib in Subjects With Advanced or Metastatic Non-Clear Cell Renal Cell Carcinoma (CA209-9KU)

Memorial Sloan Kettering Cancer Center

Ipilimumab

Eligible patients will be enrolled and receive treatment with

* Cycle 1-4 (cycles of 21 days)

  * Cabozantinib predetermined protocol dosage po daily
  * Nivolumab predetermined protocol dosage via IV every 3 weeks
  * Ipilimumab predetermined protocol dosage via IV every 3 weeks
* After the first four cycles of therapy,

  * Cabozantinib determined protocol dosage po daily
  * Nivolumab predetermined protocol dosage via IV every 3 weeks (cycles of 28 days)

Cabozantinib predetermined protocol dosage po daily

Cabozantinib

Nivolumab predetermined protocol dosage via IV every 3 weeks

Ipilimumab predetermined protocol dosage via IV every 3 weeks

Bradley McGregor, MD

David F McDermott, MD

Hans Hammers, M.D., PhD

This research study will assess whether cabozantinib, nivolumab and ipilimumab in combination are safe and effective in slowing down the growth of kidney cancer(renal cell carcinoma or RCC) that has advanced or spread to other areas the body.

This research study involves an investigational drug combination not approved by the FDA (the U.S. Food and Drug Administration) for your kidney cancer.

The names of the study drugs in this investigational combination are:

* Cabozantinib
* Nivolumab
* Ipilimumab

The research study procedures include screening for eligibility, study treatment, participant evaluations and safety follow-up visits, in addition to general health status follow-up after study treatment.

It is expected that about 40 people will take part in this research study.

Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC

A Phase 2 Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Advanced Non-Clear Cell Renal Cell Carcinoma

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Percent of patients who achieve overall response (CR or PR) by RECIST 1.1 will be summarized with 80% two-sided exact binomial confidence intervals (CI)

will be estimated using the method of Kaplan-Meier, for all patients and by histology subtypes. M

the method of Kaplan-Meier, for all patients and by histology subtypes evaluation.

the method of Kaplan-Meier, for all patients and by histology subtypes

For toxicity reporting, all adverse events will be graded and analyzed using CTCAE version 5.

The Functional Assessment of Cancer Therapy-Kidney Symptom (FKSI-19) is a 19 item questionnaire with each item scored on a scale of 0-4 for a total score of 0-76 with higher scores indicating fewer symptom

The Brief Fatigue Inventory (BFI) is a 9-item questionnaire with each item scored on a scale of 0-10.

Scores are categorized as mild (1-3), moderate (4-6), or severe (7-10). A global fatigue score can be found by averaging the score obtained on each test item completed

ORR by RECIST 1.1 according to histology subtypes (Papillary RCC versus other histology types) will be summarized with 80% two-sided exact CIs.

Bristol-Myers Squibb

Exelixis

Bradley A. McGregor, MD

Sponsor Investigator

Symptoms and General Pathology

Neoplasm Metastasis

Carcinoma, Ductal

Carcinoma, Medullary

Carcinoma, Neuroendocrine

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Thyroid Cancer, Medullary

Renal Medullary Carcinoma

Neuroendocrine Tumor

Neuroepithelioma

Radium Ra 223 dichloride

Patients receive radium Ra 223 dichloride IV over 1 minute on day 1 of cycles 1-6 and cabozantinib S-malate PO QD on days 1-28 of every cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive cabozantinib S-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate

Quality-of-Life Assessment

Questionnaire Administration

Radium Ra 223 Dichloride

Site Public Contact

Rana R. McKay

Mamta Parikh

Thomas C. Westbrook

Walter M. Stadler

Bryan A. Faller

Joshua Lukenbill

Yousef Zakharia

Elizabeth M. Wulff-Burchfield

Mark Sides

Bradley A. McGregor

Kriti Mittal

Tareq Al Baghdadi

Daniel M. Anderson

Hiram A. Gay

Ana M. Molina

Tracy L. Rose

Michael R. Harrison

Yuanquan Yang

Tyler Gunter

Ravi Patel

Suzanne M. Cole

Umang Swami

Deepak Kilari

Rana R McKay

This phase II trial studies whether adding radium-223 dichloride to the usual treatment, cabozantinib, improves outcomes in patients with renal cell cancer that has spread to the bone. Radioactive drugs such as radium-223 dichloride may directly target radiation to cancer cells and minimize harm to normal cells. Cabozantinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving radium-223 dichloride and cabozantinib may help lessen the pain and symptoms from renal cell cancer that has spread to the bone, compared to cabozantinib alone.

PRIMARY OBJECTIVE:

I. To assess the symptomatic skeletal event (SSE)-free survival of metastatic renal cell cancer (mRCC) patients with bone metastases treated with cabozantinib S-malate (cabozantinib) + radium Ra 223 dichloride (radium-223 dichloride) compared to cabozantinib alone.

SECONDARY OBJECTIVES:

I. To investigate the safety, toxicity and tolerability as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 in patients treated with cabozantinib + radium-223 dichloride compared to cabozantinib alone.

II. To assess SSE-free survival of each treatment arm in predefined sub-groups. III. To assess progression-free survival (PFS) in each treatment arm. IV. To assess overall survival (OS) in each treatment arm. V. To assess time to first SSE (defined as first use of radiation therapy to relieve skeletal symptoms, new symptomatic pathologic vertebral or non-vertebral bone fractures, spinal cord compression, or symptomatic tumor-related orthopaedic surgical intervention) in each treatment arm.

VI. To assess the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

VII. To assess time to subsequent anti-cancer systemic therapy and type of systemic therapy.

EXPLORATORY QUALITY OF LIFE OBJECTIVES:

I. To compare patient-reported pain as assessed by the Brief Pain Inventory questionnaire (BPI) between patients randomized to cabozantinib versus cabozantinib + radium-223 dichloride at 6 months.

II. To compare patient-reported pain as assessed by the BPI between patients randomized to cabozantinib versus cabozantinib + radium-223 dichloride at other timepoints.

III. To compare overall health-related quality of life as assessed by the Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health 10 between patients randomized to cabozantinib versus cabozantinib + radium-223 dichloride.

IV. To compare quality-adjusted survival (overall survival x utility score assessed by European Quality of Life Five Dimension Five Level Scale \[EQ5D-5L\]) between patients randomized to cabozantinib + radium-223 dichloride.

CORRELATIVE OBJECTIVES:

I. To evaluate changes in the following bone turnover markers between arms:

Ia. Marker of bone formation: P1NP, BSAP. Ib. Marker of bone resorption: CTX, NTX. II. To correlate changes in bone turnover markers with SSE-free survival. III. To assess the immunomodulatory properties of cabozantinib with or without radium-223 dichloride at baseline, during treatment, and at progression.

IV. To identify prognostic and predictive genomic biomarkers of response to cabozantinib and radium-223 dichloride via assessment of tissue, circulating tumor cells (CTCs) and circulating tumor deoxyribonucleic acid (DNA) (cfDNA).

V. To assess the association between bone response according to MD Anderson response criteria and SSE-free survival (FS).

VI. To correlate change in level of total alkaline phosphatase and bone-specific alkaline phosphatase to overall response to cabozantinib + radium-223 dichloride compared to cabozantinib alone.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive radium Ra 223 dichloride intravenously (IV) over 1 minute on day 1 of cycles 1-6 and cabozantinib S-malate orally (PO) once daily (QD) on days 1-28 of every cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive cabozantinib S-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 5 years from study registration.

Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer That Has Spread to the Bone, the RadiCaL Study

A Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients With Advanced Renal Cell Carcinoma With Bone Metastasis (RadiCal)

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

SSE-FS distribution will be estimated using the method of Kaplan-Meier by treatment arm. Comparison between the two arms will be performed using a one-sided log-rank test and one-sided p-value less than 0.025 will indicate that the experimental arm is superior to the control arm. SSE-FS will be censored at the date of last SSE assessment for those alive and SSE free. Hazard ratio (experimental over control arm) as well as two-sided 90% confidence interval (CI) for treatment will be estimated using the stratified Cox proportional hazard model with a single treatment covariate.

Will be determined using Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be summarized and compared between arms using chi-square or fisher exact tests as appropriate.

Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test.

Radiographic progression will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test.

Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test. Patients who are alive will be censored at last follow up date.

Will be determined in each treatment. The median estimate to first SSE-FS will be calculated.

Will be defined by RECIST version 1.1. Number and proportion of patients achieving ORR (by RECIST) will be summarized with two-sided 90% CI by treatment arm; comparison between arms will be conducted using chi-square or Fisher's exact test as appropriate.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy	NCT03055013	Metastatic Rena... Sarcomatoid Ren... Stage II Renal ... Stage III Renal... Unclassified Re...	Nephrectomy Nivolumab Patient Observa...	18 Years -	National Cancer Institute (NCI)
A Study of Nivolumab In Combination With Cabozantinib in Patients With Non-Clear Cell Renal Cell Carcinoma	NCT03635892	Advanced or Met... Unclassified Re... Papillary Renal... Fumarate Hydrat... Succinate Dehyd... Collecting Duct... Chromophobe Ren...	cabozantinib nivolumab	18 Years -	Memorial Sloan Kettering Cancer Center
Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC	NCT04413123	Papillary Renal... Unclassified Re... Translocation R... Chromophobe Ren... Collecting Duct... Renal Cell Carc... Unresectable Ad... Metastatic Ncc ...	Cabozantinib Nivolumab Ipilimumab	18 Years -	Dana-Farber Cancer Institute
Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy	NCT03055013	Metastatic Rena... Sarcomatoid Ren... Stage II Renal ... Stage III Renal... Unclassified Re...	Nephrectomy Nivolumab Patient Observa...	18 Years -	National Cancer Institute (NCI)
Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC	NCT04413123	Papillary Renal... Unclassified Re... Translocation R... Chromophobe Ren... Collecting Duct... Renal Cell Carc... Unresectable Ad... Metastatic Ncc ...	Cabozantinib Nivolumab Ipilimumab	18 Years -	Dana-Farber Cancer Institute
A Study of Nivolumab In Combination With Cabozantinib in Patients With Non-Clear Cell Renal Cell Carcinoma	NCT03635892	Advanced or Met... Unclassified Re... Papillary Renal... Fumarate Hydrat... Succinate Dehyd... Collecting Duct... Chromophobe Ren...	cabozantinib nivolumab	18 Years -	Memorial Sloan Kettering Cancer Center
Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer That Has Spread to the Bone, the RadiCaL Study	NCT04071223	Advanced Renal ... Chromophobe Ren... Clear Cell Rena... Collecting Duct... Kidney Medullar... Metastatic Mali... Papillary Renal... Stage IV Renal ... Unclassified Re...	Cabozantinib S-... Quality-of-Life... Questionnaire A... Radium Ra 223 D...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for unclassified renal cell carcinoma