Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Adenocarcinoma

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

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

All Drugs and Chemicals

Antineoplastic Agents

Anti-Infective Agents

Immunomodulating Agents

Sunitinib

Interferons

Trovax

Placebo

subcutaneous low dose IL-2, interferon-α or sunitinib

Standard of care therapy

The purpose of this study is to investigate whether TroVax, when added to first line standard of care therapy, improves survival for patients with locally advanced or metastatic clear cell renal adenocarcinoma.

This is an international, randomised, double blind, placebo controlled, parallel group study to investigate whether a minimum of three doses of TroVax® added to first-line standard of care therapy, prolongs the survival of patients with locally advanced or metastatic renal clear cell adenocarcinoma.

The primary endpoint is survival. The study is designed to be pragmatic, limiting additional study related investigations to a minimum. Protocol mandated scans and X-rays are limited to two time points (baseline and week 26) to permit comparison of the percentage of patients with progressive disease at 6 months as a secondary efficacy endpoint. Six months was selected based on review of published literature indicating that progressive disease was commonly observed by 26 weeks in patients with renal cancer. Endpoints such as tumour response by RECIST are considered of secondary importance to survival and will be determined by radiological examinations ordered at the discretion of the investigator based on the clinical status of the patient and will be based the interpretation of the patient's care-team (investigator and local radiologist).

After signing the study informed consent form and meeting the baseline enrolment criteria patients will be assigned by the investigator (their physician) to one of the following defined first-line standard of care regimens based on what is best for the patient and consistent with local practice:

1. subcutaneous low dose IL-2
2. interferon-α (excluding pegylated IFNα)
3. sunitinib

TroVax® is administered at a dose of 1E9TCID50/ml in 1ml by injection into the deltoid muscle of the upper arm at regular intervals up to 8 weeks apart up to a maximum of 13 doses.

TroVax Renal Immunotherapy Survival Trial

Randomised,Double-blind,Placebo-controlled,Parallel Group Study TroVax, Added to First-line Standard of Care, Prolongs Survival of Patients With Locally Advanced or Metastatic Clear Cell Renal Adenocarcinoma.

Sanofi

Oxford BioMedica

Adenocarcinoma, Clear Cell

Adenomyoepithelioma

Epithelial-myoepithelial Carcinoma

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Sunitinib 50 mg/day, 4 weeks on/2weeks off

Enrique Grande, MD

Cristina Suárez, MD

Xavier García del Muro, MD

Oscar Reig, MD

María J Méndez, MD

Daniel Castellano, MD

Teresa Alonso, MD

The therapeutic scenario of metastatic renal cancer is undergoing a new revolution with the appearance of a novel therapeutic strategy after the antiangiogenic treatments, that is the immunotherapy, in addition to the approval of new active drugs in the following lines of treatment.

There are currently two phase III trials in the first line of treatment in metastatic renal cancer that include different combinations of treatment based on immunotherapy. If results of these studies were positive, the therapeutic algorithm would be modified so that the remaining drugs would have to be repositioned within the therapeutic decision scheme.

Sunitinib has previously demonstrated its benefit in patients who had failed to prior treatment with cytokines, so it is likely to continue to be effective in patients who have become resistant to treatment with new drugs based on immune checkpoint blockade.

This phase II study is developed to evaluate the activity of sunitinib after treatment with immunotherapy-based regimens that are currently being developed within phase III clinical trials.

Study to Evaluate Efficacy and Safety of Sunitinib in Renal Cell Carcinoma Progressed to 1L Immunotherapy Treatment.

Phase II Study to Evaluate Efficacy and Safety of Sunitinib Therapy in Patients With Metastatic Renal Clear Cell Carcinoma Who Have Progressed to First-line Immunotherapy Treatment (INMUNOSUN Study)

Percentage of patients with documented response according RECIST 1.1 criteria (complete response + partial response)

Time from start of treatment to disease progression or death.

Time from start of treatment to disease progression or death due to the illness

Time from first response to disease progression or death.

Percentage of patients with documented response or disease stabilization according RECIST 1.1 criteria

Percentage of patients with each of the adverse event per grade

Pfizer

Apices Soluciones S.L.

Spanish Oncology Genito-Urinary Group

Antibodies

Bevacizumab

Pembrolizumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle.

Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV

MK-3475

Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV

Arm B: Phase II Treatment: administered at the maximum safe dose of 10mg or 15mg as established in the Phase 1b dose escalation cohort study.

Arkadiusz Z Dudek, M.D., Ph.D.

This is an open label, multi-institutional, single arm study of dose escalation phase Ib cohort, followed by a phase II cohort of anti-PD-1 antibody MK-3475 in combination with bevacizumab. No randomization or blinding is involved.

OUTLINE: This is a multi-center study.

The phase Ib dose escalation study will evaluate MK-3475 in combination with bevacizumab in subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease. The phase II trial will determine the activity of the combination of MK-3475 and bevacizumab in first line therapy for subjects with metastatic clear cell renal carcinoma.

PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

PHASE II INVESTIGATIONAL TREATMENT:

The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities will be followed for a total of 24 months.

Karnofsky Performance Status (KPS) ≥ 70% within 28 days prior to registration for protocol therapy.

Life Expectancy: 6 months or greater

The following baseline labs must be completed within 28 days prior to registration for protocol therapy:

Hematopoietic:

* Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L
* Platelets ≥ 100 × 10 9/L
* Hemoglobin (Hgb) ≥ 9.0 g/dL

Renal:

* Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
* OR, if serum creatinine \> 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min

Hepatic:

* Total serum bilirubin ≤ 1.5 × ULN
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN
* OR, AST and ALT ≤ 5 × ULN if liver function abnormalities are due to underlying malignancy

Coagulation:

* INR \< 1.5 × ULN
* OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.

Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma:

Phase Ib and Phase II Studies of Anti-PD-1 Antibody MK-3475 in Combination With Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma: Big Ten Cancer Research Consortium GU14-003

To establish the maximum tested safe dose of bevacizumab in combination with 200mg of MK-3475(pembrolizumab) for subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease.

To determine the activity of combination of MK-3475 and bevacizumab in first line therapy for subjects with treatment naïve metastatic clear cell RCC as assessed by response rates (complete or partial response) By calculating the proportion of subjects with a response (CR, PR) based on RECIST 1.1 where:

Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

To determine median progression-free survival (PFS) for this patient population, per RECIST 1.1 where:

Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

To determine if treatment regimen improves overall survival for this patient population. Median overall survival will be calculated up to 2 years from registration.

To determine the proportion of subjects with clinical benefit (complete response, partial response, or stable disease) based on RECIST 1.1, where:

Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab in subjects with metastatic RCC after failure of at least one systemic therapy. Toxicity will be assessed using CTCAE version 4. All grade 3 and 4 treatment-related adverse events will be reported.

Merck Sharp & Dohme LLC

Big Ten Cancer Research Consortium

Arkadiusz Z. Dudek, MD

Sponsor-Investigator

Adverse events are summarized for all study participants who received at least one dose of study drug. Per the protocol, the safety analysis population "will comprise all subjects who received at least one dose of study drug". Consequently, no per-group analyses were planned or performed.

All Subjects

Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV

Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV

Arm A - Phase 1b Dose Escalation Cohort

The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle.

MK-3475: Arm B: Phase II Treatment: 200mg IV

Bevacizumab: Arm B: Phase II Treatment: administered at the maximum safe dose of 5mg or 10mg as established in the Phase 1b dose escalation cohort study.

Arm B - Phase II Investigational Treatment

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

KPS 70

KPS 80

KPS 90

KPS 100

KPS is a general indicator of a subject's well being and ability to carry on daily activities.

100:Normal no complaints 90:Able to carry on normal activity 80:Normal activity with effort; some signs or symptoms of disease. 70:Cares for self 60:Requires occasional assistance, but is able to care for most of his personal needs. 50:Requires considerable assistance and frequent medical care.

40:Disabled 30:Severely disabled 20:Very sick 10:Moribund 0:Dead

Karnofsky Performance Status (KPS)

Prior Nephrectomy

Bone Metastases

The IMDC\\Heng Score is calculated based on the number of risk factors:

0 Risk Factors: Favorable Prognosis 1-2 Risk Factors: Intermediate Prognosis 3-6 Risk Factors: Poor Prognosis

Metastatic RCC Prognosis (by IMDC/Heng Score)

No per-group analysis was completed in the dose escalation cohort because the Phase IB dose-finding study found no dose-limiting toxicities and the primary objective (determine MTD) was satisfied. The baseline demographics as presented have been presented in several abstracts and published in the Journal of Clinical Oncology.

Clinicaltrials.gov Results Coordinator

Phase 1b: Maximum Safe Dose of Treatment Regimen

Results for Arm A - Phase Ib are reported as a single group, no per-group analyses were planned or performed.

Overall Response Rate

Progression-Free Survival

Overall Survival

Clinical Benefit Rate

Duodenal ulcer: Grade 4

Hyponatremia: Grade 4

Hypertension: Grade 3

Proteinuria: Grade 3

Adrenal insufficiency: Grade 3

Pain/Headaches: Grade 3

Pneumonitis: Grade 3

Hyponatremia: Grade 3

Generalized muscle weakness: Grade 3

Dehydration: Grade 3

Skin Rashes: Grade 3

Anemia: Grade 3

Nausea: Grade 3

Vomiting: Grade 3

Thromboembolic event: Grade 3

Seizure: Grade 3

Myocardial infarction: Grade 3

Mucositis oral: Grade 3

Immune mediated hepatitis: Grade 3

Immune mediated gastritis: Grade 3

Hypothyroidism

Hematuria

Flu like symptoms: Grade 3

Diarrhea: Grade 3

Arthralgia: Grade 3

Alkaline phosphatase increased: Grade 3

Adverse events are summarized for all study participants who received at least one dose of study drug.

The analysis population for this objective was defined in the protocol as "all subjects who received at least one dose of study drug". No per-arm or per-cohort analyses were planned or performed.

Characterize Adverse Events

Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV

Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV;

Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV

Bevacizumab: Arm A: Phase 1b Cohort 2: 15mg IV

Arm A - Phase Ib Dose Ecalation Cohort 2

Overall Study

A single administration of 37 MBq (+/-10%) 89Zr-girentuximab, containing a mass dose of 5 mg of girentuximab

Single diagnostic injection on Day 0, followed by diagnostic scans on Days 3 and 7±1, as well as the whole body dosimetric imaging on Days 0, 1, 3 and 7±1

89Zr-Girentuximab

Michael Tapner

Peter F. A. Mulders, Prof.

The study is designed to explore the safety and tolerability as well as diagnostic 89Zr-girentuximab for imaging CCRC by PET/CT. This study does not offer any treatment for patients with CCRC; therefore, patients will be offered state of the art therapeutic options after imaging with the study drug 89Zr-girentuximab. Cancer treatment will not be delayed by study participation.

The identification of RCC is crucial for planning possible surgery and treatment. The aim of this study is to investigate the safety, tolerability, radiation dosimetry, as well as the diagnostic performance of 89Zr-girentuximab PET/CT in patients with suspected CCRC. The results of this study will be used to pave the way for further studies with 89Zr-girentuximab as a PET/CT imaging agent which was shown to have higher diagnostic resolution 124I-girentuximab in animal studies due to prolonged trapping of the radiolabel in the tumour and simultaneous washout from normal tissues. It is anticipated to develop 89Zr-girentuximab as an improved imaging agent for CCRC.

This will be an exploratory, open-label, Phase 1 study to evaluate safety, tolerability, whole body dosimetry, and imaging properties of 89Zr-girentuximab, when image acquisition is made using different PET reconstruction methods, namely time-of-flight (TOF-PET) and conventional (PET) reconstruction, in order to estimate a possible impact of variable scanner technology on image quality variability in a planned multi-centre study.

In addition, different acquisition durations (5 -20 min) will be explored using an activity dose of 37 mBq (1 mCi), in order to establish, whether acquisition time has an impact on diagnostic performance.

It is anticipated to recruit 8-10 patients with suspected or established CCRC to

* Receive a slow intravenous injection with 89Zr-girentuximab (1-2 minutes slow bolus injection), followed by
* Dosimetric and tumour PET/CT imaging. The study duration will be approximately 12 months. Primary endpoint is safety, a part of which is determining the effective dose (mSv/MBq) to the whole body, and absorbed dose (mGy/MBq) to individually discernible organs.

Secondary endpoints include physicians assessment of PET image quality and tumour detectability comparing the following reconstruction settings:

TOF-PET PET 37 MBq 5, 10, 15 and 20 min 5, 10, 15 and 20 min Additionally, images partitioned to acquisition times of 5, 10, 15 and 20 min will be comparatively analysed in a blinded read.

In order to comprehensively characterise safety and tolerability, standard safety parameters (labs, 12-lead ECG, adverse events, and concomitant medications) will be systematically assessed at baseline and at appropriate intervals post dosing. Patients with clinical suspicion of CCRC, based on imaging evidence of a renal mass, requiring further diagnostic work-up, or patients with established diagnosis of CCRC requiring imaging for recurrent disease will be recruited by the urological service of the study centre, and undergo a formal screening visit, during which the study schedule will be planned, and consent obtained.

All successfully screened patients will be injected with 89Zr-girentuximab on Day 0 by the nuclear medicine service, followed by:

Sequential static whole body PET/CT imaging:

For dosimetry analysis, biodistribution whole body PET/CT imaging will be performed at 0.5, 4, 24, 72 and 168±24 h (Day 7±1) post injection, using low dose CT. Patients will be imaged on a TOF-PET scanner, offering the possibility of TOF (time-of-flight) and non-TOF reconstruction.

Comparative tumour PET/CT imaging:

On Days 3 and 7±1 (after the biodistribution whole body scans on Days 3 and 7), tumour imaging will be performed using gated or list mode acquisition, for generation of sub-partitioned data. Such data allow the mathematical generation of statistically independent images for various dose levels, based on the actual dose administered in the trial. Acquisition will be for 20 min.

An end of study visit will be conducted on Day 8±1. 89Zr-girentuximab dosimetry will be centrally analysed for absorbed organ and whole body doses in a standardised fashion. In addition, tumour absorbed doses will be determined for scientific purposes (estimation of achievable tumour doses of therapeutic nuclides labelled to girentuximab).

All image data analyses will be performed / confirmed centrally.

89Zr-girentuximab ) Dosimetry in CCRC Study - ZIR-DOSE

An Open-label, Phase I Study to Assess Safety, Tolerability, Radiation Dosimetry, and Imaging Properties of 89Zr-labelled Girentuximab (89Zr-girentuximab) for in Vivo Detection of Clear Cell Renal Carcinoma (CCRC) by Positron Emission Tomography (PET) Using Different PET Imaging Methodologies

Frequency of occurrence and severity of abnormal findings in safety investigations regarding the physical examination.

Frequency of occurrence and severity of abnormal findings in safety investigations regarding the Vital signs including the 12-lead ECG.

Frequency of occurrence and severity of abnormal findings in safety investigations regarding Adverse Events.

Frequency of occurrence and severity of abnormal findings in safety investigations regarding Laboratory examinations.

Frequency of occurrence and severity of abnormal findings in safety investigations regarding concomitant medications.

Normalised whole body effective radiation dose (mSv/MBq)

Visualisation of tumours will be qualitatively assessed across acquisition conditions (AC; i.e. reconstruction (Non-TOF/TOF), acquisition duration; details see above) by 2 readers experienced in oncology who will be blinded with regard to the AC.

1. Percentage of images rated good or excellent / AC
2. Percentage of images rated unevaluable / AC
3. Total number of tumour lesions detectable / AC
4. Comparative analysis of 5, 10, 15 and 20 min results at lesion basis.

Absorbed dose (Gy) from 89Zr-girentuximab to discernible tumour lesions, considering tumour volume, determined by pre-study contrast enhanced CT.

Determination of tumour tissue girentuximab exposure kinetics and AUC values (area under the curve), considering 89Zr-girentuximab specific activity at injection time point, injected activity, decay correction using the physical half-life of 89Zr, and anatomical tumour volume to obtain mg/mL.

Estimation of achievable absorbed tumour doses (Gy), assuming identical tumour biodistribution as observed for 89Zr-girentuximab, however therapeutic labelling with alpha and beta emitters.

ABX CRO

Telix Pharmaceuticals (Innovations) Pty Limited

Radboud University Medical Center

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Immunosuppressive Agents

Immunologic Factors

In the experimental arm (Arm A) alternating treatment will consist of 8 weeks of Pazopanib 800 mg qd alternated by 8 weeks of Everolimus 10 mg qd until first progression(PD per RECIST 1.1)followed thereafter by Pazopanib (when PD after 8 weeks of Everolimus)or Everolimus (when PD after 8 weeks of Pazopanib) monotherapy until second progression.

The comparative arm (Arm B) will be the standard regimen of Pazopanib (800 mg qd continuously) until progression, followed thereafter by Everolimus (10 mg qd continuously) until progression.

Pazopanib

tablet 800mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus

tablet 10mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus

Everolimus 10mg qd monotherapy until second progression (PD per RECIST 1.1)when first progression after 8 weeks of Pazopanib in alternating regimen

Pazopanib 800mg qd monotherapy until second progression (PD per RECIST 1.1) when first progression after 8 weeks of Everolimus in alternating regimen

E.E. Voest, MD/PhD

In this study will be examined whether alternating treatment between two classes of drugs (TKI's and m-TOR inhibitors) postpones or prevents drug resistance in patients with renal cancer.

Current practice is to treat with VEGFR-TKI or mTOR inhibitors until progression and then continue with the next active agent. From a biological perspective, TKI's will most likely activate compensatory pathways which, may ultimately lead to the development of resistance. Recent studies suggest that resistance to treatment with TKI may be reversible after stopping treatment. There is therefore a rationale to alternate treatment to prevent or delay the occurrence of resistance.

Our hypothesis is that alternating active agents in clear cell renal carcinoma (ccRCC) may reduce side effects, improve tolerability and compliance of treatment and prolong progression free survival and overall survival compared to the standard of care.

Rotating Pazopanib and Everolimus to Avoid Resistance

A Randomized Phase II Study to Explore the Efficacy and Feasibility of Upfront Bi-monthly Rotations Between Everolimus and Pazopanib in Patients With Advanced or Metastatic Clear Cell Renal Cancer

Time between first progression and second progression (PD) per RECIST 1.1 on Everolimus monotherapy (when PD after 8 weeks Pazopanib) or Pazopanib monotherapy (when PD after 8 weeks Everolimus) as second line treatment in experimental arm and time to progressive disease on Everolimus as second line treatment in comparative arm.

Quality of life will be assessed bi-monthly by using the FACT Kidney Symptom Index (FKSI)-Disease Related Symptom (DRS)and the EORTC QLQ-C30 questionnaire. The symptoms covered by the FKSI-DRS include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. The EORTC QLQ-C30 questionnaire evaluates five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact).

Adverse events will be reported according Criteria for Adverse Events v4.0 (NCI CTCAE v4)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
TroVax Renal Immunotherapy Survival Trial	NCT00397345	Clear Cell Rena...	Trovax Placebo Standard of car...	18 Years -	Oxford BioMedica
Study to Evaluate Efficacy and Safety of Sunitinib in Renal Cell Carcinoma Progressed to 1L Immunotherapy Treatment.	NCT03066427	Clear Cell Rena...	Sunitinib	18 Years -	Spanish Oncology Genito-Urinary Group
Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma:	NCT02348008	Clear Cell Rena...	MK-3475 Bevacizumab MK-3475 Bevacizumab	18 Years -	Big Ten Cancer Research Consortium
89Zr-girentuximab ) Dosimetry in CCRC Study - ZIR-DOSE	NCT03556046	Clear Cell Rena...	89Zr-Girentuxim...	50 Years -	Radboud University Medical Center
Rotating Pazopanib and Everolimus to Avoid Resistance	NCT01408004	Clear Cell Rena...	Pazopanib Everolimus Pazopanib Everolimus Everolimus Pazopanib	18 Years -	Netherlands Working Group on Immunotherapy of Oncology
Rotating Pazopanib and Everolimus to Avoid Resistance	NCT01408004	Clear Cell Rena...	Pazopanib Everolimus Pazopanib Everolimus Everolimus Pazopanib	18 Years -	Netherlands Working Group on Immunotherapy of Oncology
Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients	NCT01599754	Clear Cell Rena...	Axitinib Placebo	18 Years -	SFJ Pharmaceuticals, Inc.
Pilot Study of Neo-Adjuvant Everolimus to Treat Advanced Renal Cell Carcinoma - Analysis of Biomarkers	NCT01107509	Carcinoma, Rena...	everolimus	18 Years -	St. Joseph's Healthcare Hamilton
Pazopanib/DCE-MRIs in Renal Cell Carcinoma (RCC)	NCT01221506	Carcinoma, Rena...	Pazopanib DCE-MRI and Qua...	18 Years -	Abramson Cancer Center at Penn Medicine
Rotating Pazopanib and Everolimus to Avoid Resistance	NCT01408004	Clear Cell Rena...	Pazopanib Everolimus Pazopanib Everolimus Everolimus Pazopanib	18 Years -	Netherlands Working Group on Immunotherapy of Oncology
Near Infrared Technology and Laparoscopic Resection of Pancreatic Lesions: the COLPAN Project	NCT02685553	Pancreatic Neur... Clear Cell Rena... Solid Pseudopap...	NIR	18 Years - 80 Years	Universita di Verona
GSK3359609 Plus Tremelimumab for the Treatment of Advanced Solid Tumors	NCT03693612	Neoplasms	feladilimab Tremelimumab Docetaxel Paclitaxel Cetuximab	18 Years -	GlaxoSmithKline
Pazopanib/DCE-MRIs in Renal Cell Carcinoma (RCC)	NCT01221506	Carcinoma, Rena...	Pazopanib DCE-MRI and Qua...	18 Years -	Abramson Cancer Center at Penn Medicine

Spots Global Cancer Trial Database for clear cell renal carcinoma