Expanded Phase I Pazopanib and Everolimus in Advanced Solid Tumors and Previously Treated Advanced Urothelial Cancer

Study Overview
=================
Brief Summary
-----------------
This research study is evaluating the combination of pazopanib and everolimus in patients that have a malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective, or metastatic or locally advanced unresectable kidney cancer. In this research study the investigators are testing the safety of the combination of pazopanib and everolimus and finding the appropriate doses to use for further studies.

Detailed Description
-----------------
This protocol has two parts, Phase I Dose Finding and Phase 1 Expansion. Once the maximum tolerated dose has been identified in the Phase I Dose Finding portion, a Phase I expansion cohort of patients with metastatic or locally advanced unresectable kidney cancer will be enrolled.

Official Title
-----------------
An Expanded Phase I Study of Pazopanib and Everolimus in Patients With Advanced Solid Tumors and Previously Treated Advanced Urothelial Cancer

Conditions
-----------------
Solid Tumor, Kidney Cancer

Intervention / Treatment
-----------------
* Drug: pazopanib
* Drug: everolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Phase I: Participants must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effected. Expansion Cohort Only: Participants must have histologically or cytologically confirmed metastatic or locally advanced unresectable kidney cancer. Expansion Cohort Only: Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension at 20mm or greater with conventional techniques or as 10mm or greater with spiral CT. Expansion Cohort Only: Previously treated with at least one anti-angiogenic agent, including but not limited to bevacizumab, sunitinib, or sorafenib. No more than 4 lines of prior systemic therapy for kidney cancer, mTOR pathway inhibitors other than RAD001 are allowed. 18 years of age or older Life expectancy of greater than 3 months ECOG performance status of 0 or 1 Normal organ and marrow function as outlined in the protocol Able to swallow oral medications Resolution of any pre-existing toxicity from prior therapy to NCI CTCAE v4.0 grade 1 or less Women are eligible to participate if she is of non-child bearing potential or agrees to use adequate contraception Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug A male with a female partner of childbearing potential must use a barrier method of contraception or abstinence during the study Exclusion Criteria: Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or thos who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Current treatment with leuprolide or other GnRH agonists is permitted on the Phase 1 portion of the study. Participants may not be receiving any other study agents. Prior RAD001 or pazopanib therapy History of clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 weeks prior to the first dose of study drug. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or everolimus History of any of the following cardiovascular conditions within the past 6 months: Cardiac angioplasty or stenting; myocardial infarction; unstable angina; coronary artery by-pass graft surgery; symptomatic peripheral vascular disease; Class III or IV congestive heart failure Poorly controlled hypertension History of cerebrovascular accident, pulmonary embolism, or untreated deep venous thrombosis within the past 6 months Prior major surgery or trauma within 28 days prior to first dose of study drug, and/or not recovered from effects of that surgery, and/or presences of an non-healing wound, fracture or ulcer, or patients that may require surgery during the course of treatment Evidence of active bleeding or bleeding diathesis Known endobronchial lesions or involvement of large pulmonary vessels by tumor Hemoptysis within 6 weeks of the first dose of study drug Clinically significant gastrointestinal abnormalities that may increase the risk of GI bleeding Expansion Cohort Only: Currently active second malignancy other than non-melanoma skin cancers Presence of uncontrolled infection Liver disease such as chronic cirrhosis, active hepatitis or chronic persistent hepatitis Uncontrolled diabetes Pregnant or breastfeeding Chronic treatment with systemic corticosteroids or other immunosuppressive agent Treatment with strong CYP3A4 inhibitors Treatment with strong CYP3A4 inducers Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period Prolongation of corrected QT interval > 480msecs History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of stomach or small bowel that could interfere with absorption, distribution, metabolism, or excretion of study drugs Any ongoing toxicity from prior anti-cancer therapy that is greater than grade 1 and/or that is progressing in severity. Any serious and/or pre-existing medical, psychiatric, or other condition that could interfere with subject safety, obtaining informed consent or compliance with study procedures HIV-positive individuals on combination antiretroviral therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: This is a Phase I study with multiple arms related to planned dose escalation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 0: Everolimus 5mg + Pazopanib 600 mg<br>Everolimus 5mg + Pazopanib 600 mg once daily for 28 days each cycle Participants were treated until disease progression, unacceptable toxicity or patient withdrawal. | Drug: pazopanib<br> <br> * Other names: Votrient;Drug: everolimus<br> <br> * Other names: RAD001;|
| Experimental: Dose Level -1: Everolimus 5mg + Pazopanib 400 mg<br>Everolimus 5mg + Pazopanib 400 mg once daily for 28 days each cycle Participants were treated until disease progression, unacceptable toxicity or patient withdrawal. | Drug: pazopanib<br> <br> * Other names: Votrient;Drug: everolimus<br> <br> * Other names: RAD001;|
| Experimental: All Phase I Dose Expansion Participants<br>All phase I dose expansion participants received Everolimus 5mg and Pazopanib at the maximum tolerated dose established in the dose finding part of the study. | Drug: pazopanib<br> <br> * Other names: Votrient;Drug: everolimus<br> <br> * Other names: RAD001;|
| Experimental: All Phase I Participants<br>All phase I participants received Everolimus 5mg and Pazopanib according to the established dose escalation schedule or the maximum tolerated dose established in the dose finding part of the study. | Drug: pazopanib<br> <br> * Other names: Votrient;Drug: everolimus<br> <br> * Other names: RAD001;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) [Phase I Dose Finding] | The MTD of Pazopanib in combination with Everolimus 5 mg PO QD was determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached. | Participants were assessed for adverse events on days 1 and 15 for cycles 1-2 and every cycle thereafter; The observation period for MTD evaluation was the first 28 days of treatment. | 
| Dose Limiting Toxicity (DLT) [Phase I Dose Finding] | A DLT was defined as an adverse event (a) with treatment attribution of possible, probable, or definite, and (b) occurs during cycle 1, and (c) meets any of the following criteria: Grade 3 or 4 non-hematologic toxicity excluding: nausea/vomiting controlled with antiemetics, Grade 3 hypertension that resolves to ≤150/90 within 7 days with supportive care, and Grade 3 asymptomatic, clinically insignificant laboratory abnormalities (LDH, alkaline phosphatase due to bone metastases, and asymptomatic hypophosphatemia). Hematologic toxicity: Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding, Grade 4 neutropenia which persists for >7 days, Grade 4 neutropenia associated with fever >38.5C; Hematologic toxicity excluded lymphopenia or anemia of any grade. Missing more than 5 days of planned doses for drug-related intolerable grade 2 toxicity;Toxicity related to therapy severe enough to require a dose-reduction. | Participants were assessed for adverse events on days 1 and 15 for cycles 1-2 and every cycle thereafter; The observation period for DLT evaluation was the first 28 days of treatment. | 
| Objective Response Rate [Expansion] | The objective response rate (ORR) was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. | TDisease was evaluated radiologically at baseline and every 8 weeks on treatment; Treatment duration was up to 6 cycles in the Dose Level 0 cohort, 14 cycles in the Dose Level -1 cohort and 10 cycles in the expansion cohort (1 cycle=28 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 4 Treatment-Related Toxicity Rate [Dose Finding] | Grade 4 treatment-related toxicity rate is the percentage of participants experiencing at least one treatment-related grade 4 adverse event (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) as reported on case report forms. | Participants were assessed for adverse events on days 1 and 15 for cycles 1-2 and every cycle thereafter; Treatment duration was up to 6 cycles in the Dose Level 0 cohort and 14 cycles in the Dose Level -1 cohort (1 cycle=28 days). | 
| Median Progression-Free Survival [Expansion] | Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Participants alive without PD are censored at date of last disease assessment. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions. | Disease was evaluated radiologically at baseline and every 8 weeks on treatment; PFS follow-up was up to 9.2 months in the expansion cohort. | 
| Mean Duration of Response [Expansion] | Duration of response was calculated as the time from achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment until disease progression. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. For target lesions: PD is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions. | Disease was evaluated radiologically at baseline and every 8 weeks on treatment; PFS follow-up was up to 9.2 months in the expansion cohort. | 
| Grade 4 Treatment-Related Toxicity Rate [Expansion] | Grade 4 treatment-related toxicity rate is the percentage of participants experiencing at least one treatment-related grade 4 adverse event (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) as reported on case report forms. | Participants were assessed for adverse events on days 1 and 15 for cycles 1-2 and every cycle thereafter; Treatment duration was up to 10 cycles in the expansion cohort (1 cycle=28 days). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RAD001, pazopanib, everolimus, advanced cancer