Expanded Phase I Pazopanib and Everolimus in Advanced Sol... | NCT01184326

NCT01184326

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Beth Israel Deaconess Medical Center	OTHER
Brigham and Women's Hospital	OTHER
GlaxoSmithKline	INDUSTRY
Novartis

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dose Level 0: Everolimus 5mg + Pazopanib 600 mg	Experimental	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 Drug: everolimus
Dose Level -1: Everolimus 5mg + Pazopanib 400 mg	Experimental	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 Drug: everolimus
All Phase I Dose Expansion Participants	Experimental	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 Drug: everolimus
All Phase I Participants	Experimental	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 Drug: everolimus

Interventions

Name	Type	Description	Arm Group Labels	Other Names
pazopanib	Drug		All Phase I Dose Expansion Participants All Phase I Participants Dose Level -1: Everolimus 5mg + Pazopanib 400 mg Dose Level 0: Everolimus 5mg + Pazopanib 600 mg

Outcomes Module

Primary Outcomes

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.

Secondary Outcomes

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).

Eligibility Module

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

Name	Affiliation	Role
Mark Pomerantz, MD	Dana-Farber Cancer Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Beth Israel Deaconess Medical Center		Boston	Massachusetts	02115	United States
Dana-Farber Cancer Institute

PubMed Identifier	Type	Citation	Retractions
30220708	Result	Bellmunt J, Lalani AA, Jacobus S, Wankowicz SA, Polacek L, Takeda DY, Harshman LC, Wagle N, Moreno I, Lundgren K, Bosse D, Van Allen EM, Choueiri TK, Rosenberg JE. Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma. Br J Cancer. 2018 Sep;119(6):707-712. doi: 10.1038/s41416-018-0261-0. Epub 2018 Sep 17.

ID	Title	Description
FG000	Dose Level 0: Everolimus 5mg + Pazopanib 600 mg	Everolimus 5mg + Pazopanib 600 mg once daily for 28 days each cycle Participants were treated until disease progression, unacceptable toxicity or patient withdrawal.
FG001	Dose Level -1: Everolimus 5mg + Pazopanib 400 mg	Everolimus 5mg + Pazopanib 400 mg once daily for 28 days each cycle Participants were treated until disease progression, unacceptable toxicity or patient withdrawal.
FG002	All Phase I Dose Expansion Participants	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.

ID	Title	Description
BG000	Dose Level 0: Everolimus 5mg + Pazopanib 600 mg	Everolimus 5mg + Pazopanib 600 mg once daily for 28 days each cycle Participants were treated until disease progression, unacceptable toxicity or patient withdrawal.
BG001	Dose Level -1: Everolimus 5mg + Pazopanib 400 mg

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

All phase I dose finding participants who received at least one dose of the study drug were evaluable for MTD.

Posted

Number

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.

ID	Title	Description
OG000	All Phase I Dose Finding Participants	All phase I dose finding participants received Everolimus 5mg and Pazopanib according to the established dose escalation schedule.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Dose Level 0: Everolimus 5mg + Pazopanib 600 mg	Everolimus 5mg + Pazopanib 600 mg once daily for 28 days each cycle Participants were treated until disease progression, unacceptable toxicity or patient withdrawal.

ID	Term
D014571	Urologic Neoplasms
D014565	Urogenital Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms

ID	Term
D020123	Sirolimus
D018942	Macrolides
D007783	Lactones
D009930	Organic Chemicals