Clinical trial NCT01184326: Expanded Phase I Pazopanib and Everolimus in Advanced Solid Tumors and Previously Treated Advanced Urothelial Cancer
Official title: An Expanded Phase I Study of Pazopanib and Everolimus in Patients With Advanced Solid Tumors and Previously Treated Advanced Urothelial Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Kidney Cancer
Keywords: RAD001
pazopanib
everolimus
advanced cancer
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Beth Israel Deaconess Medical Center
name: Brigham and Women's Hospital
name: GlaxoSmithKline
name: Novartis
First posted: 2010-08-18
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: This is a Phase I study with multiple arms related to planned dose escalation.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) [Phase I Dose Finding]
timeFrame: 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.
measure: Dose Limiting Toxicity (DLT) [Phase I Dose Finding]
timeFrame: 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.
measure: Objective Response Rate [Expansion]
timeFrame: 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 outcomes:
measure: Grade 4 Treatment-Related Toxicity Rate [Dose Finding]
timeFrame: 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).
measure: Median Progression-Free Survival [Expansion]
timeFrame: 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.
measure: Mean Duration of Response [Expansion]
timeFrame: 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.
measure: Grade 4 Treatment-Related Toxicity Rate [Expansion]
timeFrame: 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).
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Mark Pomerantz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.