An Expanded Phase I Study of Pazopanib and Everolimus in Patients With Advanced Solid Tumors and Previously Treated Advanced Urothelial Cancer
Overview
- Phase
- Phase 1
- Intervention
- pazopanib
- Conditions
- Solid Tumor
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 23
- Locations
- 2
- Primary Endpoint
- Dose Limiting Toxicity (DLT) [Phase I Dose Finding]
- Status
- Completed
- Last Updated
- 6 years ago
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.
Investigators
Mark Pomerantz, MD
Assistant Professor of Medicine, Harvard Medical School
Dana-Farber Cancer Institute
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
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
Arms & Interventions
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.
Intervention: pazopanib
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.
Intervention: everolimus
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.
Intervention: pazopanib
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.
Intervention: everolimus
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.
Intervention: pazopanib
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.
Intervention: everolimus
All Phase I Participants
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.
Intervention: pazopanib
All Phase I Participants
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.
Intervention: everolimus
Outcomes
Primary Outcomes
Dose Limiting Toxicity (DLT) [Phase I Dose Finding]
Time Frame: 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.
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.
Maximum Tolerated Dose (MTD) [Phase I Dose Finding]
Time Frame: 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.
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.
Objective Response Rate [Expansion]
Time Frame: 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).
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
- Grade 4 Treatment-Related Toxicity Rate [Dose Finding](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).)
- Grade 4 Treatment-Related Toxicity Rate [Expansion](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).)
- Median Progression-Free Survival [Expansion](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](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.)