The purpose of this study is to find the safest dose level of an approved drug, carfilzomib, in solid tumors when given over a different period of time than normally used. The study will also use markers in blood from routine blood draws to help check the levels of the drug. Lastly, the study will check how well this drug works with regards to keeping cancer cells from growing with the new time frame of delivery.
The role of the proteasome in carcinogenesis and cell survival has been well established, and its inhibition associated with an accumulation of pro-apoptotic proteins and cell death. Proteasome inhibitors, such has bortezomib, have been extensively studied and are widely used as effective therapy in the treatment for hematologic malignancies, such as multiple myeloma where circulating proteasome levels have been correlated with survival. Carfilzomib, a novel irreversible proteasome inhibitor which specifically targets the chymotryptic site of the proteasome has shown more potency than bortezomib and may be able to overcome bortezomib resistance. Response rates between 25-54% were seen in patients with previously treated myeloma in the phase 2 setting. Given the effectiveness of proteasome inhibition in multiple myeloma, the role of proteasome in solid tumors is under active investigation. Previous trials of bortezomib in breast, prostate, lung, and pancreatic cancer have shown little activity of this agent in these diseases. Whether the lack of activity may be mechanistically related (bortezomib inhibits chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing (PGPH)-like activities of the proteasome), or a lack of potency in target inhibition, is unknown. In a phase Ib/II study of 14 patients (phase I) and 51 patients (phase II) with advanced solid tumors, Rosen and colleagues noted single-agent activity with carfilzomib. Carfilzomib was dosed on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle to a maximum of 12 cycles, with 20-36 mg/m² noted as the recommended phase 2 dose based on DLT data. A PR in both renal and small cell lung cancer, and stable disease \> 16 weeks in mesothelioma, ovarian, renal, and non-small cell lung cancer was observed. The treatment was tolerable with the most common adverse events (AEs) including fatigue, headache, diarrhea, nausea and constipation. Given the activity of carfilzomib seen in selected solid tumors, and unpublished data to suggest weekly dosing may result in a similar pharmacokinetic profile including AUC, the investigators propose to study the safety, tolerability, pharmacokinetics, and anti-tumor activity of carfilzomib monotherapy given on a weekly dosing schedule. Weekly dosing has the advantage of patient convenience, and if acceptable toxicity and pharmacokinetics, it allows for easier integration of this schedule into subsequent combination therapy clinical trials.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Carfilzomib will be given as an IV infusion over 4 hours. Subjects will remain at the clinic under observation for at least 1 hour following each dose of carfilzomib in Cycle 1 and following the dose on Cycle 2 Day 1. During these observation times, post dose IV hydration may be given at physician's discretion.
Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses.
Emory University Winship Cancer Institute
Atlanta, Georgia, United States
Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a weekly 4-hour carfilzomib infusion in patients with advanced solid malignancies
Evaluate safety and tolerability of weekly dosed carfilzomib as assessed by using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v.4 criteria to determine DLTs, the MTD, and RP2D
Time frame: Up to 18 months
Pharmacokinetics (PK) of escalating doses of weekly intravenous carfilzomib
Pharmacokinetic analysis (Tmax, Cmax, t1/2, AUC)
Time frame: 1, 2, 4, 6, 8, 28 hours post-dose
Changes in pharmacodynamic (PD) biomarkers before and during treatment with carfilzomib using peripheral blood mononuclear cells (PBMC) and paired tumor biopsies
Pharmacodynamic (PD) evaluation of degree of 20S proteasomal inhibition in PBMC assays conducted at Emory University before treatment and at time of first restaging scan
Time frame: Days 1, 2, 3, 8, 15, 21
Preliminary anti-tumor efficacy (objective response rate)
Objective Response Rate (CR + PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients who completed at least 2 cycles of protocol therapy
Time frame: Up to 18 months
Preliminary anti-tumor efficacy (clinical benefit rate)
Clinical Benefit Rate (CR + PR + SD) by RECIST 1.1 criteria in patients who completed at least 2 cycles of protocol therapy
Time frame: Up to 18 months
Preliminary anti-tumor efficacy (progression free survival)
Time frame: Up to 18 months
Preliminary anti-tumor efficacy (overall survival)
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Time frame: Up to 18 months