Neoplasms Clinical Trial
Official title:
A Phase I Study of Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Malignancies
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.
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