Small Cell Lung Carcinoma Clinical Trial
Official title:
Phase 1b/II Trial of Carfilzomib With Irinotecan in Irinotecan-Sensitive Malignancies (Phase Ib) and Small Cell Lung Cancer Patients (Phase II) Who Have Progressed on Prior Platinum-based Chemotherapy
The purpose of this study is to determine a well-tolerated dose of Carfilzomib in combination
with Irinotecan (Phase 1b portion of the study) in subjects with relapsed small and non-small
cell lung cancer or other irinotecan-sensitive cancers and to assess the 6 month survival of
relapsed small cell lung cancer patients treated with this combination therapy. **The Phase
1b portion of the study is now complete**.
Phase 2 portion of the study. The safest, maximally tolerated dose established as established
in Phase 1 for Phase 2 is as follows -- Carfilzomib will be provided at 20/36 mg/m2 with
Irinotecan dosed at 125 mg/m2. The purpose of the Phase 2 portion of the study is to assess 6
month survival of relapsed small cell lung cancer ins subjects treated with this combination
therapy.
Small cell lung cancer accounts for approximately 15% of all lung cancer diagnoses in the
United States (US), with 60-80% response rates to platinum-based chemotherapy in extensive
disease. Despite its sensitivity to chemotherapy, small cell lung cancer is characterized by
its tendency to spread to other locations in the body such as the bloodstream and other
organs such as the liver. Currently, the only FDA-approved second-line therapies are oral and
parenteral topotecan, although irinotecan is also commonly used in primary and relapsed
disease. Novel combination therapies are desperately needed in this disease. in order to
improve survival.
Carfilzomib (also known as Kyprolis) is an anti-cancer drug classified as a selective
proteasome inhibitor. Proteasome inhibition affects the levels of numerous cell cycle control
proteins, apoptosis (i.e., cell death), cell adhesion, angiogenesis, and chemoresistance
proteins. Chemically, it is a tetrapeptide epoxyketone, similar to epoxomicin.
Carfilzomib and other proteasome inhibitors interrupt cellular pathways integral to the
survival of small cell lung cancer, namely the apoptic pathway involving activated nuclear
factor-kB (or NF-kB). NF-kB activates the transcription of anti-apoptotic and proliferation
genes, mediating tumor cell survival in response to cytotoxic stress thus resulting in
chemoresistance, a common problem in small cell lung cancer. Carfilzomib prevents the
breakdown of IkB, a protein which inhibits NF-kB, controls levels of the anti-apoptotic gene
Bcl-2 and the tumor suppressor p53. Overexpression of Bcl-2, a key mediator of resistance to
apoptosis following chemotherapy, which is an important problem in small cell lung cancer.
In this trial, Carfilzomib is combined with Irinotecan. Irinotecan, a camptothecins, inhibits
topoisomerase I, thought to be important in the growth and spread of cancer. As a class,
camptothecins have shown efficacy in small cell lung cancer in a variety of settings.
Topoisomerase-1 is thought to cause apoptosis via mechanisms other than NF-kB, adding to the
potential synergy of these compounds. In addition, topoisomerase-1 is overexpressed in the
majority of subjects with SCLC and decreased degradation of this enzyme is expected to lead
to further enhancement of this mechanism of apoptosis
The pivotal phase III study which led to FDA approval of topotecan in relapsed small cell
lung cancer was by Von Pawel et al, and included 211 subjects with sensitive (> 60 days since
prior therapy) relapse and randomized them to either topotecan (107 subjects) daily for 5
days or to cyclophosphamide, doxorubicin, and vincristine (CAV), each given every 21 days.
Topotecan showed no significant improvement in the median time to progression (13.3 weeks
vs.12.3 weeks, p=0.552) or median survival (25 weeks vs. 24.7 weeks, p=0.795), however,
subjects treated with topotecan had improvement in cancer-related symptoms (dyspnea,
hoarseness, anorexia, and fatigue) as well as hematologic toxicity. Irinotecan, has
established activity in small cell lung cancer, as well as non-small cell lung cancer,
colorectal cancer and ovarian cancer.
In this Phase 2 study patients will be treated with the Maximum Tolerated Dose (MTD) of
Carfilzomib 25/30 mg/m2 as stepped up dosing determined in Phase 1b and 125mg/m2 of
Irinotecan.
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