Study of Carfilzomib With Irinotecan in Irinotecan-Sensitive Malignancies and Small Cell Lung Cancer Patients

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.

Inclusion Criteria:

- Patients must have histologically or cytologically-confirmed diagnosis of progressive
or recurrent malignancy as follows:

- Phase II: extensive stage small cell lung cancer with progression or recurrence after
exactly one platinum-containing regimen. Patients who progressed during or within one
month of completing platinum-based chemotherapy will be excluded. Patients who
received primary curative chemoradiation therapy for limited disease, but who recur
within the primary tumor site, previously radiated field or with distant metastases
are also allowed to participate. Patients who have clinical evidence of recurrent
small cell lung cancer do not require a confirmatory biopsy to be eligible for this
trial. Prior irinotecan is not allowed.

- Patients must have measurable disease per RECIST criteria 1.1 performed within 28 days
prior to enrollment. All other required tests to assess non-measurable disease must be
performed within 42 days prior to enrollment.

- Patients with known brain metastases are eligible only if he/she has been treated for
brain metastasis, are asymptomatic after treatment, have a stable CT or MRI of the
brain within 28 days of enrollment and are not receiving corticosteroid therapy to
control symptoms from brain metastasis. Only a non-enzyme inducing anticonvulsant
(e.g., Keppra) will be permitted for those patients requiring anticonvulsants.
(Topical and/or inhaled steroids are allowed.)

- Patients may have received previous radiation therapy, but it must have been completed
at least 21 days prior to enrollment and the patient should have recovered from all
associated toxicities. Measurable or non-measurable disease must be present outside
the previous radiation field or a new lesion inside the radiation port must be
present.

- Patients may have received prior surgery provided that at least 28 days have elapsed
since major surgery (thoracic or other major surgeries) and the patient has recovered
from all associated toxicities. Patients must have disease outside of the previous
surgical resection area or a new lesion must be present.

- Patients must have a serum creatinine ≤ the institutional upper limit of normal OR a
creatinine clearance ≥ 60 cc/min, measured or calculated (Cockcroft-Gault formula),
obtained within 14 days prior to registration.

- Patients must have adequate hepatic function as documented by a bilirubin ≤ 2 x the
institutional upper limit of normal, an alkaline phosphatase ≤ 2 x the institutional
upper limit of normal, and an SGOT and SGPT ≤ 2 x the institutional upper limit of
normal all obtained within 14 days prior to enrollment.

- Patients must have an ANC ≥ 1,500/μl and a platelet count ≥ 100,000/μl obtained within
14 days prior to registration.

- Patients must be 18 years of age or older.

- Patients must have a Zubrod Performance Status as follows:

1. Phase Ib: 0 or 1

2. Phase II: 0, 1 or 2

- Patients must not be pregnant or nursing. Women/men of reproductive potential must
have agreed to use an effective contraceptive method (hormonal or barrier method of
birth control; abstinence) prior to study entry and for the duration of study
participation.

- Male subjects must agree to practice contraception.

- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines.

Exclusion Criteria:

- No prior irinotecan or carfilzomib

- Must not have leptomeningeal metastases.

- Must be no anticipated need for concurrent radiation therapy during protocol
treatment.

- Subjects that progressed during or within one month of completion of first-line
platinum-based chemotherapy will be excluded.

- Patients must not be pregnant or lactating females.

- Must have had no major surgery within 28 days prior to enrollment.

- Must not have acute active infection requiring treatment (systemic antibiotics,
antivirals, or antifungals) within 14 days prior to enrollment.

- Must not have any known human immunodeficiency virus infection.

- Must not have known active or clinically significant hepatitis A, B or C infection.

- Must not have had any unstable angina or myocardial infarction within 4 months prior
to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, history of
severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick
sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3
conduction system abnormalities unless subject has a pacemaker.

- Must not have any uncontrolled hypertension or uncontrolled diabetes within 14 days
prior to enrollment.

- Must not have any evidence of other clinically active cancer and have no history of
prior malignancy within the past 3 years with the exception of a) adequately treated
basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in
situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with
stable prostate-specific antigen levels; or d) cancer considered cured by surgical
resection or unlikely to impact survival during the duration of the study, such as
localized transitional cell carcinoma of the bladder or benign tumors of the adrenal
glands or pancreas.

- Must not have any significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14
days prior to enrollment.

- Must not have any known history of allergy to Captisol® (a cyclodextrin derivative
used to solubilize carfilzomib).

- Must have no contraindication to any of the required concomitant drugs or supportive
treatments, including hypersensitivity to all anticoagulation and antiplatelet
options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or
cardiac impairment.

- Must not have any other clinically significant medical disease or condition that, in
the Investigator's opinion, may interfere with protocol adherence or a subject's
ability to give informed consent.