Phase 1b/2 Study of Carfilzomib in Relapsed Solid Tumors, Multiple Myeloma, or Lymphoma

Inclusion Criteria:

Disease related

Phase 1 Subjects (Bolus and Infusion):

Solid Tumor:

- Histologically confirmed advanced solid tumor

- 1 to 3 prior treatment regimens

- At least one site of radiographically measurable disease of ≥ 2 cm in the largest
dimension by traditional computed tomography (CT) scanning technique or ≥ 1 cm in the
largest dimension by spiral CT scanning (per Response Evaluation Criteria in Solid
Tumors [RECIST] criteria); or if, in the Principal Investigator's opinion, evaluable
disease can be reliably and consistently followed, the subject may be eligible upon
approval by the Medical Monitor

Multiple Myeloma (MM):

- Relapsed and/or refractory multiple myeloma following 2 or more prior treatment
regimens.

- Measurable disease as indicated by one or more of the following:

- Serum M-protein ≥ 1 g/dL

- Urine M-protein ≥ 200 mg/24 hr

- Serum Free Light Chain: Involved free light chain (FLC) level ≥ 10 mg/dL provided
serum FLC ratio is abnormal

Lymphoma:

- Histologically or cytologically confirmed lymphoma.

- Patients must have had an initial diagnosis of indolent non-Hodgkin lymphoma (NHL)
(including follicular, small lymphocytic, lymphoplasmacytoid, and marginal zone
lymphoma), indolent disease that transformed to a more aggressive subtype, as
previously described or patients may have mantle cell lymphoma.

- Patients are required to have received prior rituximab (alone or combined with other
treatment) and are considered refractory to (defined as no response, or progression
within 6 months of completing therapy) or intolerant of continued rituximab.

- Patients may have received up to a maximum of four prior unique chemotherapy
regimens, including if not contra-indicated autologous stem-cell transplantation
(ASCT).

- For patients to enroll in the expanded dose group for lymphoma, patients must have
measurable disease

Phase 2 Bolus Subjects:

-Histologically confirmed advanced solid tumor diagnosis and:

- Non-small cell lung cancer (NSCLC): Failed at least 1 prior platinum-based
chemotherapy regimen but not more than 3 prior therapies for metastatic disease

- Small cell lung cancer (SCLC): Failed 1 to 3 prior chemotherapy regimens

- Ovarian: Failed at least 1 prior platinum-based chemotherapy regimen but not more
than 4 therapies for metastatic disease

- Renal: Failed at least 2 prior chemotherapy regimens for metastatic disease

- Other solid tumor types: Failed at least 1 prior chemotherapy regimen for metastatic
or relapsed disease and for which standard of care therapy is no longer effective or
does not exist

- At least one site of radiographically measurable disease of ≥ 2 cm in the largest
dimension by traditional CT scanning technique or ≥ 1 cm in the largest dimension by
spiral CT scanning (per RECIST criteria); or if, in the Principal Investigator's
opinion, evaluable disease can be reliably and consistently followed, the subject may
be eligible upon approval by the Medical Monitor

Demographic

- Males and females ≥ 18 years of age

- Life expectancy of more than 3 months

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

Laboratory

- Adequate hepatic function, with bilirubin 1.5 times the upper limit of normal (ULN),
and alanine aminotransferase (ALT) 3 times ULN

- Absolute neutrophil count (ANC) > 1000/mm³, hemoglobin ≥ 8 gm/dL for solid tumors or
7.0 gm/dL for MM, and platelet count ≥ 100,000/mm³ for solid tumors or ≥ 30,000/mm³
for MM.

- Subjects should not have received platelet transfusions for at least 1 week
prior to screening

- Screening ANC should be independent of granulocyte- and granulocyte/macrophage
colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of
pegylated G-CSF for ≥ 2 weeks

- Subjects may receive red blood cell (RBC) transfusions or receive supportive
care with erythropoietin or darbepoetin in accordance with institutional
guidelines

- Calculated or measured creatinine clearance (CrCl) of ≥ 20 mL/minute calculated using
the formula of Cockcroft and Gault. Subjects with calculated CrCl < 20 mL/min may be
allowed, only with prior approval by the Medical Monitor.

Ethical/Other

- Written informed consent in accordance with federal, local, and institutional
guidelines

- Female subjects of childbearing potential must have a negative serum or urine
pregnancy test within 3 days of the first dose and agree to use dual methods of
contraception during the study and for 3 months following the last dose of study
drug. Post-menopausal females (> 45 years old and without menses for > 1 year) and
surgically sterilized females are exempt from these requirements. Male subjects must
use an effective barrier method of contraception during the study and for 3 months
following the last dose if sexually active with a female of childbearing potential.

Exclusion Criteria:

Disease Related

- Chemotherapy with approved or investigational anticancer therapeutics, including
steroid therapy, within 3 weeks prior to first dose or 6 weeks for antibody therapy

- Radiation therapy or immunotherapy within 3 weeks prior to first dose (except for
antibody therapy, where 6 weeks is required); localized radiation therapy within 1
week prior to first dose

- Subjects with prior brain metastases are permitted, but must have completed treatment
and have no evidence of active central nervous system (CNS) disease for at least 4
weeks prior to first dose

- For lymphoma patients; patients with prior stem cell transplant therapy (autologous
SCT within the prior 8 weeks; allogeneic SCT within the prior 16 weeks). Patients
with prior allogeneic SCT should not have evidence of moderate-to-severe
graft-versus-host disease (GVHD)

- Evidence of CNS lymphoma

- Participation in an investigational therapeutic study within 3 weeks prior to first
dose

- Prior treatment with carfilzomib

Concurrent Conditions

- Major surgery within 3 weeks prior to first dose

- Congestive heart failure (New York Heart Association class III to IV), symptomatic
ischemia, conduction abnormalities uncontrolled by conventional intervention, or
myocardial infarction within 3 months prior to first dose

- Acute active infection requiring systemic antibiotics, antivirals, or antifungals
within 2 weeks prior to first dose

- Known or suspected human immunodeficiency virus (HIV) infection or subjects who are
HIV seropositive

- Active hepatitis A, B, or C infection

- Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the
first dose

- Subjects with pleural effusions requiring routine thoracentesis or ascites requiring
routine paracentesis

- Subjects at risk* in whom the required program of oral and intravenous fluid
hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal
impairment

- High risk for Tumor Lysis Syndrome.

Ethical / Other

- Female subjects who are pregnant or lactating

- Any clinically significant psychiatric or medical condition that in the opinion of
the Investigator could interfere with protocol adherence or a subject's ability to
give informed consent