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