phase 1b/2 study of carfilzomib in relapsed solid tumors, multiple myeloma, or lymphoma

Conditions: Ovarian Cancer; Renal Cancer; Non-small Cell Lung Cancer; Small Cell Lung Cancer; Solid Tumors; Multiple Myeloma; Lymphoma

Summary: the primary objectives of this phase 1b/2 study were as follows: * phase 1b (bolus and infusion): to evaluate the safety and tolerability of carfilzomib in patients with relapsed solid tumors and in patients with relapsed and/or refractory multiple myeloma and in patients with refractory lymphoma. * phase 2 (bolus): to evaluate the overall response rate (orr) after 4 cycles of carfilzomib in patients with relapsed solid tumors.


Eligibility criteria:
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

Keywords: non-small cell lung carcinoma small-cell lung carcinoma ovarian cancer renal cancer other solid tumors multiple myeloma lymphoma