Clinical trial NCT00531284: Phase 1b/2 Study of Carfilzomib in Relapsed Solid Tumors, Multiple Myeloma, or Lymphoma
Official title: Phase 1b/2, Multicenter Open-label Study of the Safety and Activity of Carfilzomib in Subjects With Relapsed Solid Tumors, Multiple Myeloma or Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Ovarian Cancer
Renal Cancer
Non-small Cell Lung Cancer
Small Cell Lung Cancer
Solid Tumors
Multiple Myeloma
Lymphoma
Keywords: Non-small cell lung carcinoma
Small-cell lung carcinoma
Ovarian Cancer
Renal Cancer
Other solid tumors
multiple myeloma
lymphoma
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2007-09-18
Enrollment: 184
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT)
timeFrame: 28 days
measure: Phase 2: Percentage of Participants With an Overall Response After 4 Treatment Cycles
timeFrame: 4 months
Secondary outcomes:
measure: Percentage of Participants With an Overall Response Throughout the Study
timeFrame: Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.
measure: Duration of Response
timeFrame: Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.
measure: Progression-Free Survival
timeFrame: Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.
measure: Time to Progression
timeFrame: Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.
measure: Maximum Observed Plasma Concentration of Carfilzomib
timeFrame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
measure: Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib
timeFrame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib
timeFrame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib
timeFrame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
measure: Elimination Half-life (t½) of Carfilzomib
timeFrame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
measure: Clearance (CL) of Carfilzomib
timeFrame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
measure: Volume of Distribution at Steady State (Vss) of Carfilzomib
timeFrame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
measure: Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib
timeFrame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Pinnacle Oncology
state: Arizona
city: Beverly Hills
country: United States
facility: Tower Cancer Research Foundation
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Cancer Center
state: Maryland
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Nashville
country: United States
facility: The Sarah Cannon Research Institute
state: Tennessee
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics (START)
state: Texas
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Papadopoulos KP, Siegel DS, Vesole DH, Lee P, Rosen ST, Zojwalla N, Holahan JR, Lee S, Wang Z, Badros A. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015 Mar 1;33(7):732-9. doi: 10.1200/JCO.2013.52.3522. Epub 2014 Sep 15.
citation: Ohshima-Hosoyama S, Davare MA, Hosoyama T, Nelon LD, Keller C. Bortezomib stabilizes NOXA and triggers ROS-associated apoptosis in medulloblastoma. J Neurooncol. 2011 Dec;105(3):475-83. doi: 10.1007/s11060-011-0619-0. Epub 2011 Jun 3.