Patients will receive single agent carfilzomib on a weekly dosing schedule (days 1, 8, 15) in a 21 day cycle. The initial dose will be 20 mg/m² for cycle 1, day 1. Dose escalation will proceed in a standard 3+3 fashion with the requirement that dose escalation to the next level can only proceed if 0 of 3 or ≤ 1 of 6 patients experience a dose limiting toxicity (DLT). Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses.

Neoplasms

Malignancies

Carfilzomib will be given as an IV infusion over 4 hours. Subjects will remain at the clinic under observation for at least 1 hour following each dose of carfilzomib in Cycle 1 and following the dose on Cycle 2 Day 1. During these observation times, post dose IV hydration may be given at physician's discretion.

Carfilzomib

Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses.

Dexamethasone

Emory University Winship Cancer Institute

Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Tumors

A Phase I Study of Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Malignancies

Evaluate safety and tolerability of weekly dosed carfilzomib as assessed by using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v.4 criteria to determine DLTs, the MTD, and RP2D

Pharmacokinetic analysis (Tmax, Cmax, t1/2, AUC)

Pharmacodynamic (PD) evaluation of degree of 20S proteasomal inhibition in PBMC assays conducted at Emory University before treatment and at time of first restaging scan

Objective Response Rate (CR + PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients who completed at least 2 cycles of protocol therapy

Clinical Benefit Rate (CR + PR + SD) by RECIST 1.1 criteria in patients who completed at least 2 cycles of protocol therapy

Bradley Carthon MD, PhD

Assistant Professor

Emory University

Amgen

Patients receive carfilzomib IV over 10-30 minutes on days 1, 2, 8, and 9; rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

CD20 Positive

Recurrent Diffuse Large B-Cell Lymphoma

Refractory Diffuse Large B-Cell Lymphoma

Stage I Diffuse Large B-Cell Lymphoma

Stage II Diffuse Large B-Cell Lymphoma

Stage III Diffuse Large B-Cell Lymphoma

Stage IV Diffuse Large B-Cell Lymphoma

Carboplatin

Etoposide

Ifosfamide

Laboratory Biomarker Analysis

Pharmacological Study

Rituximab

Roswell Park Cancer Institute

Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma

Phase I/Ib Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus Carboplatin Plus Etoposide (C-R-ICE) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Efficacy rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson. The relationship between binary outcomes and collected demographic and baseline variables will be statistically assessed using logistic regression.

The estimated distributions of overall survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

A population PK/PD structural model will be developed for carfilzomib based on degree of proteasome inhibition in relation to efficacy and toxicity endpoints in the proposed study using NONMEM. This model will describe the potential relationship between carfilzomib exposure in relation to proteasome inhibition to the time course of thrombocytopenia and neutropenia as indicators of pharmacodynamics response.

The estimated distributions of progression-free survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

Toxicity rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson. The relationship between binary outcomes and collected demographic and baseline variables will be statistically assessed using logistic regression.

National Cancer Institute (NCI)

A single arm multi-drug regimen is used to delete immunologic memory in order to reduce or eliminate alloreactive anti-HLA antibodies in highly sensitized heart transplant candidates. The intervention includes a protocol of Thymoglobulin, Rituximab, plasmapheresis and Bortezomib.

A Multi-drug regimen is used to delete immunologic memory in order to reduce or eliminate alloreactive anti-HLA antibodies in highly sensitized heart transplant candidates.
Bortezomib, Thymoglobulin, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis (Multidrug Protocol): Bortezomib, Thymoglobulin, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis

Elimination of Immunologic Memory

Sex: Female, Male

Heart transplant candidates with CPRA > 50%

Region of Enrollment

Percentage of highly sensitized heart transplant candidates, (patients with a CPRA greater than 50%), who have desensitization therapy, and then achieve a reduction in alloantibody such that their CPRA falls below 20%. For an individual patient, the outcome measure time frame is the one year of the Recovery Phase which begins after 218 days from the time that the patient begins the Induction Immunotherapy Phase, which is the same as the end of the Bortezomib Treatment Phase.

The percentage of patients with a CPRA less than 20% during the Recovery Phase of the protocol

Highly Sensitized Heart Transplant Candidates

Percentage of Patients With a Reduction in CPRA to Less Than 20%

Percentage of patients, who are transplanted within one year of finishing the Bortezomib treatment phase.

Highly sensitized heart transplant candidates with a CPRA greater than 50% that complete the Bortezomib treatment phase and are transplanted within one year

Percentage of Patients Transplanted

Percentage of study patients who experience a serious safety issue during the three phases of the study as measured by all cause mortality, serious adverse reactions and other adverse reactions.

Mortality for any reason during the study period

All Cause Mortality

The number of study patients with serious adverse events.

Serious Adverse Events

The number of study patients who had adverse events other than serious.

Other Adverse Events

Percentage of Patients Who Suffer Mortality, a Serious Adverse Event, or Other Adverse Event During the Study Period

Percentage of patients who experience of grade 3 and above non-hematologic toxicities as measured by the incidence of hypersensitivity reaction, fever, nausea and vomiting or dehydration during the study period.

Percentage of patients who experienced a Grade 3 or above non-hematologic toxicity during any phase of the study

Percentage of Patients With Grade and Above Non-Hematologic Ti

Percentage of Patients Who Experience Grade 3 and Above Non-Hematologic Toxicities

The percentage of patients in the study who experience any grade of peripheral neuropathy during the study period

Percentage of study patients with all grades of peripheral neuropathy during the study period

The Percentage of Patients Who Experience Any Grade of Peripheral Neuropathy

Percentage of patients who experience cytomegalovirus (CMV), post-transplant lymphoproliferative disease (PTLD), or progressive multifocal leukoencephalopathy (PML) during the study period.

Percentage of patients who experience CMV, PTLD or PML within the study period

Incidnce of CMV, PTLD, PML

Percentage of Patients Who Experience CMV, PTLD, and PML

The percentage of study patients who experience infectious complications in either the respiratory or urinary tracts during the study period.

Number of Participants with Respiratory Tract Infections

Respiratory Tract Infections

Number of participants with urinary tract infections

Urinary Tract Infections

The Percentage of Patients Who Experience Either a Respiratory Tract Infection or a Urinary Tract Infection

The percentage of study patients who experience an exacerbation of cardiac dysrhythmias and heart failure during the study period

The study patients, who all have heart failure and need a heart transplant, but experience an exacerbation of their heart failure during the study period.

Percentage of Patients With Exacerbation of Heart Failure

The percentage of study patients who experienced an exacerbation of the incidence of cardiac dysrhythmias during the study period.

Percentage of Patients With Exacerbation of Dysrythmias

The Percentage of Patients Who Experience Exacerbations Cardiac Dysrhythmias or Heart Failure

A Grade 4 hematologic toxicity includes a platelet count < 25,000/mm3 or an absolute neutrophil count < 500/mm3

The percentage of patients who experienced a grade 4 hematologic toxicity as manifested by a platelet count < 25,000 mm3 or an absolute neutrophil count of < 500/mm3

Percentage of Patients With Grade 4 Hemotologic Toxicities

Percentage of Patients With Grade 4 Hematologic Toxicities

The percentage of patients who experience antibody mediated rejection at 6 months and 1 year post transplant. The study period was 583 days, during which a patient was eligible for transplant during the last 365 days. If a patient was transplanted on day 583, then the patient is followed for one year after the transplant, then the total time to assess the two patients would have been a period of two years or 730 days. In fact, neither patient was transplanted within the study period.

Percentage of study patients who were transplanted and then developed AMR by 6 months after transplant

Percentage of TX Patients With AMR at 6 Months

The percentage of study patients who have developed AMR within 12 months of their transplant. This number includes those patients who had AMR diagnosed within 6 months of transplant.

Percentage of TX Patients With AMR at 12 Months

The Percentage of Patients With Antibody Mediated Rejection After Transplantation

Percentage of patients who are transplanted with the study period who then develop de novo or donor-specific alloantibody (DSA) within one year post-transplant. The patients would be eligible for transplant after day 218 in the study protocol and the study had 365 days in which to be transplanted. If a patient was transplant on day 583,( the last day of eligibility), and then followed for one year, then the outcome time frame would be a total of two years. No patient was transplanted within the study period.

Study patients who received a transplant and then developed de novo or donor specific antibodies after transplant.

Percentage of Pts. Who Develope De Novo or DSA < 1 yr After TX

Percentage of Patients Who Develop De Novo Alloantibody or DSA Alloantibody After Transplant

Percentage of patients who receive a transplant within the study period who are then DSA negative at 1 year following transplantation.

Study patients who received a transplant during the study period and then are negative for donor specific antibodies at one year after transplant

Percentage of Transplanted Pt That Are DSA Negative at 1 Year

Percentage of Patients Post-Transplant That Are DSA Negative

The percentage of allografts transplanted during the study period that survive to 6 and 12 months post transplant.

Study patients who receive a heart transplant within the study period whose allografts survive to 6 months.

Allograft Survival at 6 Months

Study patients who are transplanted and whose allografts survive to one year. This number includes those allografts that survived to 6 months that then survived to 12 months.

Allograft Survival at 12 Months

Percentage of Allograft Survival

The percentage of allografts that have an acute rejection episode per the criteria of the International Society of Heart and Lung Transplantation (ISHLT) within one year of transplantation. Allografts implanted during the Recovery Phase are monitored for a year for acute rejection per the study protocol. An allograft potentially implanted on the last day of a patient's recovery period would still be monitored for a year, so the potential outcome measure time would be 730 days. Since no allografts were implanted during the recovery period, there are no results to report.

Allografts implanted within the study period are followed for one year after transplantation and are routinely monitored for allograft rejection.

Percentage of Allografts With Acute Rejection

The Percentage of Allografts That Endure Acute Rejection Within One Year of Transplantation

Proportion of patients who achieve a Calculated Panel Reactive Antibody test CPRA of < 20%, but are not transplanted within the study period.

Percentage of patients with a CPRA < 20% but not transplanted within one year

Patients With CPRA < 20% Who Were Not Transplanted

Percentage of Patients With a CPRA <20%, But Were Not Transplanted During the Study Period

Percentage of study patients who receive transplants within the study period who then experience death, allograft loss, hospitalization due to infection, and non-fatal serious adverse cardiac event (defined as acute myocardial infarction, congestive heart failure, need for percutaneous cardiac intervention, coronary artery bypass grafting, cardiac defibrillator placement, cerebral vascular accident, peripheral vascular disease) within 1 year of transplantation.

The incidence of death in transplanted patients at one year from transplant

Transplant Patient Death

Study patients who were transplanted and lost their allografts

Allograft Loss in Transplanted Patients

Study patients who were transplanted and then required hospitalization for infection within one year of the transplant

Hospitalization Due to Infection in Transplanted Patients

Study patients who were transplanted and had a non-fatal cardiac event(acute MI, congestive heart failure, coronary intervention, etc) at one year

Non-fatal Serious Cardiac Event

Percentage of Patients Who Receive Transplants Who Then Suffer Serious Post-transplant Complications

This was a Single Group Assignment Interventional Study to determine if a multi-drug regimen could be used to delete immunologic memory in order to reduce or eliminate alloreactive anti-HLA antibodies in highly sensitized heart transplant candidates. It was a non-randomized, open label, safety/efficacy (pilot) treatment study. It was hoped that if the calculated panel reactivity antibody (CPRA) was reduced to less than 20% via the protocol, then the patients could become functionally transplantable. There were three phases of the study, an Induction Immunotherapy Phase, a Bortezomib Treatment Phase, and a Recovery Phase. Both patients completed each of the three phases.

Induction Immunotherapy

Bortezomib Treatment Phase

Recovery Phase

Timothy B Icenogle MD

All subjects will receive the study treatment. This is a non-randomized, open label study. The study treatment consists of an Induction phase with Thymoglobulin, Rituximab and Methylprednisolone, a Treatment phase with Bortezomib and a Recovery phase to follow-up and re-immunize and transplant the subject.

Study Treatment Group

Heart Transplantation

Bortezomib, Thymoglobulin, Rituximab, Gamimune N, (IVIG), Plasmapheresis

Providence Sacred Heart Medical Center

Multi-Drug Desensitization Protocol for Heart Transplant Candidates

Timothy Icenogle, MD

Director, Inland Northwest Thoracic Transplant Program

Providence Health & Services

Advanced Solid Tumor Malignancies and Refractory Lymphoma

Cancer

Lymphomas

NPI-0052 IV injection at doses ranging from 0.0125 to 0.8 mg/m2 over 1 to 10 minutes on Day 1, Day 8, Day 15 of each 28-day Cycle; 11 dose cohorts during dose-escalation

chymotrypsin/kansè

Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Tumors

Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma

Multi-Drug Desensitization Protocol for Heart Transplant Candidates

Phase 1 Clinical Trial of NPI-0052 in Patients With Advanced Solid Tumor Malignancies or Refractory Lymphoma

Bortezomib and CHOP in Patients With Advanced Stage Aggressive T Cell or Natural Killer (NK)/T Cell Lymphomas

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