Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Breast Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Ovarian Cancer

Ovarian Epithelial Cancer

Antineoplastic Agents

All Drugs and Chemicals

Poly(ADP-ribose) Polymerase Inhibitors

Cystatins

Kidney function will be assessed by serum creatinine, serum cystatin C, and urine creatinine clearance calculation for patients who opt-in to 24 hour urine collection.

These laboratory measures will be completed by patients at the following time points:

* Timepoint A: Baseline (prior to PARP inhibitor initiation, at the time of standard of care clinical testing)
* Timepoint B: On-treatment (within 3-9 weeks of PARP inhibitor initiation, at the time of standard of care clinical testing)
* Timepoint C: Post-treatment (within 4 weeks of PARP inhibitor discontinuation, only for those patients with clinically significant changes in GFR based on serum creatinine, cystatin C, or 24 hour urinalysis at Timepoint B

Kidney Function Test

Payal Shah, MD

The purpose of this study is to observe whether PARP inhibitors have an effect on serum creatinine level, and whether this reflects a change in creatinine secretion or a true change in kidney function.

PARPi medications interact with transporters along the renal tubules involved in the secretion of creatinine and an increase in serum creatinine is often observed in patients treated with these agents; however, it is not known whether PARP inhibitors are associated with an actual change in the glomerular filtration rate, or if the observed elevations of serum creatinine are a result of a drug effect on creatinine secretion unrelated to changes in kidney function. The investigators therefore propose a prospective observational study to examine the incidence of elevation in serum creatinine from baseline levels in patients initiated on PARP inhibitors and compare the estimated glomerular filtration rate based on creatinine to that from alternative tests.

The primary purposes of this study are to:

* Assess the incidence of increase in serum creatinine in patients with a solid-organ cancer on treatment with a PARP inhibitor.
* To compare the estimated glomerular filtration rate based on serum creatinine with that of alternative biomarkers to assess whether changes in serum creatinine reflect changes in kidney function or creatinine secretion.
* To examine the persistence or resolution of creatinine increase and/or GFR decrease noted after discontinuation of PARPi

Kidney function will be assessed by serum creatinine, serum cystatin C, and urine creatinine clearance calculation for patients who opt-in to 24 hour urine collection.

Effect of PARP Inhibitors on Glomerular Filtration Rate

Change in eGFR from baselineto on-treatment by ≥20% as measured using either cystatin C or 24h urine collection

The percentage of patients who experience a eGFR reduction of ≥30%, and/or

University of Pennsylvania

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Acute Kidney Injury

Renal Insufficiency

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Kidney Diseases

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Acute Graft Versus Host Disease

Plasma Exchange

William F Clark, MD

Background:Plasma exchange has been suggested to be of theoretical benefit in the treatment of acute renal failure at the onset of multiple myeloma. Two small-randomized trials provide conflicting evidence.

Objective: To assess the effect of 5 to 7 plasma exchanges in the treatment of acute renal failure at the onset of multiple myeloma.

Design: Randomized controlled trial with 4 strata (chemotherapy and dialysis dependence) from 1998 to 2004.

Setting: Hospital plasma exchange units in 14 major Canadian medical centers.

Participants: 92 voluntary patients between the ages of 18 to 81 with acute renal failure at the onset of myeloma after volume repletion and hypercalcemia.

Intervention: 5 to 7 plasma exchanges of 50 ml/Kgm of 5% Human Serum Albumin in first 10 days plus conventional therapy versus conventional therapy alone.

Measurements: The primary outcome is a composite measure of death, dialysis dependence or Modification of Diet in Renal Disease Study glomerular filtration rate (MDRD GFR) \< 30mg/min/1.73 meter squared at 6 months.

Hypothesis: 5 to 7 plasma exchanges in addition to conventional therapy at onset of myeloma with acute renal failure, reduces the composite outcome of death, dialysis dependence or a GFR \< 30 ml/min/1.73 meter squared at 6 months.

Entry Criteria: The inclusion criteria are a new diagnosis of multiple myeloma and progressive acute kidney failure. The former is defined as a bone marrow aspirate with \> 10% plasma cells and a monoclonal light chain in the urine, plasma or renal tissue. The latter is defined as a serum creatinine \> 200 mmol/L with a rise \> 50 mmol/L in the preceding two weeks despite correction of hypercalcemia, hypovolemia and metabolic acidosis as required in a patient with a normal sized kidney on renal ultrasound.

Exclusion criteria are age \< 18 or \> 81 years, obstruction on renal ultrasound (required examination), use of intravenous contrast or non-steroidal anti-inflammatory drugs during the previous 2 weeks, prior treatment for myeloma, pregnancy or inability to provide informed consent.

Research Design: This is a 14 centre randomized clinical trial. Patients who fulfill the entry criteria are referred by their oncologist or nephrologist to the apheresis physician at their centre who will explain the nature of the study via a human ethics approved letter of information. An informed consent is requested and if obtained the participants will be randomized centrally by telephone, using a random numbers generator, to either receive or not receive plasma exchange. Recruiting physicians are unaware of the treatment allocation prior to study entry and subsequent randomization, which is stratified by four strata (Vincristine, Adriamycin and Dexamethasone (VAD)/no VAD + on/not on acute hemodialysis with 28 possible allocations per strata for each centre). Following random blinded allocation, participants are treated in an unblinded manner. Patients are followed with standard forms which indicate their serum creatinine, dialysis and survival status at 10 days, 1 month and 6 months. Participants are enrolled from September 1998 to October 2003. The study is conducted after approval from the institutional ethics review boards of the 14 Canadian sites.

Treatment: Patients, who are randomized to receive plasma exchange, undergo 5-7 plasma exchange procedures within the first 10 days of study entry, concurrent with the initiation of chemotherapy. They receive a routine plasma exchange of 50 ml/kg with acid citrate dextrose as the anticoagulant via a Gambro BCT, Spectra cell separator using 5% human serum albumin and normal saline as the replacement solutions. Chemotherapy will be either Melphalan and prednisone taken daily for 4 days every 28 days for up to 12 cycles or with 4 days of slow intravenous infusion of Vincristine and Adriamycin coupled with Dexamethasone (VAD) given on days 1 to 4, 9 to 12 and 17 to 20 for 28 day cycles up to 6 cycles. Those allocated to plasma exchange, have the VAD stopped 1.5 hours before the plasma exchange and no VAD will be given during the plasma exchange. Following the exchange, subjects receive a bolus volume of VAD that would have been the amount infused during this time period.

Measurements: Blood and urine testing is performed at the time of study entry at 1 and 6 months for serum creatinine, serum calcium, serum albumin, 24-hour urine for protein. Subjects are classified for severity of multiple myeloma presentation by Durie-Salmon staging and GFR is estimated using the Modified Diet in Renal Disease Equation (MDRD).

Outcome Measurements: Following blinded random allocation to plasma exchange or control, the treating physicians who report the primary outcome will be aware of treatment assignment. The composite outcome includes death, dialysis dependence and a MDRD GFR calculated from a serum creatinine at 6 months follow-up. The addition of a GFR \<30ml/min/1.73m2 to our negative composite outcome reflects a significant increased risk of death, cardiovascular events and hospitalization associated with this degree of kidney impairment.

Statistical Analysis: All statistical analyses will be conducted using the Statistical Package for the Social Sciences (SPSS), Version 12.0 for Windows Release 12.0.0 Chicago:SPSS Inc, 2003. All significance testing utilizes two-tailed tests, reflecting the open-ended research hypothesis.

Sample Size: There are few data in the literature on which to base a sample size calculation for the composite outcome selected. Based on historical data, which indicated an event rate \> 50%, we calculated a sample size designed to detect an effect of plasma exchange on dialysis dependence, without informative censoring from death, at 6 months. In order to detect a difference of 50% in that outcome with a type 1 error of 0.05 (two-sided) and a type 2 error probability of 0.20, the sample size requirement was 46 per group. We will use this historical based power analysis to provide a conservative estimate of sample size to detect a statistically significant difference in the composite outcome of death, dialysis dependence or a GFR of \< 30ml/min/1.73m2 in our future study.

Comparison of Baseline Characteristics: Pearson's Chi-square with the Yates continuity correction will be used to test for statistically significant differences between treatment groups on categorical variables in two by two tables. The Mann-Whitney U was employed with continuous variables with skewed frequency distributions, while an independent sample t-Test was used with normally distributed continuous variables.

Interim Analysis: An interim analysis will be conducted by the Safety Subcommittee when the 50th participant had completed the 6-month follow-up to prevent some patients from unnecessarily receiving a less effective treatment.

Outcome Differences: Differences between the plasma exchange and control groups, with respect to the primary composite and secondary outcomes at 6 months, will be evaluated by Pearson's Chi-square. The time to death by treatment groups will be evaluated by Kaplan-Meier survival analysis using a log rank test for differences between groups. Uni- and multi-variate modeling of the primary composite outcome will be conducted by means of logistic regression, to determine for plasma exchange the unadjusted and adjusted odd ratios for the selected baseline determinants of chemotherapy, dialysis, age, urine protein, serum albumin and Durie-Salmon stage.

Trial of Plasma Exchange for Acute Renal Failure at the Onset of Myeloma

A Randomized Controlled Trial of Plasma Exchange for Acute Renal Failure at the Onset of Myeloma

Canadian Institutes of Health Research (CIHR)

The Kidney Foundation of Canada

London Health Sciences Centre

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Upon enrollment, all subjects will receive a urine collection kit by mail. Participants will bring in a first-morning urine specimen on the day of their routinely scheduled long-term follow-up visit, and will then have an additional blood and urine sample drawn with their other clinical care labs upon arrival to MSK.

The urine collected from the first morning void will be used to assess urine creatinine and microalbumin. The fresh urine specimen will be analyzed for novel urinary biomarkers of (urinary NGAL, TGF-β1, IL-18 and KIM-1). Serum BUN, creatinine, and cystatin-C will be assessed using serum samples drawn for routine clinical care.

Urine sample

Danielle Friedman, MD

The main purpose of this study is to learn more about biomarkers of kidney function in the blood and urine of neuroblastoma survivors. A biomarker is a biological molecule found in blood, urine, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition.

Biomarkers of Renal Dysfunction in Neuroblastoma Survivors

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

urine collected from the first morning void will be used to assess urine creatinine

Memorial Sloan Kettering Cancer Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effect of PARP Inhibitors on Glomerular Filtration Rate	NCT04367467	Solid Tumor Ovarian Cancer Breast Cancer	Kidney Function...	18 Years -	University of Pennsylvania
Trial of Plasma Exchange for Acute Renal Failure at the Onset of Myeloma	NCT00120263	Multiple Myelom... Acute Renal Fai...	Plasma Exchange	18 Years - 81 Years	London Health Sciences Centre
Effect of PARP Inhibitors on Glomerular Filtration Rate	NCT04367467	Solid Tumor Ovarian Cancer Breast Cancer	Kidney Function...	18 Years -	University of Pennsylvania
Trial of Plasma Exchange for Acute Renal Failure at the Onset of Myeloma	NCT00120263	Multiple Myelom... Acute Renal Fai...	Plasma Exchange	18 Years - 81 Years	London Health Sciences Centre
Biomarkers of Renal Dysfunction in Neuroblastoma Survivors	NCT03947346	Neuroblastoma S...	Urine sample	- 20 Years	Memorial Sloan Kettering Cancer Center
Effect of PARP Inhibitors on Glomerular Filtration Rate	NCT04367467	Solid Tumor Ovarian Cancer Breast Cancer	Kidney Function...	18 Years -	University of Pennsylvania
Biomarkers of Renal Dysfunction in Neuroblastoma Survivors	NCT03947346	Neuroblastoma S...	Urine sample	- 20 Years	Memorial Sloan Kettering Cancer Center
Biomarkers of Renal Dysfunction in Neuroblastoma Survivors	NCT03947346	Neuroblastoma S...	Urine sample	- 20 Years	Memorial Sloan Kettering Cancer Center

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