Compassionate Use Protocol Research Articles

Efficacy of Cytoreg in the treatment of diabetic foot disease.

Complications from diabetic foot wounds, including bacterial infection, ulceration and gangrene, are major causes of hospitalisation and are responsible for 85% of amputations in patients with diabetes. Given that orally administered investigational therapeutic Cytoreg (Cytorex de Venezuela SA, Venezuela), a defined aqueous mixture of hydrofluoric, hydrochloric, sulfuric, phosphoric, citric and oxalic acids, has been shown to increase levels of arterial blood oxygen in a Wistar rat model, oral and oral+topical Cytoreg were tested on patients with diabetic foot ulcers (DFUs) under a humanitarian, compassionate-use protocol. All patients received oral Cytoreg (5.0 ml concentrate in fruit juice) for 30 days; half also received weekly wound washing with Cytoreg concentrate in isotonic saline (1:50 volume/volume) (oral+topical group). In addition to standard clinical observations, wounds were monitored against the Saint Elian checklist system for the diabetic foot. A total of 10 patients took part in the study. Complete wound closure was observed in 4/5 patients in the oral+topical group; in the remaining patient, necrotic and fibrin tissues on the wound edges were eliminated. Half (2/4) of the patients receiving oral-only Cytoreg experienced complete wound closure; one patient in this group was removed prematurely because of an unrelated illness and was not replaced. During the study, no significant differences were observed between groups in either the oxygen saturation of the affected tissues or in insulin and glycaemia levels (p<0.05). Significant increases in arterial haemoglobin and arterial oxygen partial pressure (p<0.05) were observed, and significant decreases were measured in the levels of glycosylated haemoglobin, aspartate aminotransferase, glutamic-pyruvic transaminase, creatine and urea (p<0.05). The results of this study justify an expanded clinical study for the treatment of DFUs with Cytoreg.

Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study

Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71–93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. Controlled clinical trials are necessary to establish efficacy of ruxolitinib in COVID-19.

Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Enterobacteriales Coresistant to Carbapenems and Polymyxins.

In this article, we report a case series of patients with infections caused by Enterobacteriales coresistant to carbapenems and polymyxins who were treated with ceftazidime/avibactam (CAZ-AVI) salvage therapy on a compassionate-use protocol. We enrolled 29 adult patients in 3 centers that had an infection due to a resistant microorganism and for whom the treatments available were considered ineffective, treated them with CAZ-AVI, and assessed clinical and microbiological cure at the end of treatment and all-cause mortality at 14 days and 30 days. The antimicrobial susceptibility profile was determined using broth microdilution, and total genomic DNA was sequenced. Twelve (41.4%) patients had bacteremia, and 48.3% (14/29) of the infections were treated with combination therapy. All strains were producers of KPC-2 and were susceptible to CAZ-AVI (MIC90, 1 μg/ml). Clinical success was high (24/29 [82.7%; 95% confidence interval, 64.2 to 94.2%]), even for the bacteremic cases (75%). The 14-day and 30-day mortality rates were 9/29 (31%) and 15/29 (51.7%), respectively. The 14-day mortality rate for pneumonia was the same as that for bloodstream infections (33.3%) and although not significant, we found that patients with renal impairment that received adjusted doses of CAZ-AVI had high mortality (4/9 [44%]; P = 0.22). We concluded that CAZ-AVI is an option for the treatment of severe infections due to difficult-to-treat drug-resistant Enterobacteriales.

Abstract P6-20-02: Activity of larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase, in TRK fusion breast cancers

Abstract Background: Tropomyosin receptor kinase (TRK fusions) involving the genes NTRK1, NTRK2, and NTRK3 occur in a broad range of malignancies including breast cancers (BC) with secretory features. Larotrectinib, the first selective TRK inhibitor in clinical development, has demonstrated an overall response rate of 75% by independent radiology review across various solid tumors, with a favorable safety profile. Here we report on a case series of TRK fusion BC patients treated with larotrectinib alone or in combination. Methods: Patients were treated with oral larotrectinib in the NAVIGATE global phase II study or in single-patient compassionate-use protocols. All patients received the Phase 2 dose of 100mg BID on a continuous 28d schedule. Efficacy was evaluated using RECIST v1.1. Results: As of June 2018, 5 TRK fusion BC patients had been treated, all with secretory characteristics, but diverse ER/PR/HER2 positivity (Table); 2 patients were triple negative. Four patients harbored ETV6-NTRK3 fusions. Larotrectinib treatment yielded a response rate of 80% (4/5 PRs). All responses occurred within the first 2 cycles of therapy and cancer-related symptoms resolved rapidly. No treatment-related Grade ≥3 adverse events have been reported. Patient 2 (14 yr) presented with a recurrent fungating mass (10.4x8.5 cm) having failed multiple rounds of chemotherapy. Significant reduction in tumor size was noted after one week of larotrectinib treatment with near complete resolution after 2 months.1 Patient 3 (37 yr) had extensive involvement of the lung and pleura, bilateral pleural effusions, peritoneal infiltration with ascites, severe dyspnea with PS=3. There was rapid improvement with larotrectinib treatment and the patient was PS=1 after 2 weeks. At 6 weeks, there was &amp;gt;80% reduction in tumor size.2 Patient 5 had a synchronous, locally advanced TRK fusion positive, ER+/HER2- secretory BC and TRK fusion negative, ER+/HER2- metastatic lobular BC. Prior to TRK inhibition, this patient received 2-months of palbociclib/letrozole to which the TRKfusion negative lobular cancer responded, while the TRK fusion SBC did not. The patient tolerated the larotrectinib/letrozole combination with no notable toxicities and experienced a PR in both sites, now ongoing for 11 months. Conclusions: We provide the first evidence that larotrectinib is effective in the treatment of BC harboring NTRK gene fusions. Assays capable of identifying NTRK gene fusions should be considered when profiling patients with BC, especially for patients with secretory BC. Table:Subject summarySubject IDSubtypeRegimenNTRK gene fusionER/PR/HER2 statusBest ResponseProtocol1Invasive ductal carcinoma (NOS)larotrectinibTPM3-NTRK1ER+/PR+/HER2-PDNAVIGATE Ph II2SecretorylarotrectinibETV6-NTRK3ER-/PR-/HER2-PRCompassionate use3Invasive ductal with secretory featureslarotrectinibETV6-NTRK3ER-/PR-/HER2-PRCompassionate use4Invasive ductal with secretory featureslarotrectinibETV6-NTRK3ER+/PR+/HER2+PRCompassionate use5*Secretorylarotrectinib + letrozoleETV6-NTRK3ER+/PR-/HER2-PRCompassionate use*- synchronous TRK fusion negative invasive lobular 1. Shukla et al., JCO Precis Oncol 2017, epub 2. Landman et al., Clin Breast Cancer, 2018, 18:e267-e270. Citation Format: Meric-Bernstam F, Shukla N, Peled N, Landman Y, Onitilo A, Montez S, Ku NC, Hyman DM, Drilon A, Hong DS. Activity of larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase, in TRK fusion breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-02.

DAS181 for Treatment of Parainfluenza Virus Infections in Hematopoietic Stem Cell Transplant Recipients at a Single Center

Parainfluenza virus (PIV) causes severe respiratory infections in hematopoietic stem cell transplant (HSCT) recipients. Currently, no effective therapies are available. DAS181 is a novel antiviral agent that inhibits attachment of PIV to respiratory cells, but clinical data on the use of DAS181 for PIV infection are limited to case reports. We report the clinical manifestations and outcomes of 16 HSCT recipients who received DAS181 daily for the treatment of PIV infection through a compassionate-use protocol or a single-arm clinical trial. Of the 16 patients (clinical trial: 9; compassionate use: 7), 13 were allogeneic HSCT recipients and 8 had graft-versus-host disease. PIV types were 3 (n = 7), 4 (n = 5), 1 (n = 3), and type 3 and 4 coinfection (n = 1). Fourteen patients had pneumonia. All patients presented with cough, 14 had dyspnea, 11 had hypoxia, and 8 had a fever. Patients received 5 to 10 days of treatment. Nine patients (56%) had a complete clinical response after DAS181 therapy and 4 (25%) had a partial response. The 3 patients without a clinical response had coinfections with other pathogens. Of the 7 patients with virologic and spirometric data, 5 had >1-log reduction in nasopharyngeal swab PIV viral load and 4 had improved forced expiratory volumes by the end of treatment. Three patients (19%) died within 30 days and 2 of these deaths were related to PIV infection. Our data suggest that DAS181 may be an effective therapy for PIV pneumonia in HSCT recipients. Randomized placebo-controlled trials are needed to better evaluate its efficacy.

Mechanism of Binding to Ebola Virus Glycoprotein by the ZMapp, ZMAb, and MB-003 Cocktail Antibodies.

Cocktails of monoclonal antibodies (MAbs) that target the surface glycoprotein (GP) of Ebola virus (EBOV) are effective in nonhuman primate models and have been used under emergency compassionate-treatment protocols in human patients. However, the amino acids that form the detailed binding epitopes for the MAbs in the ZMapp, ZMAb, and the related MB-003 cocktails have yet to be identified. Other binding properties that define how each MAb functionally interacts with GP—such as affinity, epitope conservation, and epitope accessibility—also remain largely unknown. To help define how each MAb interacts with GP, here we used comprehensive alanine-scanning mutagenesis (shotgun mutagenesis), neutralization escape, and whole virion binding to define each MAb's specific epitope, epitope accessibility, epitope conservation, and apparent affinity. Each of the six therapeutic MAbs binds nonidentical epitopes in the GP base, glycan cap, or mucin-like domain. Their apparent affinity, epitope complementarity, and epitope accessibility helps explain why MAbs 4G7 and 13C6 are more protective than 2G4 and 1H3. The mucin-like domain MAbs 6D8 and 13F6 bind with the strongest apparent affinity, helping to explain their effectiveness in vivo despite their inability to neutralize virus. Ebola virus disease (EVD) can be caused by four different filovirus family members, including Ebola virus (EBOV), which infected 10 times more people in western Africa over the last year than all previous EVD outbreaks combined, with a number of cases distributed across the globe by travelers. Cocktails of inhibitory monoclonal antibodies (MAbs), such as ZMAb, MB-003, and in particular ZMapp, have demonstrated in animal models some of the most significant therapeutic potential for treating EVD, and in 2014, 15 patients were treated with ZMapp or ZMAb under compassionate-use protocols. Here, we have defined the epitope features for the most important therapeutic MAbs against EBOV developed to date. Defining the epitopes and binding characteristics for these MAbs, as well as the commonly used reference MAb KZ52, helps explain their breadth of reactivity against different ebolavirus species, predict viral evasion against these MAbs, and design new cocktails of MAbs with improved complementarity.

Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy

IntroductionSince the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[124I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of 131I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of 131I-MIP-1095.MethodsSixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of 124I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of 131I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA.ResultsI-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed.ConclusionBased on the biodistribution and dose calculations of the PSMA-targeted small molecule 124I-MIP-1095 therapy with the authentic analog 131I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-014-2713-y) contains supplementary material, which is available to authorized users.

Fish oil-based lipid emulsions in the treatment of parenteral nutrition-associated liver disease: an ongoing positive experience.

We previously reported the beneficial effect of fish oil-based lipid emulsions (FOLEs) as monotherapy in the treatment of parenteral nutrition-associated liver disease (PNALD). In this report, we share our ongoing experience at Texas Children's Hospital, Houston, Texas in the use of FOLE in treatment of PNALD as presented at the 2013 Experimental Biology meeting. We describe the findings of a single center, prospective, observational study of infants <6 mo of age with PNALD who received parenteral FOLE as monotherapy. A total of 97 infants received FOLE under the compassionate-use protocol for the treatment of PNALD. Eighty-three (86%) survived with resolution of cholestasis and 14 (14%) died. The median conjugated bilirubin (CB) concentration at the initiation of FOLE therapy was 4.8 mg/dL (range 2.1-26). The median time to resolution of cholestasis was 40 d (range 3-158). Compared with infants with mild cholestasis (CB of 2.1-5 mg/dL at the initiation of FOLE), nonsurvivors were significantly more premature and took longer to resolve their cholestasis. Gestational age at birth correlated inversely with CB at the beginning of FOLE and peak CB. Infants with an initial CB >10 mg/dL had a higher mortality rate than infants with an initial CB <5 mg/dL (35% vs. 6%; P < 0.05). Our experience with the use of FOLE in PNALD continues to be encouraging. Prematurity continues to be a major determinant in mortality and severity of cholestasis. This calls for further controlled studies designed to optimize dose and timing of intervention in the use of FOLE in neonates.

Impact of new-generation parenteral lipid emulsions in pediatric nutrition.

Advancements in the care of premature infants and infants with severe bowel disease have occurred in which long-term use of i.v. nutrition is a cornerstone of successful therapy. Concern about the role of i.v. lipid emulsions in causing severe liver damage to high-risk infants receiving long-term i.v. nutrition has led to a variety of intervention strategies. These have had relatively limited success until the recent introduction of omega-3 (n-3) fatty acid-containing forms of lipid emulsions in place of the current omega-6 fatty acid-predominant lipid emulsions currently exclusively used in the United States. Preliminary data based on nonrandomized trials performed using compassionate-use protocols in the United States suggest very high rates of resolution of cholestasis with the use of an omega-3 fatty acid-predominant lipid emulsion. This result is supported by animal models of liver disease that demonstrate decreased liver damage when animals are provided omega-3 fatty acid-containing lipid emulsions compared with those primarily omega-6 fatty acid based. However, human trials are limited at this time and further research is needed to establish the best approach to preventing liver damage in infants receiving i.v. nutrition and the optimal dose and timing of intervention with novel lipid emulsions.

A Novel Hybrid CFH/CFHR1–3 Gene in Atypical Hemolytic Uremic Syndrome

AbstractAbstract 4644 Background:Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and renal failure in the absence of Shiga toxin exposure. Dysregulation of the alternative pathway by mutations in complement regulatory proteins or antibodies to these proteins have been implicated in the pathogenesis of the disorder. Aims:We report the late onset of aHUS in association with heterozygous deletion of two genes, CFHR1 and CFHR3, and a mutation in CFH, c.497G>T, p.Arg166Leu. The latter mutation has not previously been reported with aHUS. Methods:A 20-year-old female whose past history was unremarkable with the exception of a spontaneous abortion 3 months earlier, presented to an emergency room with abdominal pain and bloody diarrhea three days after eating raw fish. Within 4 days of hospitalization she developed MAHA, thrombocytopenia and renal failure. Studies were negative for Shiga toxin and showed an ADAMTS13 level of 40%. A diagnosis of aHUS was made. Treatment was initiated with daily plasma exchange (PE) which was increased to twice daily for 6 weeks. Response was poor. After discontinuing PE, the patient was treated on an IRB-approved compassionate-use protocol with eculizumab 900 mg weekly for four weeks followed by 1200 mg every two weeks. Results:The patient responded slowly to eculizumab. PK values of eculizumab were sub-therapeutic at week 4. On week 5, she was switched to the maintenance dose of 1200 mg every two weeks, which resulted in a rapid normalization of her platelet count and LDH, with further improvement of her renal function and normalization of her mental status. The patient is doing well on continued eculizumab treatment. Genetic testing revealed a known copy-number variation (CNV), hemizygosity for CFHR1 and CFHR3, and a mutation in short consensus repeat (SCR) 3 of CFH, p.Arg166Leu. Summary/Conclusions:This patient presented with aHUS unresponsive to PE, but responsive to eculizumab treatment. Genetic testing of complement regulatory genes identified a known CNV and a mutation in CFH, p.Arg166Leu. This mutation lies in SCR3 of CFH, a region of the protein important for fluid-phase regulation of the C3 convertase. Although it has been seen in a rare case of dense deposit disease, it has not has not been reported with aHUS. This patient's poor response to PE suggests that additional genetic factors may be present in this patient that affected the course of disorder. Her slow response to eculizumab may have been due to third spacing of the drug secondary to hypoalbuminemia with anasarca as documented sub-therapeutic levels were present on week 4. When the dose was increased to 1200 mg every two weeks, the patient rapidly improved with resolution of the aHUS. Disclosures:No relevant conflicts of interest to declare.

L-asparaginase (L-ASP)-related toxicities with Erwinia L-ASP in a large compassionate-use protocol.

9534 Background: L-ASP is an important component of the multi-agent chemotherapy in children and young adults for treatment of acute lymphoblastic leukemia (ALL). The pegylated E. coli derived form, Oncaspar (PEG-ASP) is most commonly used because of its longer half-life; however, clinical hypersensitivity reactions can occur in 10-30% of patients requiring its discontinuation. Erwinia L-ASP (E) is an L-ASP derived from a different bacterium and is immunologically distinct from the E. coli L-ASP. We conducted a compassionate use trial of E in patients with ALL and hypersensitivity to PEG-ASP to collect safety information. Methods: Patients were ≥ 1 year of age with ALL who developed a clinical hypersensitivity reaction to PEG-ASP. Patients with a history of pancreatitis, previous allergic reaction to E, or pregnant, were excluded. E was administered at 25,000 IU/m2 IM/IV/SC 3 times per week on a Monday/Wednesday/Friday schedule for 2 weeks to replace each dose of PEG-ASP. The study was IRB approved at each institution and patients/family provided informed consent. Safety information on E-related adverse events (AEs) was captured on Case Report Forms (CRFs) submitted to the Sponsor when the patient completed his/her entire E treatment plan. Results: Between February 2006 and April 2010, 569 patients were treated with E and had CRFs completed. The average age was 9.4 years (range 1-66). The majority of patients (61.2%) were male. 13.9% of patients withdrew due to AEs, 7.6 % due to allergic reactions. Anaphylactic and hypersensitivity reactions were reported in 6.5% and 4.6% respectively. The incidence of pancreatitis was 2.5% thromboembolic disorders 1.3%, hyperglycemia 1.4% and elevation in liver enzymes 1.6%. There were 5 deaths on study (4 relapses, 1 thromboembolic event). Conclusions: This is the largest study of patients treated with E to determine the toxicity profile. E was well tolerated with no unexpected toxicities identified. This compassionate use trial showed E was well tolerated and permitted continued asparaginase treatment in 85% of patients with hypersensitivity reactions to E.coli formulations. Updated data will be presented.

Continuous veno-venous single-pass albumin hemodiafiltration in children with acute liver failure*

To investigate the applicability, efficacy, and safety of single-pass albumin dialysis in children. Retrospective data review of uncontrolled clinical data. University-based pediatric intensive care unit collaborating with a local center for liver transplantation. Nine children, aged 2 to 15 yrs, who were treated with single-pass albumin dialysis for acute liver failure of various origins under a compassionate-use protocol between 2000 and 2006. All patients met high-urgency liver transplantation criteria. Single-pass albumin dialysis was performed as rescue therapy for children with acute liver failure. The decrease in hepatic encephalopathy (grades 1-4) and the serum levels of bilirubin, bile acids, and ammonium were measured to assess the efficacy of detoxification. As a measure of liver synthesis function, thromboplastin time and fibrinogen were analyzed. The safety of the procedure was assessed by documenting adverse effects on mean arterial blood pressure, platelet count, and clinical course. Seven out of nine patients were bridged successfully to either native organ recovery (n = 1) or liver transplantation (n = 6), one of them twice. Six out of nine patients undergoing single-pass albumin dialysis (ten treatments) survived. In six patients, hepatic encephalopathy could be reduced at least by one degree. Ammonium, bilirubin, and bile acid levels decreased in all patients. One patient had an allergic reaction to albumin. In childhood acute liver failure, treatment with single-pass albumin dialysis was generally well tolerated and seems to be effective in detoxification and in improving blood pressure, thus stabilizing the critical condition of children before liver transplantation and facilitating bridging to liver transplantation. It may be beneficial in avoiding severe neurologic sequelae after acute liver failure and thereby improve survival. Single-pass albumin dialysis is an inexpensive albumin-based detoxification system that is easy to set up and requires little training. Whether and to what extent single-pass albumin dialysis can support children with acute liver failure until native liver recovery remains unclear.

Optimal use of recombinant factor VIIa in the control of bleeding episodes in hemophilic patients

One of the last remaining clinical hurdles in the treatment of people with hemophilia is the development of inhibitors. Alloantibodies or autoantibodies directed at coagulation factors render the infusion of coagulation factor concentrates ineffective, and alternative means must be used to achieve hemostasis. Recombinant factor VIIa (rFVIIa) was developed to control bleeding episodes in hemophilic patients with inhibitors. Clinical efficacy in achieving hemostasis in inhibitor patients was demonstrated by a compassionate-use protocol, as well as in randomized controlled trials. To date, over 1.5 million doses of rFVIIa have been given to inhibitor patients, with an excellent efficacy and safety record. Because of its short half-life, alternative means of dosing and infusing rFVIIa have been explored and are reviewed here.

Temsirolimus in second or subsequent line in patients with metastatic renal cell carcinoma (mRCC): Better activity in good-intermediate prognosis patients.

e15081 Background: To evaluate the activity and safety of the inhibitor of mammalian target of rapamycin (mTOR) temsirolimus in unselected, pre-treated patients with mRCC. Methods: Eligible cases had mRCC of clear or non-clear renal cell histology and accessibility for treatment. Any previous treatment was allowed. Patients received 25 mg of intravenous temsirolimus on a weekly basis in the context of a IRB-approved compassionate-use protocol, and were evaluated every 8 weeks for toxicity and tumor response. Results: From March 2007 to date 34 patients have been evaluated and 28 treated (median age 54, range 24-76; male/female ratio: 22/6; clear vs non-clear histology: 23/4, one case not evaluable for histology; 18 cases were treated with sorafenib, 23 with sunitinib and 13 with both drugs). Median number of previous treatments was 2 (range 0-5). According to the Motzer prognostic criteria, 17 were classified as poor-risk, 9 as good-intermediate risk, and 2 had an unknown status. Most common treatment-related adverse events, mainly of grade 1-2, were: hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, neutropenia, lymphocytopenia, stomatitis, skin rash. Dose reduction has been provided in 25% of the cases. Of 28 patients with an available actual tumour re-evaluation none qualified for objective response, 16 achieved a stable disease (57%) and 12 progressed (43%). Considering the prognostic criteria, 9/17 (35%) poor-risk and 8/9 (89%) good-intermediate risk patients achieved a stable disease. All the 4 patients with non-clear-cell histology reported a progressive disease within the first 8 weeks. With a median follow-up of 9 months (range 1-26+) the mean (median) PFS was 5.9 (3.6) months. The median overall survival from the onset of metastatic disease is 28 months (mean OS 42.4 months, range 4-161+ months). The median number of cycles administered was 13. Conclusions: temsirolimus confirms its activity and good safety profile also in a heavily pre-treated population of refractory/relapsed mRCC patients. Further investigations of this drug are warranted. No significant financial relationships to disclose.

Percutaneous Therapy for Valvular Heart Disease

In this week’s Circulation , Webb and colleagues1 report on the use of percutaneous “valve-in-valve” rereplacement in the treatment of 24 ill patients with prosthetic valve failure under compassionate-use protocols. Ten procedures addressed the aortic valve; 7, the mitral valve; 6, the pulmonary valve; and 1, the tricuspid valve. The 30-day survival rate was 96%. Clinically, the results were excellent, with 88% of these highly symptomatic patients returning to New York Heart Association class I or II. Hemodynamically, the results were more modest, with an average postprocedure transaortic gradient of 20 mm Hg and a transmitral gradient of 8 mm Hg. Article see p 1848 Although the above results are gratifying, they go far beyond the fact that 24 ill patients received valve-in-valve replacement. They focus on the next step in the therapy of valvular heart disease (VHD) ushered in by the advent of percutaneous devices. Where exactly this group of therapies will lead is uncertain, but what is certain is that each step of the way will be an exciting one with many successes and some failures. All severe symptomatic VHD is eventually fatal if left untreated, and the only effective treatment is restoration of valve function toward normal. No medical therapies significantly alter the course of VHD; only mechanical relief of the pressure or volume overload created …

Successful Stem Cell Remobilization Using Plerixafor (Mozobil) Plus Granulocyte Colony-Stimulating Factor in Patients with Non-Hodgkin Lymphoma: Results from the Plerixafor NHL Phase 3 Study Rescue Protocol

In a phase 3 multicenter, randomized, double-blinded, placebo-controlled study of 298 patients with non-Hodgkin lymphoma (NHL), granulocyte colony-stimulating factor (G-CSF) plus plerixafor increased the proportion of patients who mobilized >or=5 x 10(6) CD34(+) hematopoietic stem cells (HSCs)/kg compared with placebo plus G-CSF (P < .001). Patients in either study arm who failed mobilization (< 0.8 x 10(6) CD34(+) cells/kg in 2 collections or <2 x 10(6) CD34(+) cells/kg in 4 collections) were eligible to enter the opened-label rescue protocol. Following a 7-day minimum rest period, these patients received G-CSF (10 microg/kg/day) for 4 days, followed by daily plerixafor (0.24 mg/kg) plus G-CSF and apheresis for up to 4 days. Of the 68 patients failing initial mobilization (plerixafor, n = 11; placebo, n = 57), 62 patients (91%) entered the rescue procedure (plerixafor, n = 10; placebo, n = 52). Four of 10 patients (40%) from the plerixafor group and 33 of 52 (63%) from the placebo group mobilized sufficient CD34(+) cells (>or= 2 x 10(6) cells/kg) for transplantation from the rescue mobilization alone (P = .11). Engraftment of neutrophils (11 days) and platelets (20 days) was similar to that in patients who did not fail initial mobilization, and all patients had durable grafts at the 12-month follow-up. Common plerixafor-related adverse events (AEs) included mild gastrointestinal (GI) effects and injection site reactions. There were no drug-related serious AEs. These data support that plerixafor plus G-CSF can safely and effectively remobilize patients with NHL who have failed previous mobilization.

Cost Analysis of Mobilization and Autologous Transplantation in Patients Who Received AMD 3100 after Failing Standard Mobilization.

AMD3100 administered with G-CSF has been demonstrated to mobilize hematopoietic stem cells in patients (pts) who do not collect sufficient cells for autologous transplant following other mobilization regimens. This retrospective study evaluated the difference in clinical outcomes and costs of mobilization and transplant between pts who achieved sufficient CD34+ cells to proceed to transplant using a standard mobilization regimen (control group) versus pts who had failed previous mobilization regimens and were remobilized with AMD3100 and G-CSF in the compassionate use protocol (CUP). Between 2005 and 2008, a total of 88 pts in the control group and 36 pts in CUP were evaluated. In the latter group, mobilization data were available for 35 pts, post-transplant care information was obtainable for 28 pts, and 23 pts had cost data. Prior mobilization attempts in this group included cyclophosphamide plus G-CSF (67%) or G-CSF alone (33%). Following AMD3100 administration, 33 (94%) pts achieved successful mobilization of > 1.9 million/kg CD34+ cells. A median of 3.36 x106 CD34+ cells/kg (range, 0.51–13.05) were collected in a median of 3 (range, 1–4) apheresis days. In comparison, control pts collected a median of 10.8 x106 CD34+ cells/kg (range, 1.95–69.32) in a median of 2 (range, 1–6) apheresis days. Twenty-eight CUP pts went on to transplant and received a median of 3.71 x106 CD34+ cells/kg (range, 1.91–13.05) compared to a median of 5.5 x106 CD34+ cells/kg (range, 1.95–18.76) infused into the control group. The CUP pts had a median day to ANC > 500/μl of 11 days (range, 9–17) and platelets > 20,000 /μl of 27 days (range, 13–37). At day 100, 92% of the CUP pts reached engraftment and there were no transplant related mortalities. The control population had a median day to ANC > 500/ ul of 11 days (range, 8–14) and platelets > 20,000/μl of 18 days (range, 9–83). The control group experienced 100% engraftment and one transplant related fatality. Relapse occurred in 14% of the CUP pts and 32 % of the control pts. With a median follow up of 385 days (range, 55–992) in the CUP pts and 560 days (range, 156–867) in the control pts, 86% of CUP pts and 91% of control pts are alive (p=NS). The median cost of remobilization with AMD3100 was $2,959 less in the CUP pts than the median cost of initial mobilization for the control group, but this was not significantly different between the groups. As expected, the median total cost of mobilization in the CUP pts, including initial mobilization costs, was $16,927 more than in the control pts (p<0.0001). Total cost of mobilization in the CUP pts does not include the cost of AMD3100 as drug was administered on study. In both groups of pts, greater than 95% of total transplant costs occurred in the first 30 days of the transplant course. The difference in the total median transplant costs at day 30 in the CUP pts was $7,373 more than in the control pts. (p=0.0024). The primary difference in cost between the groups was reflected in total inpatient costs; CUP pts incurred 91% of total costs and control pts 57% of total costs in the first 30 days. In conclusion, this single center review shows remobilization with AMD3100 + G-CSF allowed a high percentage of patients who failed standard mobilization to subsequently mobilize adequate CD34+ cells and proceed to autologous transplant with acceptable clinical outcomes. Pts who required remobilization also had an increased cost of transplantation because of increased inpatient costs. Additional pharmacoeconomic studies that compare the costs of utilizing AMD3100 in the first-line setting and comparing it to costs of cytokines with or without chemotherapy are warranted.

AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data

AMD3100 given with G-CSF has been shown to mobilize CD34+ cells in non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and Hodgkin's disease (HD) patients who could not collect sufficient cells for autologous transplant following other mobilization regimens. These poor mobilizers are usually excluded from company-sponsored trials, but have been included in an AMD3100 Single Patient Use protocol, referred to as a Compassionate Use Protocol (CUP). A cohort of 115 data-audited poor mobilizers in CUP was assessed, with the objective being to collect > or =2 x 10(6) CD34+ cells per kg following AMD3100 plus G-CSF mobilization. The rates of successful CD34+ cell collection were similar for patients who previously failed chemotherapy mobilization or cytokine-only mobilization: NHL -- 60.3%, MM -- 71.4% and HD -- 76.5%. Following transplant, median times to neutrophil and PLT engraftment were 11 days and 18 days, respectively. Engraftment was durable. There were no drug-related serious adverse events. Of the adverse events considered related to AMD3100, two (1.6%) were severe (one patient -- headache, one patient -- nightmares). Other AMD3100-related adverse events were mild (84.8%) or moderate (13.6%). The most common AMD3100-related adverse events were gastrointestinal reactions, injection site reactions and paresthesias. AMD3100 plus G-CSF offers a new treatment to collect CD34+ cells for autologous transplant from poor mobilizers, with a high success rate.

AMD3100 Plus G-CSF Mobilizes the Majority of Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and Hodgkin's Disease (HD) Patients Who Failed Prior Mobilization with Other Regimens.

Background: AMD3100, an inhibitor of SDF1 binding to CXCR4, synergizes with G-CSF to allow mobilization of sufficient CD34+ cells/kg for autologous transplantation in pts unable to collect adequate CD34+ cells with G-CSF alone. Therefore, a single patient use (SPU) protocol for AMD3100 was adopted for more than one patient entry per site and termed Compassionate Use Protocol (CUP). The only difference of standard of care was the addition of AMD3100 to a G-CSF mobilization on the evening prior to each day of apheresis. Pts who could not proceed to apheresis due to low peripheral blood counts or pts who did not collect a minimum of 2 × 10^6 CD34+ cell/kg were eligible.Methods: Overall, more than 280 patients with proven poor mobilization including 137 NHL, 73 MM, and 31 HD have been included in CUP. A data audit was performed to validate data from pts with either non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Hodgkin's Disease (HD). Sites were selected based on most patients entered, >3 of all diseases entered at a site, and sites conducting an AMD3100 trial. Audit included all pts, regardless of success or failure of the outcome; all information was collected on CRFs. Success of outcome was collection of ≥ 2×10^6 CD34+ cells/kg during the CUP procedure. CUP apheresis was done on day 5 after G-CSF (10mg/kg SC QD) and AMD3100 (240mg/kg SC Q10 PM) starting day 4.Results: Charts and CRFs were available for review for 115 pts; 63 (55%) were NHL patients from 29 sites, 35 (30%) were MM from 23 sites and 17 (15%) were HD from 13 sites. Of these pts, 58% were male, the median age was 59 years (range 21–77), 88% were Caucasian, and patient weight ranged from 43–128 kg. Prior treatments included a median of two regimens of chemotherapy in each of the three groups. Safety was generally favorable with no drug-related SAE's and with an AE profile similar to that seen in research trials. The rates of successful collection of ≥ 2×10^6 CD34+ cells/kg per disease state as well as prior mobilization regimen are summarized in table 1. The median number of mobilizations for the successful patients was 3 days for NHL and HD and 4 for MM. Eighty-eight of the patients underwent transplantation with any cells. For example, of the 47 NHL patients transplanted, 24 had CUP only cells and 23 had mixed cells. The median number of days to engraftment was 11 for PMN and 18 for platelets. Long term follow up is limited, but there do not appear to be graft failures. At least 12 of the pts have died.Conclusions: AMD3100 in a poor mobilizer population is generally safe and well tolerated and is very effective in mobilizing > 2×10^6 CD34+ cells/kg.Mobilization success rate by disease state: overall and prior mobilization regimenOverallPrior CytokinePrior ChemotherapyNHL60%53%68%HD76%78%75%MM71%73%71%

Uncertain Compassion in Using a Drug Before the Risks and Benefits Are Known

F IRST, DO NO HARM,” IS a critical dictum in medica l prac t ice . Medical practitioners from ancient times to the present have used individual and shared scientific observations to determine the risks and benefits of individual therapies. However, the yield in this somewhat random process is certainly low. Since the development of the modern pharmaceutical industry as well as the Food and Drug Administration (FDA) as a regulatory agency, we as a medical and scientific community have been held to higher standards to provide proof of safety and efficacy of new treatments through randomized clinical trials. Phase 3 randomized clinical trials are the final phase of testing prior to FDA approval of a drug or technology for marketing. In general, this level of study compares the results of patients randomly assigned to a new treatment with those of a control group of patients randomly assigned to standard treatment or placebo to assess which group has better survival/ response rates or fewer adverse effects. However, the presence of a control reference group of patients from whom a potentially promising therapy is withheld has been deemed by many clinicians as lacking in compassion. Compassion, which is defined as intent to help, can be viewed altruistically as the objective of all new drug and procedure investigation activities. Although there is no FDA regulation or policy to define “compassionate use” of drugs, it is commonly understood as the use of drugs to treat diseases, usually serious lifethreatening conditions such as AIDS and cancer, without first going through the full process of randomized, controlled clinical trials through phase 3. However, without adequate controls in a pivotal phase 3 randomized clinical trial, the safety and benefit of new therapies cannot be adequately assessed until after approval and potentially not at all if the promised postapproval studies are not performed. As of 2005, there have been 91 drugs approved since 1992 with industry commitments to the FDA to perform postapproval studies: only 49 of those have been completed, and fully 21 have not even been started. While the few patients enrolled in a trial may potentially benefit from an as yet unapproved drug or procedure, the larger group of people suffering from the same condition will never see any benefit if the study is poorly controlled and therefore uninterpretable, resulting in either no approval or poor utilization of an approved drug. Although many new drugs and procedures show early promise, when they are subjected to a well-controlled randomized clinical trial, it is not unusual for the placebo group to show superior safety and the standard-of-care group to show better efficacy. Given the dilemma of balancing cold science and clinical compassion, one can invoke a differential approach in providing ethical and compassionate care, depending on whether the clinician is proposing the off-label use of an approved drug, a new surgical procedure, or a new drug. The last option can only be performed under the watchful eyes of the FDA, and significant benefit and safety of the drug have to be shown in the early phases before the drug can be subjected to a phase 3 trial. Once a trial has completed enrollment and the minimum follow-up mandated by the FDA in the required two phase 3 pivotal studies, many companies have created expanded access compassionateuse protocols to provide more patients with the opportunity to be treated with promising new therapies prior to approval. These compassionate-use protocols also provide the added benefit of being able to collect data from patients, principally for additional safety analyses. Regarding new surgical procedures and off-label use of existing drugs, there are several important examples of the role of randomized clinical trials. Randomized clinical trials such as the Diabetic Retinopathy Study, the Early Treatment Diabetic Retinopathy Study, and the Macular Photocoagulation Study, all sponsored by the National Eye Institute, clearly established the benefits and risks of laser photocoagulation in patients with diabetic retinopathy and choroidal neovascularization associated with agerelated macular degeneration and have served as the gold standards for subsequent clinical trials in ophthalmology. Regarding expanding offlabel use of approved drugs, physicians have been allowed more Author Affiliations: Department of Ophthalmology, University of California Irvine (Drs Narayanan and Kuppermann), and LV Prasad Eye Institute, Banjara Hills, Hyderabad, India (Dr Narayanan).