Expanded Access Protocol Research Articles

2022 Monkeypox Case Report: Beyond Borders and Expectations

Monkeypox is a zoonotic virus that is in the same family as smallpox. It is primarily spread through various forms of close contact with an infected individual, including direct contact with an infected person’s bodily fluids or surfaces and fabrics that have been contaminated. Its symptoms are generally characterized by rashes or lesions that are firm or supple, restricted to its area, and raised in its center. Vaccines for this disease were actually developed for smallpox. There are two main types of vaccinations: ACAM2000 and 0Jynneos. ACAM2000 uses a live vaccine virus while Jynneos uses a non-replicating virus. Due to the similarity between smallpox and monkeypox, Tpoxx is being researched as a potential treatment. FDA approved Tpoxx – or Tecovirimat – in 2018 as an effective treatment for smallpox after extensive animal trials and safety studies. Currently, the drug is not FDA-approved for monkeypox; however, under an expanded access protocol, it is clinically available. There are two cases presented in this article. The first case was a heterosexual male in his 30s who contracted monkeypox while having multiple sexual encounters with women while moving from tent to tent as an unhoused resident. He also shared pipes with others for recreational marijuana use. This case illustrates that monkeypox is a virus that isn’t restricted to sexuality, especially that of the LGBTQ+ community. To clarify, this virus is not an STI/STD, it’s spread by skin-to-skin contact, contact with an object that was in contact with an infected individual, or contact with respiratory secretions. However, there are fears of singling out the LGBTQ+ community and using the monkeypox virus to stigmatize these communities, much like the AIDS pandemic in the 1980s. In this case, a large proportion of those infected identifies as non-heterosexual, which may just be a result of the nature of a viral illness. Tightly knit groups and communities that spend a lot of time with each other create many opportunities for contact and facilitate disease spread. Second case is a homosexual male in his 60s who received childhood vaccination for smallpox, and yet contracted the monkeyvirus during his travels to Germany and Switzerland, where he had encountered multiple sex partners. This case presents how previous vaccination for smallpox may not be effective against monkeypox virus. Thus, prior smallpox vaccines in the distant past offered no protection against monkeypox and are capable of spreading to people outside of the borders of LGBTQ+ community.

Food and Drug Administration Approval of Artesunate for Severe Malaria: Enough to Achieve Best Practice?

Intravenous artesunate has been the global standard of care for severe malaria for over 2 decades. Yet, until recently, artesunate has only been available to patients through an expanded-access protocol from the Centers for Disease Control and Prevention. In May 2020, the Food and Drug Administration approved artesunate, allowing US hospitals to stock the drug and ensuring prompt treatment for this life-threatening infection. However, because of artesunate's high cost and the infrequency of severe malaria in the United States, hospitals may be reluctant to stock the drug. As US health systems weigh the decision to stock artesunate, we propose a hospital tier framework to inform this decision and support clinicians caring for patients who present with severe malaria.

Lessons learned from the use of COVID-19 convalescent plasma at Kaiser Permanente.

BackgroundIn April 2020, the Mayo Clinic helped establish the US Food and Drug Administration Expanded Access Protocol for COVID-19 (coronavirus disease 2019) convalescent plasma (CCP). The effectiveness of CCP in the published literature is contradictory because some retrospective studies showed benefit in reducing mortality and severe illness, whereas prospective randomized controlled trials demonstrated no benefit of CCP.ObjectivesTo discuss (1) the implementation of CCP across Kaiser Permanente Southern California between April 2020 and April 2021, (2) retrospective multivariable analysis of 2,831 patients with COVID-19 who were transfused with CCP compared with 18,475 patients with COVID-19 who did not receive CCP, (3) how to reconcile contradictory published data regarding the efficacy of CCP, and (4) guidance regarding the future use of convalescent plasma in a large community hospital setting.MethodsMultivariable analysis was controlled for demographic characteristics, level of oxygen delivery, intensive care unit stay, selected laboratory findings, and other concurrent treatment-related variables. Tubing segments from 151 CCP units transfused between October 2020 and April 2021 were retrospectively tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti–spike protein receptor-binding domain IgG. Multivariable analysis showed that CCP transfusion did not affect mortality rates at 30 days and 5 months (odds ratio, 1.04, 95% CI, 0.87-1.25, and hazard ratio, 1.05, 95% CI, 0.93-1.19).ConclusionsIf convalescent plasma is offered as a therapeutic in a future viral pandemic, we recommend (1) transfusing only those patients who are negative for neutralizing antibodies, (2) transfusing very early during the disease course, (3) only using convalescent plasma with known levels of neutralizing antibodies, or (4) alternatively providing fractionated hyperimmune globulin.

Updated clinical outcomes from ULI-EAP-100, an intermediate expanded access program for ulixertinib (BVD-523).

e15101 Background: Ulixertinib is a first-in-class selective small molecule inhibitor of ERK1/2 with demonstrated clinical efficacy in patients with solid tumors harboring MAPK pathway alterations in BRAF and NRAS. Emerging clinical data suggest improved efficacy for certain patient populations when MEK/ERK inhibitors are combined with inhibitors of autophagy (hydroxychloroquine), CDK4/6 (palbociclib), or EGFR/BRAF (cetuximab/encorafenib). Methods: ULI-EAP-100 (NCT04566393) is an ongoing intermediate expanded access protocol (EAP) that offers ulixertinib to US patients with advanced solid tumors harboring MAPK pathway alterations including but not limited to KRAS, BRAF, NRAS, MEK1/2, and ERK1/2, who have exhausted or not tolerated standard-of-care. Combinations with approved agents are permitted at the discretion of the treating physician and approval. Clinical data is collected and structured in a 21 CFR Part 11-compliant database according to XCELSIOR (NCT03793088), a real-world observational registry. Results: As of February 1st, 2022, 48 patients (pts) across 17 sites have been treated with ulixertinib under ULI-EAP-100 including pts with colorectal cancer (CRC) (21), melanoma (8), pancreatic ductal adenocarcinoma (PDAC) (6), lung cancer (5), cholangiocarcinoma (4), glioblastoma (2), and appendiceal cancer (2). Qualifying alterations were mutations in KRAS (21 pts), BRAF (13), NRAS (3), MAP2K1 (1), multiple genes (7), and overexpression of MAPK1 (1). Regimens included ulixertinib monotherapy (28 pts), ulixertinib + hydroxychloroquine (12), ulixertinib + encorafenib + EGFRi (cetuximab, panitumumab) (5), ulixertinib + palbociclib (2), and ulixertinib + encorafenib + atezolizumab (1). Thirty-nine (39) pts have discontinued ulixertinib for reasons including progression (25), AEs (9), and patient choice including hospice (5). Most common AEs (any grade/relatedness) were acneiform rash (29%), fatigue (25%), diarrhea (19%), abdominal pain (15%), and anorexia (15%). Grade 3/4 SAEs occurred in 15 pts (31%). Nine pts (19%) expired while on protocol, all attributed to disease progression. Four pts attained clinical benefit including BRAF V600E PDAC and glioblastoma pts on monotherapy for 413 and 128 days, respectively. A BRAF D594G melanoma pt’s tumor rapidly shrunk with monotherapy permitting surgery and rendering pt with no evidence of disease and a BRAF V600E CRC pt experienced a complete response following ulixertinib + encorafenib + cetuximab combination therapy. Conclusions: ULI-EAP-100 is a unique EAP permitting monotherapy and personalized combination regimens at treating physicians’ discretion. Safety of ulixertinib in this program is consistent with previous experience and all grade 5 AEs were attributed to disease progression. Multiple patients who exhausted prior therapies gained significant clinical benefit from ulixertinib under ULI-EAP-100. Clinical trial information: NCT04566393.

First-in-human experience using RBS2418, an oral ENPP1 inhibitor within an expanded access protocol in combination with pembrolizumab in a patient with metastatic adrenal cancer.

e14550 Background: ENPP1 is a type II transmembrane protein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activities. ENPP1 expression is associated with poor prognosis across cancer types. ENPP1 hydrolyzes extracellular cGAMP, nucleoside triphosphates (ATP, GTP) and dinucleotide polyphosphates. ENPP1 inhibition protects cGAMP and ATP and reduces adenosine levels in the tumor microenvironment, activates antigen-presenting cells and increases T-cell infiltration promoting anticancer immunity. RBS2418 is a potent oral inhibitor of ENPP1 enzyme activity and under evaluation in a Phase 1a/b study in subjects with advanced unresectable, recurrent or metastatic tumors as monotherapy and in combination with pembrolizumab. Methods: Expanded access to RBS2418 was granted by the FDA under a single patient IND to a subject with high grade adreno-cortical carcinoma. The subject received pembrolizumab at 200mg IV every 3 weeks with escalating doses of RBS2418 weekly, starting at 100 mg p.o. BID, followed by 200 and 400 mg p.o BID. Blood samples were collected at each dose level to determine plasma RBS2418 concentration and the corresponding serum ENPP1 level inhibition. Pharmacokinetic data supported a fixed dose of 200mg p.o. bid. Safety and target engagement were closely monitored and protein expression profiling by IHC in the pre-treatment tumor sample was done. Results: All evaluated dose levels of RBS2418 in combination with pembrolizumab were found to be safe and well tolerated. No dose-limiting drug-related toxicities were observed. The plasma concentration of RBS2418 was 29 ng/ml at 12 hours after the second 100 mg dose (Ctrough). This concentration corresponded to approximately 17-fold times the 90% inhibition level of ENPP1 in human serum (17x serum EC90). After the first dose of 200 mg RBS2418 a maximal plasma concentration of 473 ng/ml was measured, while the Ctrough at 12 hours after the second 200 mg dose was 69 ng/ml (corresponding to ̃40x serum EC90). There was ENPP1, but no detectable cGAMP in the baseline serum sample. In serum samples collected during treatment with RBS2418 there was no detectable ENPP1 enzyme activity and cGAMP was fully stable. Conclusions: RBS2418 with pembrolizumab was safe and well tolerated and no drug-related safety concerns were reported. The pharmacokinetics of RBS2418 showed excellent oral bioavailability, with plasma levels of RBS2418 > 17-fold and > 40-fold above serum EC90 of ENPP1 at the 100 and 200 mg BID dose levels, respectively. Dose levels are further studied in the current Phase 1 trial. ENPP1 activity was measurable in the serum of this subject and RBS2418 led to complete enzyme inhibition throughout the study at all dose levels investigated. These results support the continued development of RBS2418, the first member of this novel class of immunotherapy agents.

Nab-Sirolimus for patients with advanced malignant PEComa with or without prior mTOR inhibitors: Biomarker results from AMPECT and an expanded access program.

11574 Background: Malignant perivascular epithelioid cell tumor (PEComa) is a rare and aggressive sarcoma. nab-Sirolimus is an albumin-bound intravenous (IV) mTOR inhibitor (mTORi) approved for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa. The AMPECT trial (NCT02494570) was the first prospective study in advanced malignant PEComa. In exploratory biomarker analyses, TSC1 or TSC2 alterations were associated with response. We report data from the final analysis of AMPECT patients, who were naïve to mTORi, and in patients with malignant PEComa with prior mTORi exposure treated with nab-sirolimus in an expanded access program (EAP) (NCT03817515). Methods: In AMPECT, patients with malignant PEComa naïve to mTORi received nab-sirolimus (100 mg/m2 IV days 1 and 8 of every 21-day cycle) until progression or unacceptable toxicity. The primary endpoint was ORR by independent radiology review. Other endpoints included duration of response (DOR) and disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD) at ≥12 weeks. In the EAP, patients with malignant PEComa and prior mTORi exposure received the same dose of nab-sirolimus as in AMPECT. Responses and DCR were evaluated post hoc via electronic medical record review. Genetic profiling, including TSC1 or TSC2 status, was assessed in both protocols, but no specific mutation criteria were required for enrollment. Results: Data include 47 total efficacy-evaluable patients, 31 in AMPECT and 16 with malignant PEComa and prior mTORi exposure treated in the EAP from July 2019–July 2021. Prior mTORi on the EAP included sirolimus, everolimus, temsirolimus, or sapanisertib; 12 patients had exposure to 1 prior mTORi and 4 to ≥2 prior mTORi, and 50% had had progressive disease as best response on mTORi. In AMPECT, ORR was 39% (12/31 patients), and DCR was 71%. Median DOR was not reached after 3 years of follow-up. On the EAP, 4/16 patients (25%) achieved PR (DOR range: 1.3+–25.2+ months, 3 ongoing), and 8/16 (50%) had SD as best response; the DCR was 63% (10/16). Of patients with known TSC1 or TSC2 inactivating alterations in the combined datasets (n = 23), 57% had a response (AMPECT, 64%; EAP, 44%). There were no Grade 4 or 5 treatment-related adverse events on either protocol Conclusions: nab-Sirolimus provided durable responses in mTORi-naïve patients with malignant PEComa and clinical benefit in an expanded access protocol for patients with malignant PEComa with prior mTORi therapy. Although AMPECT and the EAP cannot be directly compared, response rates showed similar trends regardless of prior mTORi exposure and in patients with TSC1 or TSC2 alterations. Based on the emerging biomarker results, a tissue-agnostic study in patients with TSC1 and TSC2 alterations has been initiated (NCT05103358). Clinical trial information: NCT02494570, NCT03817515.

An Open-label, Intermediate-sized, Expanded Access Protocol of Rimegepant in the Acute Treatment of Migraine (P2-2.006)

An Open-label, Intermediate-sized, Expanded Access Protocol of Rimegepant in the Acute Treatment of Migraine (P2-2.006)

81P Safety and effectiveness of apalutamide for the treatment of non-metastatic castration-resistant prostate cancer (nm-CRPC): Preliminary results from an open-label expanded access protocol (EAP)

When apalutamide was not commercially available, expanded access protocols were key to providing treatment access and evidence generation. These preliminary results from EAP aims to describe safety and effectiveness of apalutamide plus androgen-deprivation therapy (ADT) for the treatment of nm-CRPC.

Hospital transfusion service operations during the SARS-CoV-2 pandemic: Lessons learned from the AABB hospital survey in preparation for the next infectious disease outbreak.

BackgroundThe SARS‐CoV‐2 pandemic disrupted hospital operations, affected the blood supply, and challenged the health care system to develop new therapeutic options, including convalescent plasma (CCP). The aim of this study is to describe and analyze blood supply fluctuations and the use of convalescent plasma in 2020.MethodsAABB distributed a weekly and biweekly questionnaire through email to hospital‐based members (HBM).ResultsThe survey was sent to 887 HBM with 479 unique respondents, most of the hospitals served pediatric and adult patients, and all states of the country participated, except Idaho and Vermont. Fifty four percent of HBM reported increased wastage in the early phase of the pandemic (May), which decreased to 4% by the end of June and throughout the rest of the year. The majority of HBM reported receiving alerts from their blood suppliers reporting blood shortages throughout the year. During March and April, only 12% of HBM were performing elective surgical procedures. The top reasons to delay procedures were: bed availability (28%); COVID‐19 caseload (23%; and blood availability (19%). By mid‐April, 42% HBM had transfused CCP and reported >24 h delay in getting the units; the vast majority obtained CCP using the Expanded Access Protocol, and later, the Emergency Use Authorization. HBM consistently prioritized the most severe patients to receive CCP, but the proportion of severely ill recipients fell from 52% to 37% between May and October, with an increase from 5% to 21% of HBM providing CCP transfusion early in the course of the disease.DiscussionBlood utilization and availability fluctuated during the pandemic. The fluctuations appeared to be related to the number of COVID‐19 in the community. The use and regulatory landscape of CCP rapidly evolved over the first 8 months of the pandemic.

Expanded Access Protocol of Umbilical Cord Blood Infusion for Children with Neurological Conditions: An Update.

Expanded Access Protocol of Umbilical Cord Blood Infusion for Children with Neurological Conditions: An Update.

Efficacy and Safety of ATA129, Partially Matched Allogeneic Third-Party Epstein-Barr Virus-Targeted Cytotoxic T Lymphocytes in a Multicenter Study for Post-Transplant Lymphoproliferative Disorder

Post-Transplant Lymphoproliferative Disorder (PTLD), an EBV-driven lymphoproliferative disorder (LPD), represents a life-threatening challenge for patients (pts) following solid organ transplant (SOT) or hematopoietic cell transplant (HCT). Though some pts will respond to reduction of immunosuppression or rituximab therapy, failure of rituximab-based 1st line therapy predicts a dismal prognosis in post-HCT PTLD pts with a median overall survival (OS) of 16-56 days. In SOT-associated PTLD, pts failing rituximab experience increased chemotherapy-induced treatment-related mortality compared to other lymphoma pts. EBV-CTLs have previously been shown to induce durable responses in pts with SOT- or HCT-associated PTLD despite rituximab failure. Here we report interim study results for using ATA129, an allogeneic off-the-shelf EBV-CTL cell product derived from volunteer donors, for pts with HCT- or SOT-associated PTLD treated on EBV CTL 201, a multicenter expanded access protocol (EAP) for pts with EBV-driven diseases.Methods: Eligible pts were those with EBV+ PTLD, other EBV-driven malignancies, EBV+ hemophagocytic lymphohistiocytosis (HLH), or EBV viremia; adequate organ function; adequate performance status; and measurable disease who provided informed consent. Enrollment is ongoing. Pts are treated with partially HLA-matched ATA129 sharing ≥2 HLA alleles with the pt, at least one of which is an HLA allele through which ATA129 exerts cytotoxicity (referred to as HLA restriction). The dose of ATA129 is 1.6-2 x 10^6 cells/kg on days 1, 8, and 15 of every 35d cycle. Pts undergo radiographic, biochemical (HLH), or virologic assessment at ~day 28 of each cycle Pts with progressive disease after 1 cycle may undergo Switch Therapy to an ATA129 product with a different HLA restriction. Objective response rate (ORR) is determined radiographically and represents the best response observed across all ATA129 lots received for any given pt.Results: Ten PTLD pts received ATA129 and have sufficient follow-up to assess response (efficacy population): 5 PTLD pts post-HCT; 5 PTLD pts post-SOT. For SOT-PTLD, the objective response rate (ORR) is 100%; for HCT-PTLD, the ORR is 80%. An additional 2 PTLD pts have received ATA129 but are too early to assess. For these 12 PTLD pts, median age was 27 (range 7-58); median number of ATA129 cycles was 2 (range 1-8); median follow-up was 3.3 months (range 1-12 months) and median number of ATA129 cell product lots per pt was 1 (range 1 - 5). An additional 10 pts with various non-PTLD EBV+ diagnoses are included in the safety population only. Treatment-related treatment-emergent serious AEs have been reported in 5 of the 22 treated pts (2 PTLD and 3 non-PTLD pts). However, in this generally ill population, the only safety signal observed was tumor flare in 1 patient.Conclusions: ATA129 provided a high response rate in the PTLD population (80-100%) in the multicenter EAP EBV-CTL-201, consistent with prior reports for single institution studies. A low number of related SAEs was observed across different diagnoses on EBV-CTL-201. Updated safety and efficacy data will be presented at the meeting. DisclosuresLi:Atara Biotherapeutics: Employment. Baiocchi:viracta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude therapeutics: Research Funding; essanex: Research Funding; Theravectys: Consultancy. Nikiforow:Kite Therapeutics: Membership on an entity's Board of Directors or advisory committees. Navarro:Atara Biotherapeutics: Employment. O'Reilly:Atara: Patents & Royalties, Research Funding.

Final Analysis of Day +100 Survival By Prior Hematopoietic Stem Cell Transplant Type from an Expanded Access Study of Defibrotide for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

BackgroundHepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is an unpredictable, life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT) and has an estimated overall incidence of 13.7% post-HSCT. VOD/SOS with multi-organ dysfunction (MOD, sometimes referred to as multi-organ failure) may be associated with >80% mortality. In the United States (US), defibrotide is approved for the treatment of adult and pediatric patients with hepatic VOD/SOS and renal or pulmonary dysfunction following HSCT, and it is approved in the European Union for treatment of severe hepatic VOD/SOS after HSCT therapy in patients older than 1 month. Prior to US approval, defibrotide was made available through an expanded-access protocol (T-IND). The present post hoc analysis of final data from the T-IND investigates Day +100 survival in groups of patients receiving autologous or allogeneic transplant.MethodsPatients received defibrotide 25 mg/kg/day in 4 divided doses, and treatment was recommended for ≥21 days. The original eligibility criteria were VOD/SOS by biopsy or Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain) post-HSCT, with MOD (renal and/or pulmonary); the protocol was amended to include also patients after chemotherapy without HSCT (off label), patients without MOD (off label), and patients with VOD/SOS per modified Seattle criteria (≥2 of: bilirubin >2 mg/dL, hepatomegaly, or ≥5% weight gain [in this study]).ResultsFrom 2007 to 2016, 1000 post-HSCT patients were enrolled and received defibrotide. Of these, 843 (52% pediatric; 48% adult) patients received allografts (450 of whom had MOD), and 155 (82% pediatric; 18% adult) received autografts (61 had MOD) (Table); 2 had unknown graft types. Acute leukemias were most common in the allograft group, and neuroblastoma was most common in the autograft group. Kaplan-Meier estimated survival rate at Day +100 in the allograft group was 55% (95% confidence interval [CI]: 52%-58%) overall, 47% (95% CI: 43%-52%) for those with MOD, and 64% (95% CI: 59%-69%) for those without MOD (Figure). Kaplan-Meier estimated survival rate at Day +100 in the autograft group was 80% (95% CI: 72%-85%) overall, 67% (95% CI: 53%-77%) for those with MOD, and 88% (95% CI: 80%-93%) for those without MOD (Figure).Adverse events (AEs) occurred in 74% of allograft patients (in 77% of the MOD subgroup) and 53% of autograft patients (in 64% of the MOD subgroup). Hemorrhage and hypotension were more common post-allograft (31% and 13%, respectively) than post-autograft (17% and 7%). Treatment-related AEs (TRAEs), as determined by investigators, occurred in 21% of allograft patients (22% with MOD) and 20% of autograft patients (30% with MOD); most common (≥2%, either transplant group) were pulmonary hemorrhage (allograft, 5%; autograft, 3%), gastrointestinal hemorrhage (allograft, 3%; autograft, 1%), and epistaxis (allograft, 2%; autograft, 2%). TRAEs leading to discontinuation were more frequent post-allograft (13%) than post-autograft (10%); most common (≥2%) were pulmonary hemorrhage (allograft, 4%; autograft, 3%) and gastrointestinal hemorrhage (allograft, 2%; autograft, 0.6%). TRAEs leading to death occurred in 3% of the allograft group and 0.6% of the autograft group; most common (≥1%) was pulmonary hemorrhage (allograft, 1%; autograft, 0.6%).ConclusionIn this post hoc analysis of T-IND transplant groups, Day +100 survival rates in both allograft and autograft patients with VOD/SOS, with and without MOD, were consistent with prior defibrotide studies. Taken together, the current results support the overall efficacy and safety profile of defibrotide in patients with VOD/SOS after either allogeneic or autologous HSCT. For both allogeneic and autologous transplant groups, the higher survival rates in the subgroups of patients without vs those with MOD (reinforced by 95% CIs that did not cross) indicate that further study is warranted to determine the impact of treatment earlier in the course of VOD/SOS.Support: Jazz Pharmaceuticals. [Display omitted] DisclosuresRichardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees. Kernan:Gentium: Other: NAK received grants from Gentium during the conduct of the study, and her research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA008748; the content is solely the responsibility of the author . Ryan:Celator/Jazz: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Grupp:Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant.

Clinical trial of high dose hyperthermic intravesical mitomycin C for intermediate and high-risk non–muscle invasive bladder cancer during BCG shortage

PurposeIntravesical Bacillus Calmette-Guérin (BCG) is the gold standard for intermediate and high-risk non–muscle invasive bladder cancer (NMIBC), but availability is limited by global shortages. We present the first North American clinical experience using intravesical hyperthermia (HIVEC) with high-dose mitomycin C (MMC) during BCG shortage. Materials and methodsSingle arm intermediate size expanded access protocol for high dose HIVEC MMC in patients with intermediate and high-risk NMIBC during BCG shortage. Patients received 120 mg intravesical MMC using the Combat BRS to achieve 43°C HIVEC. Primary outcome was a safety assessment of adverse events, with recurrence-free survival and a descriptive analysis of hematologic impacts as secondary outcomes. ResultsFourteen patients were treated from May 2019 to June 2020, 4 (29%) intermediate and 10 (71%) high risk. The cohort is heavily pretreated, only 2 (14%) BCG naïve and median 6 BCG instillations (IQR 5.25, 8.25), with median 3.5 recurrences per patient (IQR 1.00, 5.25) 67% with >1 per year. Patients underwent a median 6 instillations (IQR 3.25, 9.25) which were well tolerated in 11/14 (79%). Seven patients (50%) experienced 10 adverse events, all grades 1 or 2. Most common was MMC allergy (4/14, 29%), followed by bladder spasm (3/14, 21%). Two had recurrences at median 11 months follow up, but both discontinued HIVEC after only 2 treatments. ConclusionsHigh dose MMC HIVEC is a safe and well-tolerated substitute for BCG during global shortages. The higher rate of systemic effects implies increased drug delivery, which may improve efficacy.

An Anti-CD6 Antibody for the Treatment of COVID-19 Patients with Cytokine-Release Syndrome: Report of Three Cases

In COVID-19, the inflammatory cytokine-release syndrome is associated with the progression of the disease. Itolizumab is a monoclonal antibody that recognizes human CD6 expressed in activated T cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of pro-inflammatory cytokines release, including IFN-γ, IL-6 and TNF-α. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access protocol. Itolizumab was able to reduce IL-6 concentrations in all the patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.

1008. Disease Severity Impact on Long-Term Virologic Response to Ibalizumab in Expanded Access Protocol (TMB-311)

BackgroundThe principal goal of antiretroviral therapy (ART) is durable suppression of HIV RNA. In treatment-experienced (TE) patients, ongoing viremia can lead to further accumulation of drug resistance, increased morbidity and mortality. ART efficacy often depends on HIV disease severity; therefore, we sought to assess its impact on long-term virologic suppression in patients treated with Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved for multi-drug resistant (MDR) HIV-1 treatment.MethodsIn TMB-301, a Phase 3 study, 40 TE patients with viral load (VL) >1000 copies/mL (c/mL) received an intravenous (IV) loading dose of IBA (2000mg) followed by maintenance doses (800mg IV) every 2 weeks combined with an optimized background regimen. Patients who completed TMB-301 in the US (n=27) continued to an expanded access protocol TMB-311. To determine the impact of baseline (BL) disease on long-term virologic response, we conducted an on-treatment analysis stratified by BL VL and CD4 count up to week 96. Differences in the proportion of suppressed (< 50 c/mL) individuals among the strata were assessed by Fisher’s exact test.ResultsMedian BL VL and CD4 count were 35,350 c/mL and 73 cells/mL, respectively. The number of patients in the VL strata were 11, 17 and 12 for VL < 10,000, 10,000-70,000, and >70,000 c/mL, respectively. There were 12, 10, 5 and 13 patients in the subgroups with CD4 count < 10, 10-100, >100-200 and >200 cells/µL. Population disease severity was reflected by four deaths (unrelated to study drug). Overall, the proportion of suppressed patients increased from 55% at week 24 (n=31) to 75% for patients remaining on treatment for 96 weeks (n=20). Median VL decrease was 2.9 log10 c/mL. Notably, no statistically significant differences were found across groups. Among patients with advanced HIV disease, 66.7% with CD4 count < 10 cells/mL and 71.4% with VL >70,000 c/mL at BL remained fully suppressed at week 96.ConclusionIn TE patients with advanced HIV disease, maximal viral suppression with IBA was observed regardless of BL CD4 or VL strata if patients remained on treatment. This demonstrates that TE patients across the spectrum of HIV disease, can achieve viral suppression by using drugs with a new mechanism of action.Disclosures Princy Kumar, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Jason Leider, MD, PhD, THERA (Speaker’s Bureau) Jihad Slim, MD, Abbvie (Speaker’s Bureau)Gilead (Speaker’s Bureau)Jansen (Speaker’s Bureau)Merck (Speaker’s Bureau)ViiV (Speaker’s Bureau) Graeme Moyle, MD, Theratechnologies (Consultant) Maurice Leonard, PhD, Theratechnologies Europe Ltd (Employee, Shareholder) R Brandon Cash, PharmD, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)

1027. Long-Term Efficacy, Safety, and Durability of Ibalizumab-Based Regimens in Subgroup of TMB-202 Participants

BackgroundThird line antiretroviral regimens have been associated with suboptimal virologic suppression, due to drug cross-resistance and regimen complexity. Yet, in treatment-experienced (TE) HIV patients, ART durability is essential for preventing further resistance and decreasing HIV-associated morbidity and mortality. Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved to treat multi-drug resistant (MDR) HIV, may support regimen durability given its directly observed administration. We analyzed the safety, efficacy, and durability of response in 12 patients who started IBA in a Phase 2b study.MethodsIn TMB-202, 113 patients with MDR HIV received either 2000 mg IBA every 4 weeks (n=54) or 800 mg IBA every 2 weeks (n=59) for 24 weeks with an optimized background regimen (OBR). Of 96 patients who completed TMB-202, 56 transferred into an investigator-sponsored investigational new drug protocol and 12 later moved onto an expanded access protocol, TMB-311, where efficacy and safety were monitored until IBA was commercially available (approval 2018).ResultsBaseline median viral load (VL) and CD4 count for the 12 patients were 4.4 log10 copies/mL (c/mL) and 135 cells/mL, respectively. The median duration of HIV infection was 22 years (range 18-25). At the completion of TMB-202 11/12 achieved virologic suppression (VL < 200 c/mL) and 8/12 had VL < 50 c/mL. All 12 patients were suppressed (VL < 50 c/mL) at their last TMB-311 visit. Patients gained an average of 99 CD4 cells/mL relative to baseline. There were no treatment-emergent adverse events (TEAE) or therapy discontinuations related to IBA during follow-up. Two patients died from unrelated causes. Overall, the 12 patients remained on IBA for an average of 8.9 years (range 8-9.5), during which 8/12 did not require addition of new ARVs to their OBR to maintain suppression.Figure 1: duration of ibalizumab-based regimen is displayed for the 12 patients. Grey bars represent patients with no addition of new ARVs to OBR. Black bars represent patients with an addition to OBR. Asterisks represent addition of ritonavir only. ConclusionData from 12 patients who received IBA for an average of 9 years validate the long-term efficacy and safety of IBA in TE patients. Importantly, for most patients, the durability of virologic response was maintained with minimal adjustments to the OBR. Altogether, these data demonstrate the contribution of IBA towards durable viral suppression in TE HIV patients with limited therapeutic options.Disclosures William Towner, MD, Dynavax (Research Grant or Support)Gilead (Grant/Research Support)Merck (Research Grant or Support)Tai Med (Research Grant or Support)ViiV (Research Grant or Support) Edwin DeJesus, MD, Gilead Sciences (Advisor or Review Panel member) Colleen McGary, PhD, Theratechnologies (Employee) Mohammed Zogheib, PharmD, MPH, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)

Transfusion reactions associated with COVID-19 convalescent plasma therapy for SARS-CoV-2.

Convalescent plasma (CP) for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown preliminary signs of effectiveness in moderate to severely ill patients in reducing mortality. While studies have demonstrated a low risk of serious adverse events, the comprehensive incidence and nature of the spectrum of transfusion reactions to CP is unknown. We retrospectively examined 427 adult inpatient CP transfusions to determine incidence and types of reactions, as well as clinical parameters and risk factors associated with transfusion reactions. Retrospective analysis was performed for 427 transfusions to 215 adult patients with coronavirus 2019 (COVID-19) within the Mount Sinai Health System, through the US Food and Drug Administration emergency investigational new drug and the Mayo Clinic Expanded Access Protocol to Convalescent Plasma approval pathways. Transfusions were blindly evaluated by two reviewers and adjudicated by a third reviewer in discordant cases. Patient demographics and clinical and laboratory parameters were compared and analyzed. Fifty-five reactions from 427 transfusions were identified (12.9% incidence), and 13 were attributed to transfusion (3.1% incidence). Reactions were classified as underlying COVID-19 (76%), febrile nonhemolytic (10.9%), transfusion-associated circulatory overload (9.1%), and allergic (1.8%) and hypotensive (1.8%) reactions. Statistical analysis identified increased transfusion reaction risk for ABO blood group B or Sequential Organ Failure Assessment scores of 12 to 13, and decreased risk within the age group of 80 to 89 years. Our findings support the use of CP as a safe, therapeutic option from a transfusion reaction perspective, in the setting of COVID-19. Further studies are needed to confirm the clinical significance of ABO group B, age, and predisposing disease severity in the incidence of transfusion reaction events.

Acute Airway Obstruction in 4 Pediatric Patients with Congenital Plasminogen Deficiency (C-PLGD) Treated with Intravenous Plasminogen (Human) Replacement Therapy Under an Expanded Access Protocol

C-PLGD is a rare autosomal recessive multisystem disorder of the fibrinolytic system. Mutations in the PLG gene result in extravascular fibrinous deposits, termed ligneous for their woody appearance, that accumulate on mucous membranes such as the conjunctiva and airways, with resultant tissue injury or organ dysfunction. Ligneous conjunctivitis (LC) is the most common manifestation (&amp;gt; 80%) of C-PLGD. Ligneous lesions affecting the respiratory system have been reported in 20% of patients in a large case series (Schuster et. al. JTH 2007). We report 3 new cases in addition to a previously reported case of airway obstruction with respiratory distress successfully treated with intravenous Glu-plasminogen concentrate (Human) (IV-PLG). Case 1: A 16-month-old female with C-PLGD, with onset of LC at 3 weeks of age, developed a febrile illness with upper respiratory tract symptoms and exacerbation of LC. Four weeks after the exacerbation presented, she developed wheezing unresponsive to bronchodilator and corticosteroid treatment. She progressed to stridor, tachypnea and hypercapnia and was treated with fresh frozen plasma (FFP) infusions. She underwent a bronchoscopy which revealed friable airways and fibrinous lesions in the right mainstem bronchus (Figure 1). Computed tomography (CT) of the chest revealed airway narrowing (R&amp;gt;L) with distal air trapping. She was admitted to the pediatric intensive care unit (PICU) for monitoring and continued FFP treatment every 12 hours without relief. Compassionate use of IV-PLG was requested and she initiated urgent treatment under an expanded access protocol. Significant improvement in stridor and tachypnea occurred within 48 hours of starting therapy and was discharged from the PICU after 2 weeks without symptom recurrence. 10 days post treatment repeat bronchoscopy showed improvement in obstructing airway lesions (Figure 2), and CT scan revealed improvement in airway narrowing and air trapping. She is currently continuing treatment administered every 5 days. Case 2: A 16-month-old male with C-PLGD and shunted congenital hydrocephalous, presented with worsening LC (onset at 7 months) and hoarseness from suspected ligneous airway disease. He was admitted to the PICU for monitoring, supplemental oxygen therapy for hypoxemia, and FFP infusions every 12 hours with only minimal relief. Chest CT revealed bronchiectasis and possible airway lesions. IV-PLG compassionate use was requested; he initiated urgent treatment under an expanded access protocol. Four days after starting treatment he underwent bronchoscopy confirming airway ligneous involvement, and ophthalmologic membranes were also stripped. He responded to treatment with improvement of both respiratory and eye symptoms without further requirement for supplemental oxygen; he was discharged from PICU after 8 days total, and 6 days after starting IV-PLG. His eyes healed without lesion recurrence. He continues to receive IV plasminogen replacement infusions every 5 days. Case 3: A 3-year-old C-PLGD male, diagnosed at 7 weeks of age with LC, developed an upper respiratory infection with persistent hoarseness over a 3-week period. Due to potential airway involvement concern, he underwent upper airway laryngoscopy; a right vocal cord small polyp and a papillomatous mass noted below vocal cords were observed. Compassionate use of IV-PLG was requested; he initiated urgent treatment under an expanded access protocol. The patient experienced resolution of hoarseness in 4 weeks, with significant improvement in his LC. He has had no further clinical respiratory symptoms or LC exacerbations and is currently continuing treatment administered every 5 days. Plasminogen replacement has previously been reported in a fourth C-PLGD pediatric patient (22-month-old male) who had experienced cardiopulmonary arrest due to airway obstruction (Hassenpflug et. al. Blood 2016). This patient required ongoing ventilator support; treatment with IV-PLG assisted in weaning from ventilator support. These cases demonstrate the potential role for IV-PLG treatment in C-PLGD patients with airway obstruction due to fibrinous lesions, to prevent progression of obstruction resulting in respiratory failure; additional controlled studies would need to be performed to further support these observations. Disclosures Nakar: Prometic Biotherapeutics: Research Funding; Kedrion SpA: Research Funding. McDaniel:Prometic Biotherapeutics: Consultancy, Other: Investigator Clinical Trial. Parker:Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Trybul:Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Shapiro:Sangamo: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Octapharma: Research Funding; OPKO: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; BioMarin: Research Funding; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding.

Initial experience and lessons learned with implementing Lutetium-177-dotatate radiopharmaceutical therapy in a radiation oncology–based program

PurposeTo assist radiation oncology centers in implementing Lutetium-177-dotatate (177Lu) radiopharmaceutical therapy for midgut neuroendocrine tumors. Here we describe our workflow and how it was revised based on our initial experience on an expanded access protocol (EAP). MethodsA treatment team/area was identified. An IV-pump-based infusion technique was implemented. Exposure-based techniques were implemented to determine completion of administration, administered activity, and patient releasability. Acute toxicities were assessed at each fraction. A workflow failure modes and effects analysis (FMEA) was performed. ResultsA total of 22 patients were treated: 11 patients during EAP (36 administrations) and 11 patients after EAP (44 administrations). Mean 177Lu infusion time was 37 min (range 26–65 min). Mean administered activity was 97% (range 90–99%). Mean patient exposures at 1 m were 1.9 mR/h (range 1.0–4.1 mR/h) post-177Lu and 0.9 mR/h (range 0.4–1.8 mR/h) at discharge, rendering patients releasable with instructions. Treatment area was decontaminated and released same day. All patients in the EAP experienced nausea, and nearly half experienced emesis despite premedication with antiemetics. Peripheral IV-line complications occurred in six treatments (16.7%), halting administration in 2 cases (5.6%). We transitioned to peripherally inserted central catheter (PICC)-lines and revised amino acid formulary after the EAP. The second cohort of 11 patients after EAP were analyzed for PICC-line complications and acute toxicity. Nausea and emesis rates decreased (nausea G1+ 61%–27%; emesis G1+ 23%–7%), and no PICC complications were observed. FMEA revealed that a failure in amino acid preparation was the highest risk. Conclusion177Lu-dotatate can be administered safely in an outpatient radiation oncology department.

Rapid Recovery from COVID-19 Respiratory Failure after treatment with Vasoactive Intestinal Peptide

Importance: There is currently no meaningfully effective drug for Critical COVID-19 with respiratory failure, particularly in highly comorbid patients with mortality in excess of 30%. Vasoactive Intestinal Peptide (VIP) blocks replication of the SARS-CoV-2 virus, inhibits cytokine synthesis, prevents cytopathy, and upregulates surfactant production in human pulmonary cells. Objective: To determine the safety and efficacy of intravenous Aviptadil (synthetic Vasoactive Intestinal Peptide) for improving the survival and recovery from respiratory failure in patients with Critical COVID-19 and severe comorbidity.Design: Prospective, open-label, administratively-controlled trial, measuring objective endpoints only. Patients were treated in June and July 2020 and followed for 60 days or more post ICU admission. Setting: Intensive care unit and step-down units of a quaternary care hospitalParticipants: 21 consecutively admitted patients with Critical COVID-19, treated with intravenous Aviptadil (synthetic VIP), compared to all patients with comparable comorbidity (n=24) from the same ICU, treated by the same clinical team, in the same time-frame who received maximal standard of care (SOC). Intervention: 3 successive 12-hour intravenous infusions of Aviptadil at 50/100/150 pmol/kg/hr.Main Outcome Measures: Survival, Recovery from Respiratory Failure, WHO 10 point ordinal scale. Results: Seventeen of 21 patients survived to day 60 in the aviptadil-treated group compared to 5 of 24 control patients (81% vs. 21%; PAt day 60, a similar 5.5-fold advantage was seen in the cumulative probability of Recovery from Respiratory Failure (55% vs 10%; P=.002) at 60 days . The hazard ratio is 0.115 (95% CL: 0.0254, 0.5219). Patients treated with Aviptadil were 7-times more likely (% WHO 0-1 57.1% (12/21) for aviptadil vs 8.3% (2/24) control, p-value = 0.0008) to achieve resolution of their symptoms.Comment: A dramatic multi-dimensional treatment effect was observed, consistent with FDA and ICH-10 guidance for acceptance of externally-controlled, open-label trials in high-lethality conditions.