A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab

Introduction: Multiple myeloma (MM) is a neoplastic proliferation of plasma cells. It is the second most common hematological malignancy in the US. Although it is associated with poor prognosis, newer therapies have improved outcomes in MM patients. This review aims to describe novel therapies used for the treatment of relapsed/refractory multiple myeloma (RRMM). Methods: A literature search was performed on Embase and clinicaltrials.gov using the keyword "Multiple Myeloma" from 1/1/2016 to 6/25/2020 for identifying ongoing clinical trials in the treatment of RRMM. After detailed scrutiny, we included 23 ongoing clinical trials (N=4362). We excluded case reports, case series, review articles, meta-analysis, and observational studies. Results: We summarized the interim results from ongoing clinical trials evaluating treatment of RRMM under following newer categories of drugs: Immunomodulatory drugs In a phase 1b/IIa trial (NCT02773030, N=51) evaluating the efficacy of a novel immunomodulators, iberdomide CC-220 + dexamethasone (Dex) yielded an overall response rate (ORR) of 31%, clinical benefit (CB) was seen in 51% of the patients, and disease control (DC) in 88% of the patients and it was well tolerated by RRMM patients. There are other ongoing clinical trials evaluating the efficacy of Avadomide (CC-122), CC-92480 in RRMM. Alkylating agents In a phase I/II trial (NCT01897714, N=45), melphalan-flufenamide (melflufan) + Dex yielded an ORR of 31%, it was well tolerated with 49% CB. Phase III OCEAN trial (NCT03151811, N=450) is currently ongoing to compare melflufen + Dex vs. pomalidomide (Pom) + Dex. Apoptotic agents A phase 3 trial BELLINI (NCT02755597, N=291) evaluated the efficacy of veneteclox (Ven, Bcl-2 inhibitor) by randomizing patients to either Ven or Placebo arm. With a median follow up of 28.6 months (m), progression free survival (PFS) was 23.2m in the Ven arm vs. 11.4m in placebo. The interim results from a phase I/II trial (NCT03314181, N=104) of Ven + daratumumab (Dara) + Dex showed ORR of 96% with ≥ very good partial response (VGPR) of 96%. The addition of Bortezomib (Bor) to VenDaraDex had a slightly low ORR of 92%, with ≥VGPR of 79%. Another phase I/II trial (NCT01794520, N=117) is in progress to assess the efficacy and safety of Ven as monotherapy. Monoclonal Antibodies (MoAb) A phase I/II trial (NCT01421186, N=91) evaluated the efficacy of MOR202, which is a novel MoAb. MOR202 was evaluated in three arms; MOR202 + Dex, MOR202 + Lenalidomide (Len) + Dex and MOR202 + Pom + Dex. The interim analysis showed the ORR of 65% with MOR202 + Len + Dex which was better than ORR of 48% with MOR202 + Pom + Dex, while the use of MOR202 + Dex yielded only 28% ORR. Antibody-drug conjugate (ADC) Four ongoing trials are evaluating the efficacy of ADC (belantamab mafodotin), and the interim results are available for two trials. In phase II DREAMM-2 trial (NCT03525678, N=221) evaluating 2 doses of GSK2857916, 2.5mg/kg dose yielded ORR of 31% while 3.4mg/kg showed ORR of 34%. Another phase I trial (NCT02064387, N=79) evaluated belantamab mafodotin in RRMM and other hematologic malignancies expressing B-cell maturation antigen (BCMA). The results were promising with ORR of 60%. Bispecific T-cell engagers (BiTE) Phase I trial of BiTE AMG 420 (NCT02514239, N=43) showed favorable results with ORR 70%, and CR 12%. The interim results from another phase I trial (NCT03486067, N=115) which evaluated the efficacy of BiTE CC-93269 showed 43% ORR and CR 17%. CAR-T Cell therapy CAR-T cell therapy is also being studied in RRMM with JNJ-68284528 directed against BCMA in a phase Ib trial (NCT03548207, N=118). The interim analysis of 29 response evaluable patients out of 118 reported 100% ORR with stringent CR 76%. PK13 Inhibitors In a phase I/II study (NCT00401011, N=84) evaluating perifosine + Bor +/- Dex, ORR of 41% was observed in Bor RR patients, and therapy was well tolerated with PFS of 6.4m and mOS of 25m. Conclusion: This review demonstrates novel and promising therapies which are currently in early phase clinical trials for the treatment of RRMM. Based on interim results, Iberdomide, melflufan, Ven, MoAb MOR202, ADC belantamab mafodotin, BiTE Molecule AMG 420, BCMA CAR-T cell therapy and perifosine have shown promising early activity and safety data in RRMM patients. Additional exploratory clinical trials are needed to confirm the efficacy and safety of these agents. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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Adverse Events Following CAR T-Cell Therapy: A Single Institution Retrospective Analysis of Toxicities Following CAR T-Cell Therapy for Children and Young Adults with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2021-146979 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1731-1731

Author(s):

Sara K. Silbert ◽

Elizabeth M. Holland ◽

Seth M. Steinberg ◽

Lauren Little ◽

Toni Foley ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Cell Therapy ◽

Phase I ◽

Median Number ◽

Toxicity Profile ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Introduction: CAR T-cells have demonstrated remarkable ability to induce complete remission in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r ALL). This success, however, is tempered by the toxicities associated with CAR T-cell therapy. Much has been published on cytokine release syndrome (CRS), but, to date, a comprehensive profile of specific end organ toxicities secondary to CAR T-cell therapy in the pediatric and young adult population is lacking. Methods: This retrospective, single center study, was performed to characterize the specific adverse events (AEs) experienced by pediatric and young adult patients during the first 30 days following CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events (CTCAE) were collected from all patients with r/r ALL treated on one of three phase I CAR T-cell trials (CD19, CD22, and CD1922) at the Pediatric Oncology Branch of the National Cancer Institute at the National Institutes of Health from 2012-2020. The primary objective was to determine the incidence of all severe AEs, defined as > grade (Gr) 3 AEs, overall and by organ system, attributed to research or disease. Secondary objectives were to stratify severe AEs based on development of CRS and CRS grade (using ASTCT CRS grading criteria). Descriptive statistics were reported along with comparisons of continuous parameters using Mann-Whitney and binomial parameters using Fischer's exact tests. Results: We reviewed AE data from 134 patients with r/r ALL receiving one of 3 unique CAR T-cell constructs (Table). The median age was 15.2 years (Interquartile range (IQR) 9.5-21.2). The median number of prior therapies was 5 (IQR 3-6) and 57% had received a prior hematopoietic stem cell transplant (HSCT). Amongst the 134 patients, a total of 1747 individual > Gr 3 AEs were experienced by 133 patients (99%) during the first 30 days following CAR infusion (Figure 1A). The median number of > Gr 3 AEs per patient was 10 (IQR 4.8-19). Cytopenias (including neutropenia, thrombocytopenia and anemia) comprised the vast majority of total > Gr 3 AEs (n=983, 56.3%). The most common severe (> Gr 3) AEs were thrombocytopenia (n=433, 24.8%), metabolic abnormalities (i.e. electrolyte derangements) (n=333, 19.1%), neutropenia (n=332, 19%), and anemia (n=218, 12.5%). With exclusion of cytopenias, 764 > Gr 3 AEs were experienced by 111 patients (83%), with a median of 4 (IQR 1-8.3) > Gr 3 AEs per patient. One grade 5 pulmonary AE occurred in the setting of acute respiratory distress syndrome (ARDS). Focusing on non-cytopenia AEs (Figure 1B), metabolic AEs made up 43.6% of AEs; hepatic toxicities (n=115, 15%), febrile neutropenia (n=114, 14.9%), and cardiovascular toxicities (n=59, 7.7%) were the next most frequent. Of the 134 patients, 104 (77.6%) developed CRS. All 30 patients without CRS had at least 1 > Gr 3 AE (median 6, IQR 3-11.3). In contrast, the median number of > Gr 3 AEs in those with CRS was 11.5 (IQR, 6-21.5), (p=0.0021). When stratified by CRS Gr 1-2 versus CRS Gr 3-4 (Figure 2), patients with higher-grade CRS also had a higher median number of > Gr 3 AEs per patient (p= 0.0017). Conclusions: Among 134 children and young adults with r/r ALL receiving phase I CAR T-cells, we found a high incidence (99%) of severe AEs, with a per patient median of 10 (IQR 4.8-19) > Gr 3 AEs. While the majority of > Gr 3 AEs were cytopenias, 17 different categories of AEs were experienced. The development and severity of CRS associated with an increase in the median number of severe AEs per patient. As phase I trials of CAR T-cell therapy expand, it is imperative to understand the full toxicity profile of these therapies. While the definition and refined grading of CRS has helped advance the field, there is a gap in knowledge regarding patient specific end-organ toxicities beyond CRS. Our data help establish a foundation for the full toxicity profile experienced by patients enrolling on phase I CAR T-cell trials. With an emerging role for earlier intervention for CRS, we anticipate that the toxicity burden will decrease. Next steps include characterizing the specific toxicities within each AE category, evaluating duration and time to resolution, distinguishing attribution to research versus disease and studying the impact of earlier use of tocilizumab on toxicity profile. Future directions will incorporate assessment of baseline organ function pre-CAR and its impact on development of post CAR severe AEs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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