Results of the phase 2 MARCH Study: Oral ATG-010 (Selinexor) plus low dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma (RRMM) previously treated with an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20002-e20002
Author(s):  
Weijun Fu ◽  
Zhongjun Xia ◽  
Chengcheng Fu ◽  
Wenming Chen ◽  
Gang An ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Therapeutic Option ◽  
Chinese Patients ◽  
Baseline Risk ◽  
Phase 2 ◽  
Car T ◽  
Previously Treated ◽  
Line Of Therapy ◽  
Common Teaes

e20002 Background: ATG-010 is a novel, oral selective inhibitor of nuclear export inhibiting exportin 1. In preclinical and clinical studies, ATG-010 has demonstrated activity against multiple myeloma (MM). ATG-010 (80 mg biweekly) plus dexamethasone (20 mg biweekly) (Sd) was approved by US FDA for treatment of patients (pts) with penta-refractory MM in 2019 based on the STORM study. MARCH is a single arm, Phase 2 study to assess efficacy and safety of Sd in Chinese pts with RRMM. Methods: Enrolled pts have been previously treated with and refractory to PI, IMiD, and the last line of therapy. Sd is administered in 4-week cycles. Primary endpoint is overall response rate (ORR) per independent review committee. The total planned enrollment of 82 pts provides ̃80% power to test against H0 of 15% ORR at one-sided α of 0.025. This abstract provides data from a planned analysis of the first 60 treated pts. Results: As of 13 Oct 2020, 18 (30%) of the 60 pts were on treatment. Median follow-up was 9.5 months (mo) (range: 1.9-12.8). Median age was 61 years (range 43-82; 42% > 65). Pts had received a median of 5 (range 1-16) prior MM regimens, with following baseline risk factors: 72% R-ISS II/III, 70% cytogenetic abnormalities, 22% del (17p13),20% renal impairment, 15% prior CAR-T therapy, and 25% pre-treated with daratumumab (considered ‘triple-class exposed’). ORR was 26.7% (95% CI: 16.1, 39.7). Median DOR was 4.6 mo (95% CI: 1.42, NE). Median PFS was 3.7 mo (95% CI: 1.92, 4.66). Median OS was not reached; 9-mo OS rate was 68.5%. ORR was 33.3% in triple-class-exposed pts, and 44.4% in pts with prior CAR-T. ORR was generally consistent across subgroups. Common TEAEs of any grade included: thrombocytopenia (87%), nausea (87%), leukopenia (85%), anemia (85%), lymphopenia (78%), neutropenia (73%), weight loss (72%), hyponatremia (65%), decreased appetite (63%), asthenia (62%)/fatigue (17%), hyperglycemia (53%), vomiting (52%), hypocalcemia (38%), hypokalemia (30%), diarrhea (30%), pneumonia (27%). Common TEAEs of Grade ≥ 3 included: anemia (60%), thrombocytopenia (55%), leukopenia (42%), lymphopenia (42%), neutropenia (38%), hyponatremia (28%), and pneumonia (23%). Thirty pts (50%) had TESAEs, including (> 3%): thrombocytopenia (15%), pneumonia (15%), anemia (6.7%), hyponatremia (3.3%). Eight pts (13.3%) had TEAEs leading to treatment discontinuation, including (> 2%): thrombocytopenia (5%) and pneumonia (3%). Three fatal TEAEs were pneumonia, intracranial hemorrhage and sudden death (1 each). Conclusions: In Chinese RRMM pts refractory to both IMiD and PI, with a highly unmet medical need, MARCH confirms the efficacy of Sd as a promising new oral therapeutic option with a manageable safety profile, which is consistent with STORM. Clinical trial information: NCT03944057.

scholarly journals Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma

2016 ◽  
Vol 176 (5) ◽  
pp. 783-795 ◽  
Author(s):  
Noopur S. Raje ◽  
Philippe Moreau ◽  
Evangelos Terpos ◽  
Lotfi Benboubker ◽  
Norbert Grząśko ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Phase 2 ◽  
B Cell Activating Factor ◽  
Phase 2 Study ◽  
Previously Treated

scholarly journals Application of two lines of chemotherapy: gemcitabine with nab-paclitaxel and liposomal irinotecan with 5-fluorouracil and leucovorin in patient with advanced pancreatic adenocarcinoma

Oncoreview ◽  
2021 ◽  
Vol 11 (3(43)) ◽  
pp. 68-72
Author(s):  
Krystyna Ostrowska-Cichocka ◽  
Marek Z. Wojtukiewicz
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Option ◽  
Advanced Pancreatic Cancer ◽  
Distant Metastases ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Previously Treated ◽  
Liposomal Irinotecan ◽  
Line Of Therapy ◽  
Advanced Pancreatic Adenocarcinoma

Pancreatic cancer is a disease with high mortality. It is predicted to become the second leading cause of cancer death in some regions of the world. Frequent diagnosis at an advanced stage contributes to 5-year survival at a highly unsatisfactory level of 2–9%. Due to the lack of early symptoms, nearly 80% of patients receive a diagnosis when distant metastases develop. So far, the most frequently used programs in the treatment of patients with pancreatic cancer in the stage of neoplastic spreading include: FOLFIRINOX (oxaliplatin, 5-fluorouracil, irinotecan, leucovorin), gemcitabine alone or in combination with nab-paclitaxel or erlotinib. Based on the results of the phase III study NAPOLI-1, liposomal irinotecan in combination with 5-fluorouracil (5-FU) and leucovorin (LV ) was approved as the first regimen for use in the second or subsequent line of therapy in patients with advanced pancreatic cancer previously treated with gemcitabine. This paper presents a case of a patient with advanced pancreatic cancer who was treated with two lines of chemotherapy – gemcitabine in combination with nab-paclitaxel and liposomal irinotecan with 5-FU/LV . The treatment was well tolerated and was considered a valuable therapeutic option. A 2-year overall survival was obtained from the diagnosis of the disease.

scholarly journals Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3165-3165 ◽  
Author(s):  
Darrell J White ◽  
Suzanne Lentzsch ◽  
Cristina Gasparetto ◽  
Nizar Bahlis ◽  
Christine I Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction: The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma. Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Lenalidomide in combination with dexamethasone has been approved for the treatment of relapsed/refractory multiple myeloma with an ORR of 60-76%. The STOMP study assessed the efficacy and safety of the all oral combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory and newly diagnosed multiple myeloma. We previously reported the recommended phase 2 dose (RP2D) of once weekly selinexor 60 mg, lenalidomide 25 mg and dexamethasone achieved an ORR of 92% in patients with RRMM who were lenalidomide naive. Here we evaluated once weekly selinexor in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. Methods: STOMP is a multicenter, open-label study with a dose escalation (phase 1) and expansion (phase 2) to assess the maximum tolerated dose, RP2D, efficacy and safety of SRd in patients with newly diagnosed multiple myeloma. Patients with newly diagnosed multiple myeloma were eligible if they had symptomatic myeloma per the International Myeloma Working Group (IMWG) guidelines with either hypercalcemia, renal failure, anemia, bone lesions (CRAB) criteria or myeloma defining events needing systemic therapy. Enrollment in this arm is ongoing. Results: As of July 01 2019, 8 patients (4 males and 4 females ) with newly diagnosed multiple myeloma were enrolled at the starting dose level of selinexor 60 mg on days 1, 8, 15, and 22; lenalidomide 25 mg daily 1-21and dexamethasone 40 mg weekly on a 28 day cycle. The median age was 74 years (range: 51-86 years). No dose limiting toxicities (DLT) were observed in 5 DLT evaluable patients, 3 patients were not DLT evaluable because 1 patient did not finish cycle 1 due to social reasons and 2 patients missed doses due to serious adverse events (SAEs) unrelated to study drugs.. Common treatment related hematologic AEs (Grades 1/2, ≥3) were neutropenia (0%, 75%), anemia (0%, 25%), and thrombocytopenia (0%, 25%). Common non-hematologic AEs were diarrhea (63%, 0%), nausea (50%, 0%), fatigue (0%, 38%) decreased weight (38%, 0%), constipation (25%, 0%), hypokalemia (25%, 0%), and hypomagnesemia (25%, 0%). Among 7 efficacy evaluable patients, 6 patients achieved a response (ORR of 86%) including 1 complete response, 1 very good partial responses, 4 partial responses (2 unconfirmed), and 1 patient achieved a minimal response. With a median follow-up of 6.1 months, median progression-free survival was not reached. Conclusions: The all oral combination of SRd has promising activity with 6 of 7 efficacy evaluable patients achieving an objective response in patients with newly diagnosed multiple myeloma and no new or unexpected safety signals. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Bahlis:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Chen:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Onconova: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding. Tuchman:Karyopharm: Honoraria; Prothena: Research Funding; Roche: Research Funding; Alnylam: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Kotb:Karyopharm: Equity Ownership; Janssen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; J&J: Research Funding; Takeda: Honoraria; Celgene: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baljevic:Karyopharm: Other: Internal Review Committee participant; Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Selinexor containing regimens in patients with multiple myeloma (MM) previously treated with anti-CD38 monoclonal antibodies (αCD38 mAbs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20020-e20020
Author(s):  
Cristina Gasparetto ◽  
Brea Lipe ◽  
Sascha Tuchman ◽  
Nizar J. Bahlis ◽  
Heather J. Sutherland ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Median Number ◽  
Open Label ◽  
Previously Treated ◽  
Functional Inactivation ◽  
Dose Modifications

e20020 Background: Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins, is required for MM growth, is associated with poor prognosis in MM and mediates resistance to standard MM therapies. Selinexor (SEL) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound approved in combination with dexamethasone (dex) ± bortezomib for patients (pts) with previously treated MM. Once MM becomes refractory to αCD38 mAb, pts have limited effective treatment options and poor prognosis. Overall response rate (ORR) to the first regimen after refractoriness to an αCD38 mAb is 31%, median progression-free survival (mPFS) is 3.4 months (m), and median overall survival (mOS) is 8.6 m. The doublet SEL-dex (Xd) has shown ORR ̃26% in triple-class (IMID, PI, αCD38 mAb) refractory MM; SEL-based triplets could be more effective in this population. Methods: STOMP (Selinexor and Backbone Treatments of Multiple Myeloma Patients) is a multi-arm, open-label, Phase 1b/2 study evaluating SEL in various triplet combinations. Here, we retrospectively analyzed the efficacy and safety of SEL-containing triplets in pts previously treated with αCD38 mAbs. Pts received SEL-dex (Xd) plus pomalidomide (XPd, n = 19), bortezomib (XVd, n = 4), lenalidomide (XRd, n = 4), daratumumab (XDd, n = 2) or carfilzomib (XKd, n = 18). ORR, mOS, mPFS and adverse events (AEs) were analyzed. Results: Among the 47 pts, median age 64 yrs, female 53%, median time from diagnosis 5.1 yrs, median number of prior regimens 5 (range, 2–11). Prior daratumumab (96%), isatuximab (4%); 96% had MM refractory to aCD38 mAb, 81% had triple-class refractory MM, 74% and 47% were quad- and penta-exposed, 43% and 15% had quad- and penta-refractory MM. αCD38 mAb was included in the immediate prior regimen of 57% of pts and median duration from end of most recent aCD38 mAb therapy to first dose of study treatment was 6.9 weeks (range, 2.6-114.9). ORR was 51% among the 45 evaluable pts, 59% in the XPd arm (n = 17; 2 pts were not efficacy evaluable) and 67% in the XKd arm. ORR was 47% (9/19) among pts with quad-refractory MM and evaluable efficacy. Among all evaluable pts mPFS was 8.8 m (95% CI: 4.9, NE) and mOS was 20.4 m (95% CI: 9.6, NE). Among the 25 pts with αCD38 mAb in their immediate prior regimen, efficacy was similar to that regimen: ORR 52% vs. 45%, mPFS 8.8 vs. 9.3 m. The most common treatment emergent AEs were nausea (72%), anemia (64%), thrombocytopenia (60%), fatigue (57%), which were managed with standard supportive care and dose modifications. Conclusions: SEL-containing triplets in pts with MM previously treated with αCD38 mAbs, most of whom had triple-class refractory MM, exhibit tolerability and comparable effectiveness to their most recent αCD38 mAb-containing regimens. Compared to historical control, mOS was much higher among these patients. Further investigation is warranted. Clinical trial information: NCT02343042.

Infections Associated with CAR T Therapy for Treatment of Hematological Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4442-4442 ◽  
Author(s):  
Tariq Iqtidar Sadiq Syed ◽  
Syed Maaz Abdullah ◽  
Tayyab Rehan ◽  
Muhaddis Ejaz Ahmad ◽  
Syeda Sabeeka Batool ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Hematological Malignancies ◽  
Phase 1 ◽  
Infectious Complications ◽  
Phase 2 ◽  
Phase 1 Trial ◽  
Phase 2 Trial ◽  
Car T ◽  
Tract Infections

Introduction: Chimeric antigen receptor t cells (CAR T) therapy is an innovative adoptive immunotherapy being used for the treatment of CD19+ive B cell hematological malignancies, especially B cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin's lymphomas (NHL) and chronic lymphocytic Leukemia (CLL). This treatment holds the potential to be highly effective and potentially less toxic alternative to cytotoxic chemotherapy for patients with relapsed and refractory (R/R) disease.This therapeutic modality is associated with a variety of side effects which includes cytokine release syndrome (CRS), neurotoxicity, B cell aplasia, hypogammaglobulinemia and resultant high risk infections. There is paucity of data about infection related complications with CAR-T therapy. In this review, we focus on the infections associated with B cell targeting CART cell therapy for the treatment of hematological malignancies. Methods: We conducted a systematic review (following PRISMA guidelines) by completing a comprehensive PubMed, Cochrane Library and ClinicalTrials.gov search on May 15th2019. Our search strategy included using search and MeSH terms related to CAR T therapy, hematological malignancies, Infections, safety and mortality. We were able to identify 279 articles from PubMed, 26 from Cochrane, 5 from Clinical Trials.org and 7 from Web of Science. After screening we selected 13 prospective published trials (n=555) for data extraction. We manually extracted data and summarized our results. RESULTS: Total included trials were 13, and trial level data from 555 patient was summarized in Table 1. Commonly used targets were CD19 ( B cell malignancies), and BCMA (Multiple Myeloma). CAR T were used for the treatment of diseases B-cell acute lymphoblastic leukemia ( ALL), B cell NHL, CLL, and Multiple myeloma (MM). Out of the available data, the two most frequent infections were upper respiratory tract infections (RTI) and blood stream infections. Other infections observed were the lower RTI, urinary tract infections (UTI), clostridium difficile (C. Diff), meningitis, mucocutaneous herpes infections, cellulitis, mucormycosis, and aspergillosis. A Phase 1/2 trial (NCT00924326 / B-NHL / CD19 Target) demonstrated 43 cases of septicemia (23.2%), 4 cases of UTI (9.3%) and 1 case each of cellulitis (2.3%), opportunistic infections (2.3%), upper RTI and lower RTI (2.3%). Phase 1 trial (NCT01029366 / B lymphoma, leukemia / CD19 target / n=20) showed 3 cases (15%) of pneumonia, 1 case each of C Diff, Pseudomonas and salmonella (5%) infections. A Phase 2 trial (NCT02030834, B NHL, CD19 target, n=63) treated patients showed 34% patients experienced infection which included sepsis, UTI, upper and lower RTI, skin, small intestine and mucosal infections. A phase 1 trial ( NCT01840566, n=17, NHL, CD19 target) demonstrated cases of mucormycosis ( n=unknown) and 7 case of pneumonia (41.1%). In phase 2 trial (NCT02030847, B ALL, CD19, n=30) treated patients experienced cases of sepsis (10%), Pneumonia (6.7%) and 1 case each of oral Candidiasis, C Diff, influenza and meningitis (10%). A phase 1 trial (NCT01044069, n=53, RR ALL, CD19 target) showed incidence of 11 cases of blood stream infections (20.1%), 9 cases of upper RTI (16.9), 2 cases of UTI (3.8%), 2 cases of pneumonia (3.8%), 3 cases of pulmonary aspergillosis (5.7%) and a case of herpes infection (1.9). Phase 2 trial (NCT01747486, CLL, CD19, n=42) demonstrated 2 cases of sepsis (4.7%), 2 cases of influenza (4.7), 3 cases of upper respiratory tract infections (7.1%) and 2 cases of pneumonia (4.7%). NCT02215967, Phase 1 trial ( Multiple Myeloma, BCMA target, n=12) was associated with 3 cases of upper RTI (25%) and 1 case of UTI (8.3%). Table 2 summarizes additional ongoing CAR T cell trials. Conclusion: CAR T cell therapy is gaining popularity and its indications are expanding. Its complications need to be closely studied for potential infections amongst other side effects. Clinical trial results have likely under-reported infections associated with CAR-T therapy because of overlapping presentation with cytokine release syndrome (CRS), neurotoxicity and limited follow-up reported in the published trials. Additional studies with longer follow up duration are required to identify the true risk of infectious complications of CAR T therapy in patients with hematological malignancies. Real word data on CAr T patients can also reveal long term infectious complications. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: CAR-T therapy. We are summarizing infectious complications of CAR-T therapy and their projects under development.

scholarly journals Optimal Dual-Targeted CAR Construct Simultaneously Targeting Bcma and GPRC5D Prevents Bcma-Escape Driven Relapse in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 136-136 ◽  
Author(s):  
Carlos Fernandez de Larrea ◽  
Mette Staehr ◽  
Andrea Lopez ◽  
Yunxin Chen ◽  
Terence J Purdon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Car T Cells ◽  
Car T Cell ◽  
Dual Targeting ◽  
Car T ◽  
Previously Treated

Multiple myeloma (MM) remains generally incurable, calling for the development of novel treatment strategies such as chimeric antigen receptor (CAR) T cell therapy. Most clinically tested CAR T cell therapies for MM target B cell maturation antigen (BCMA), but despite high response rates, many patients relapse (Raje N. NEJM 2019). BCMA negative-low MM cells are implicated as a reservoir preceding relapse (Brudno J. JCO 2018; Cohen A. JCI 2019). Our aims are to (1) evaluate whether upfront simultaneous targeting of an additional antigen such as G protein-coupled receptor class C group 5 member D (GPRC5D; Smith EL. Sci Trans Med 2019) can mitigate BCMA escape-mediated relapse in MM, and (2) compare dual targeting strategies to identify an optimal approach. Dual targeting for CD19/CD22 malignancies has been investigated, and multiple approaches are feasible; however, approaches have yet to be comprehensively compared head to head. Here, we compare 2 parallel production and 3 single-vector dual targeting strategies (Fig. 1A). To enhance clinical translatability, all strategies are built on the BCMA(125)/4-1BBζ CAR (BCMA scFv 125; Smith EL. Mol Ther 2018), which is currently under multi-center clinical investigation (NCT03430011; Mailankody S. ASH 2018). We confirmed that all dual targeted approaches lyse, proliferate, and secrete polyfunctional cytokines specifically in response to BCMA and GPRC5D mono- and dual-positive cell lines and/or primary patient MM aspirate samples. Activity in vivo was confirmed using the bone marrow-tropic OPM2 MM model (endogenously BCMA+GPRC5D+). In all experiments MM cells (2 x 106) were injected IV into NSG mice and engrafted/expanded for 14 days before treatment. A high dose of all dual targeted CAR T cell approaches (3 x 106 CAR+) induced long-term disease control (median overall survival (mOS) BCMA(125) non-signaling del control 32d vs other groups mOS not reached; p < 0.05). Prevention of latent BCMA escape-mediated relapse was evaluated by re-challenge of previously treated long-surviving mice with 2 x 106 OPM2 BCMA CRISPR KO (OPM2BCMA KO) cells at day 100 without re-treatment. While mice previously treated with BCMA(125)/41BBζ CAR T cells succumbed to OPM2BCMA KO disease, dual targeted approaches prevented OPM2BCMA KO growth (mOS BCMA mono-targeted arm 37d post re-challenge vs other groups mOS not reached; p < 0.05). To better recapitulate human MM and distinguish among dual targeting approaches, we modeled established BCMA heterogeneous disease by spiking 5-10% OPM2BCMA KO into bulk OPM2WT cells for injection. Each OPM2 population was modified to express distinct luciferases for simultaneous in vivo monitoring by bioluminescent imaging (BLI). Treatment with a moderate (5 x 105) dose of CAR T cells eradicated OPM2WT cells in all groups, but anti-GPRC5D CARs with CD28 co-stimulation, whether included within a mixed T cell population or in a bicistronic construct (Fig. 1A ii, iv), failed to control OPM2BCMA KO cells (Fig. 1B). Correspondingly, 4-1BB-only containing CAR T cells had increased in vivo expansion (2.1-4.1-fold increase CAR T cell BLI at day 7 over CD28 containing groups; p < 0.05). As this result is likely from greater activation-induced cell death in the CD28-containing approaches that was not rescued by 4-1BB, we later compared 4-1BB-only containing approaches (Fig. 1A i, iii, v). These 3 dual targeting approaches effectively controlled OPM2WT disease at moderate (1 x 106 CAR+) and low (2.5 x 105 CAR+) doses. However, when using a sub-therapeutic dose (2.5 x 105 CAR+) in the OPM2BCMA KO-spiked model, the tandem scFv-single stalk design was least effective in controlling OPM2BCMA KO disease (Fig 1C). At a dose that is sub-therapeutic to control OPM2WT disease (1 x 105 CAR+), the bicistronic dual 4-1BB design (Fig. 1A iii) was more effective in eradicating tumor compared with the parallel production approach (6-fold difference tumor BLI at day 28; p < 0.05). These results indicate that upfront dual targeting of BCMA/GPRC5D with CAR T cells can mitigate BCMA escape-mediated relapse in a model of MM. While parallel infusion of separate BCMA- and GPRC5D-targeted CAR T cells is effective, a single bicistronic vector encoding two 4-1BB-containing CARs avoids the practical challenges of parallel manufacturing, and uniquely may provide superior anti-MM efficacy. Figure Disclosures Fernandez de Larrea: Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Brentjens:JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy.

scholarly journals ATG-010 Plus Low-Dose Dexamethasone (Sd) in Chinese Relapsed/Refractory Multiple Myeloma (RRMM) Patients Previously Received Chimeric Antigen Receptor T-Cell (CAR-T)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4778-4778
Author(s):  
Weijun Fu ◽  
Lugui Qiu ◽  
Zhongjun Xia ◽  
Zhengzheng Fu ◽  
Wenming Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Adverse Events ◽  
Disease Progression ◽  
Median Duration ◽  
Nuclear Export ◽  
Low Dose ◽  
Small Sample ◽  
T Cell Therapy ◽  
Car T

Abstract Background: There are limited treatment options for multiple myeloma (MM) patients who have a disease progression after CAR-T therapy. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, inhibiting exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM. MARCH study, a single arm, Phase 2, registrational study evaluating Sd in Chinese RRMM pts, achieved an overall response rate (ORR) of 29.3% (95% CI: 19.7, 40.4), rejecting the null hypothesis of the study. Given its unique and novel mechanism of action, Sd preserves anti-tumor activity regardless of specific prior therapies. In the MARCH study, encouraging activity was demonstrated in a small group of Chinese RRMM pts previously exposed to CAR-T therapy. Methods: The study enrolled 82 pts previously exposed and refractory to a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and last line of therapy. Among them, 10 had received lymphodepleting conditioning followed by CAR-T cell therapy before study screening. ATG-010 (80mg) plus dexamethasone (20mg) was administered orally twice weekly. Response was assessed by an independent review committee. Results: Among 10 pts, 8 were male and 2 were female. Median age was 58.5 years. Median duration from MM initial diagnosis was 5.2 years. A total of 6 pts (60.0%) had high-risk cytogenetic abnormalities, including 4 pts (40.0%) with del (17p). Three pts had baseline plasmacytoma. Five pts (50%) experienced very rapid disease progression as indicated by a median of 46.2% increase of tumor burden from screening to Cycle 1 Day 1. Patients were heavily pre-treated with a median of 9.5 prior regimens (range: 5-12), with 8 receiving more than 6 regimens. Four pts were exposed to daratumumab (triple-class exposure). ORR was 50% including 1 very good partial response and 4 partial responses. Disease control rate defined as SD and above was 70%. Median duration of response was 1.4 months (mo) (95% CI: 0.96, NE). Median progression free survival was 1.9 mo (95% CI: 0.93, 3.74). xx pts (xx%) pts died; median overall survival was not reached, and estimated 12-mo OS rate was 68.6%. Adverse events were consistent with those events previously reported with Sd regimen in RRMM patients. The most common grade≥3 treatment emergent adverse events (TEAEs) included anemia, thrombocytopenia, neutropenia and nausea. Most events were manageable with appropriate supportive care or dose modification. Four pts (40%) experienced TESAEs, including anemia, pneumonia, neutropenia, and upper gastrointestinal hemorrhage. There were no TEAEs leading to treatment discontinuation or death. Conclusions: Sd was able to induce an encouraging response with a manageable safety profile for a group of Chinese RRMM patients desperately needing treatment after failing CAR-T therapy. With the small sample size, further investigation is warranted, including using ATG-010 in combination with other anti-MM therapies to potentially enhance and prolong therapeutic benefit. Disclosures Yu: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Yu: Antengene Therapeutics Ltd.: Current Employment. Yang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

Overall survival (OS) in patients (Pts) with diagnostic positive (Dx+) breast cancer: Subgroup analysis from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in AR+ triple-negative breast cancer (TNBC) treated with 0-1 prior lines of therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1089-1089 ◽  
Author(s):  
Tiffany A. Traina ◽  
Denise A. Yardley ◽  
Lee Steven Schwartzberg ◽  
Joyce O'Shaughnessy ◽  
Javier Cortes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Option ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Study ◽  
Breast Cancer Subgroup ◽  
Grade 3 ◽  
Intent To Treat ◽  
Cox Analysis ◽  
Line Of Therapy

1089 Background: The AR may be a novel therapeutic target for pts with AR-driven TNBC. ENZA, a potent AR inhibitor approved in men with metastatic prostate cancer, was evaluated in this phase 2 study of pts with AR+ TNBC. A genomic signature associated with AR-driven biology was identified; updated OS results in pts treated with 0-1 prior lines of therapy are presented. Methods: This is an open-label, Simon two-stage study (NCT01889238) of ENZA monotherapy in advanced AR+ TNBC (AR > 0% by IHC). Bone-only disease and unlimited prior regimens were allowed; CNS metastases or seizure history were exclusionary. The primary endpoint was clinical benefit rate at 16 weeks (CBR16) in evaluable pts (AR > 10% and ≥1 postbaseline assessment). OS was an exploratory endpoint. Results in intent-to-treat (ITT) and evaluable pts were presented previously (Traina TA et al. J Clin Oncol. 2015;33:1003). Results: 118 pts were enrolled (ITT). CBR16 in 78 evaluable pts was 33.3%. Of the 118 ITT pts, 56 were Dx+ and 62 were Dx–; ≥50% received 0-1 prior lines of therapy (28 Dx+, 37 Dx–). As of 26 Nov 2016 there were 83 deaths (median follow-up 28 mo); median OS (mOS) was 13 mo (95% CI; 8-18). In the Dx+ subgroup there were 32 deaths (mOS 20 mo [95% CI; 13-29]) vs 51 deaths in the Dx– subgroup (mOS 8 mo [95% CI; 5-11]). In pts with 0-1 prior lines of therapy, there were 13 deaths in the Dx+ subgroup (mOS 29 mo [95% CI; 19-not reached] vs 28 in the Dx– subgroup (mOS 10 mo [95% CI; 7-15]). The most common adverse events (AEs) were fatigue and nausea; fatigue was the only grade 3 related AE in > 5% of pts. A multi-covariate Cox analysis identified Dx status (+ vs –) and line of therapy (0-1 vs ≥2) as the only variables significantly associated with OS. Conclusions: In this study, the mOS of pts with Dx+ TNBC who received 0-1 prior lines of therapy appears longer than that of unselected historic controls. ENZA may represent a therapeutic option in pts with AR+ TNBC who would otherwise receive cytotoxic chemotherapy and is currently being evaluated in ENDEAR, a phase 3 study in pts with Dx+ advanced TNBC and 0-1 prior lines of therapy. Clinical trial information: NCT01889238.

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