395 A first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-(L)1 therapy

BackgroundUpregulation of immune checkpoints, such as LAG-3, plays an important role in promoting resistance to anti-PD-(L)1 therapy. Targeting PD-L1 and LAG-3 using a bispecific antibody may overcome resistance to PD-(L)1 blockade.1 We report initial data from a first-in-human study evaluating FS118 in patients with advanced cancer and resistance to PD-(L)1 therapy.MethodsThe ongoing Phase I FIH study (NCT03440437) is being conducted to evaluate safety, tolerability, immunogenicity, PK/PD and clinical activity of FS118 administered IV weekly to heavily pre-treated patients who had previously received anti-PD-(L)1 therapy for a minimum of 12 weeks. Adverse events were assessed using CTCAEv4.03 and tumor responses assessed using RECISTv1.1 and iRECIST. Single subject dose escalation cohorts were followed by a 3+3 ascending dose design. Three cohorts (3, 10, 20 mg/kg) were expanded to evaluate PK, PD and clinical activity. Pharmacodynamic studies examined soluble LAG-3 production and peripheral T-cell expansion.ResultsForty-three patients (median 6 lines of prior therapy, including ICB) with solid tumors received FS118 at doses from 0.8 mg up to 20 mg/kg across 8 dose levels. Weekly administration of FS118 was well tolerated and did not result in dose- or treatment-limiting toxicities. An MTD was not reached. No safety signals unexpected for the drug class of immune-checkpoint inhibitors were identified in the early study population. The majority (95%) of treatment-emergent adverse events (TEAE) considered by the Safety Review Committee (SRC) to be treatment-related were Grade 1 and 2. Grade 3 TEAEs toxicities (elevated liver enzymes) were observed in 2 patients (5%). No SAEs or deaths were attributed to FS118 treatment. Anti-drug antibodies, observed in half of patients, were typically transient in nature. The pharmacokinetic profile confirmed preclinical predictions and PD parameters included a dose-dependent increase in serum soluble LAG-3 and expansion of peripheral T cells. Long-lasting disease stabilisation (>6 months) was observed in a subset of patients with acquired resistance (defined as a CR, PR or SD ≥3 months on previous PD-(L)1 treatment), but not in patients with primary resistance. Two patients remain on FS118 treatment as of 2 Jul 2020 (duration 10 and 16 months). Retrospective IHC analysis of PD-L1 and LAG-3 co-expression in the tumor was assessed as a potential biomarker associated with clinical outcome.ConclusionsWeekly treatment with FS118 was well tolerated up to 20 mg/kg and was associated with pharmacodynamic markers of FS118 activity. Encouraging signs of clinical activity were observed in highly pre-treated patients who had acquired resistance to prior PD-(L)1 therapy.Trial RegistrationRegistered at www.clinicaltrials.gov, NCT03440437ReferenceKraman M, Faroudi M, Allen N, Kmiecik K, Gliddon D, Seal C, Koers A, Wydro M, Winnewisser J, Young L, Tuna M, Doody J, Morrow M, Brewis N. FS118, a bispecific antibody targeting LAG-3 and PD-L1, Enhances T-Cell activation resulting in potent antitumor activity. Clin Cancer Res 2020; 26:3333–3344.

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393 First-in-human phase 1/2a study of the novel nonfucosylated anti–CTLA-4 monoclonal antibody BMS-986218 ± nivolumab in advanced solid tumors: initial phase 1 results

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0393 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A418-A418

Author(s):

Claire Friedman ◽

Paolo Ascierto ◽

Diwakar Davar ◽

Mark O’Hara ◽

Ronnie Shapira-Frommer ◽

...

Keyword(s):

T Cell ◽

Antitumor Activity ◽

Advanced Cancer ◽

Dose Escalation ◽

Medical Center ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Clinical Activity ◽

List Type ◽

Grade 3

BackgroundCTLA-4 pathway blockade with ipilimumab (IPI) ± nivolumab (NIVO; anti–PD-1) is an effective treatment for several cancers. A nonfucosylated version of IPI, BMS-986218, was developed to increase the effects of CTLA-4 blockade and enhance intratumoral regulatory T-cell depletion via its increased affinity for Fcγ receptors (FcγR, CD16) on natural killer T cells and macrophages, resulting in enhancement of antibody-dependent cellular cytotoxicity. Preclinical data supported the mechanism of action of BMS-986218 and demonstrated greater antitumor activity in an MC38 tumor model vs IPI.1 Here, we present initial results from the first-in-human phase 1/2a trial of BMS-986218 ± NIVO in previously treated patients with advanced cancer (NCT03110107).MethodsPatients with ≥1 prior therapy received BMS-986218 2–70 mg intravenously Q4W. Safety, tolerability, pharmacokinetics, and pharmacodynamics were evaluated.ResultsAs of December 12, 2019, 65 patients (median age, 61 years [range, 24–85 years]) received BMS-986218 monotherapy. TRAEs occurred in 52% of patients; most were grade 1–2. The most common (≥10%) TRAEs (any grade; grade 3) were pruritus (12%; 0%) and diarrhea (11%; 3%). Eight patients (12%) had grade 3 TRAEs; most resolved with protocol-defined management. No grade 4 TRAEs were reported; 1 grade 5 TRAE (pneumonitis; 2 mg) occurred. Seven patients (11%) discontinued treatment due to TRAEs; 4 dose-limiting toxicities occurred. The maximum tolerated dose has not been reached. BMS-986218 exposure increased dose proportionally, and the half-life was ≈2 weeks. Increased levels of serum chemokine ligands 9 and 10 and interferon-γ indicate that pharmacodynamic changes occurred at the lowest dose tested (2 mg [≈0.03 mg/kg]), similar to previous findings with IPI 3 mg/kg, and at higher doses (40–70 mg [≈0.06–1 mg/kg]), consistent with findings with IPI 10 mg/kg. In a subset of patients with paired biopsies, BMS-986218 was associated with an increased gene signature linked to CD8+ T-cell infiltration and inflammation. In a highly heterogeneous population, as part of dose escalation, BMS-986218 monotherapy treatment was associated with clinical activity in some patients. Updated data based on a September 2020 data cutoff will be presented.ConclusionsBMS-986218 monotherapy demonstrated an acceptable safety profile and signs of clinical benefit in this heterogeneous patient population with select advanced cancers. Preliminary pharmacodynamic activity was consistent with enhanced effects of CTLA-4 blockade. Data from continuing dose escalation of BMS-986218 ± NIVO along with preclinical results provide support for ongoing monotherapy expansions and for BMS-986218 + NIVO expansions in patients with advanced cancer.AcknowledgementsThe authors acknowledge Dr Charles Drake while at Columbia University Medical Center, New York, NY, USA, for his contributions to the study.Trial RegistrationNCT03110107Ethics ApprovalThis study was approved by the WCG Independent Review Board, approval number 20170464ReferenceEngelhardt J, Akter R, Valle J, et al. Preclinical characterization of BMS-986218, a novel nonfucosylated anti–CTLA-4 antibody designed to enhance antitumor activity. Presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting II; June 22–24, 2020 [poster 4552].

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406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0406 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A431-A431

Author(s):

Michael Yellin ◽

Tracey Rawls ◽

Diane Young ◽

Philip Golden ◽

Laura Vitale ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Dose Escalation ◽

Clinical Studies ◽

Cell Activation ◽

Bispecific Antibody ◽

Phase 1 ◽

Clinical Activity ◽

Tumor Types ◽

Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

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523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.523 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A553-A553

Author(s):

Elaine Shum ◽

Matthew Reilley ◽

Yana Najjar ◽

Adil Daud ◽

John Thompson ◽

...

Keyword(s):

Prostate Cancer ◽

T Cell ◽

Solid Tumors ◽

Dose Escalation ◽

Bispecific Antibody ◽

Objective Response ◽

Checkpoint Blockade ◽

List Type ◽

Advanced Solid Tumors ◽

Tumor Types

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

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Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽

10.1182/blood-2019-123954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2831-2831 ◽

Cited By ~ 1

Author(s):

Swaminathan P. Iyer ◽

Brad M. Haverkos ◽

Jasmine Zain ◽

Radhakrishnan Ramchandren ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

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Abstract 5609: ERY974, a novel T cell-redirecting bispecific antibody targeting glypican-3, shows antitumor activity in gastric cancer patient-derived xenograft models with varying glypican-3 expression

10.1158/1538-7445.am2018-5609 ◽

2018 ◽

Cited By ~ 1

Author(s):

Azuma Yumiko ◽

Yuji Sano ◽

Toshiaki Tsunenari ◽

Yasuko Kinoshita ◽

Yoko Miyazaki ◽

...

Keyword(s):

Gastric Cancer ◽

T Cell ◽

Antitumor Activity ◽

Cancer Patient ◽

Gastric Cancer Patient ◽

Bispecific Antibody ◽

Patient Derived Xenograft ◽

Xenograft Models ◽

Antibody Targeting

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Association of homogeneous inflamed gene signature with a better outcome in patients with metastatic melanoma treated with MAGE-A3 immunotherapeutic

ESMO Open ◽

10.1136/esmoopen-2018-000384 ◽

2018 ◽

Vol 3 (5) ◽

pp. e000384 ◽

Cited By ~ 1

Author(s):

Jean-François Baurain ◽

Caroline Robert ◽

Laurent Mortier ◽

Bart Neyns ◽

Florent Grange ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Metastatic Melanoma ◽

Progression Free Survival ◽

Gene Signature ◽

Skin Lesions ◽

Clinical Activity ◽

Open Label ◽

Link Type ◽

Registration Number

PurposeThis study assessed clinical activity, safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with MAGE-A3-positive metastatic melanoma.Patients and methodsIn this open-label, multicentre, uncontrolled, Phase II study (ClinicalTrials.gov NCT00896480),patients received ≤24 doses of MAGE-A3 immunotherapeutic (4-cycle schedule). At screening, two skin lesions were biopsied for MAGE-A3 expression analysis and presence/absence of a previously identified gene signature (GS) associated with favourable clinical outcome. Clinical activity was assessed in terms of clinical response, time-to-treatment failure (TTF) and progression-free survival (PFS). Adverse events (AEs) and serious AEs (SAEs) were recorded. MAGE-A3-specific immune responses were assessed. Clinical activity and immunogenicity were analysed overall and separately in patients with 2/2 (GS+/+), 1/2 (GS+/-) or 0/2 (GS-/-) biopsies presenting GS.ResultsOf 49 screened patients, 32 had MAGE-A3-positive tumours; 24 (8 GS+/+, 8 GS+/-, 8 GS-/-) were treated. Two complete (GS+/+ patients) and two partial responses (one GS+/+, one GS+/-) were reported; of note, one of the two complete responses was unlikely to be related to the study treatment. Median TTF and PFS were 14.8 and 7.2 months for GS+/+, 2.3 and 2.8 months for GS+/- and 2.4 and 2.9 months for GS-/- patients. Three grade 3 AEs and two SAEs unrelated to treatment were reported. All patients were seropositive for MAGE-A3 antibodies on vaccination with no differences between the different GS profiles. MAGE-A3-specific CD4+ and CD8+ T cell immunogenicity was detected; 12/16 (75.0%) of patients presented CD4+ T cell responses.ConclusionTreatment with MAGE-A3 immunotherapeutic showed signs of clinical activity in GS+/+ patients. Treatment was well tolerated and immunogenic. No differences in immune responses according to GS status were observed.Trial registration numberNCT00896480 (Results).

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Proof-of-concept study of Sym004, an anti-EGFR monoclonal antibody (mAb) mixture, in patients (pts) with anti-EGFR mab-refractory KRAS wild-type (wt) metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3551 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3551-3551 ◽

Cited By ~ 3

Author(s):

Rodrigo Dienstmann ◽

Josep Tabernero ◽

Eric Van Cutsem ◽

Andres Cervantes-Ruiperez ◽

Susana Rosello Keranen ◽

...

Keyword(s):

Adverse Events ◽

Mechanism Of Action ◽

Treatment Options ◽

Acquired Resistance ◽

Progression Free Survival ◽

Median Number ◽

Clinical Activity ◽

Tumor Shrinkage ◽

Proof Of Concept ◽

Open Label

3551 Background: KRAS wt mCRC pts progressing on chemotherapy and anti-EGFR mAbs have limited treatment options. Sym004 is a first-in-class drug mixture of two mAbs targeting non-overlapping epitopes on the EGFR, causing its internalization and degradation. With this unique mechanism of action, Sym004 overcomes acquired resistance to anti-EGFR mAbs in preclinical studies. Methods: Open-label, multicenter trial assessing safety (primary endpoint) and efficacy of 2 dose levels of Sym004 in KRAS wt mCRC pts with prior clinical benefit to anti-EGFR mAbs and subsequent progression during or within 6 months after treatment cessation. Sym004 was administered until disease progression or unacceptable toxicity. Tumor responses were evaluated centrally according to RECIST criteria. Paired skin and tumor biopsies were obtained at baseline and week 4. Results: In total, 42 pts were enrolled at 9 mg/kg (13) and 12 mg/kg (29). Median age was 66 years and median number of prior treatment lines 3. Central radiology review was performed in 12/13 (92%) pts at 9 mg/kg and 27/29 (93%) pts at 12 mg/kg. Tumor shrinkage > 10% was documented in 4/12 (33%) pts at 9 mg/kg, with partial response (PR) in 1/12 (8%) and stable disease (SD) in 9/12 (75%). At 12 mg/kg, 7/27 (26%) pts had > 10% tumor shrinkage, with PR in 3/27 (11%) and SD in 15/27 (56%). Median progression-free survival was 13.6 weeks (95% CI: 5.3-23) and 13.7 weeks (95% CI: 5.9-18.6), respectively. Duration of response for pts with PR was 5.6-17.6 weeks. Grade 3 or higher toxicity included skin rash in 26/42 (62%), hypomagnesemia in 16/42 (38%) and diarrhea in 2/42 (8%). Adverse events were manageable with dose reduction and supportive medication. There were no indications of immunogenicity. Pharmacodynamic analysis in serial tumor samples showed profound down-regulation of EGFR and reduction in proliferation marker Ki67. Conclusions: Sym004 at weekly doses of 9 and 12 mg/kg showed significant clinical activity in anti-EGFR treatment-refractory KRAS wt mCRC pts, clearly demonstrating proof-of-concept. Serial biopsies confirmed its mechanism of action. No unexpected adverse events were observed. Clinical trial information: NCT01117428.

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XPO1 Inhibitor (ATG-010) Plus Chemotherapy per Investigator's Choice for Heavily Pretreated Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Extranodal NK/T-Cell Lymphoma (ENKTL)：Preliminary Results from a Multicenter, Single-Arm, Phase Ib Study (TOUCH Trial)

Blood ◽

10.1182/blood-2021-147100 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2452-2452

Author(s):

Huiqiang Huang ◽

Yan Gao ◽

Huilai Zhang ◽

Keshu Zhou ◽

Jianqiu Wu ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Disease Progression ◽

Nuclear Export ◽

Cell Lymphoma ◽

Fatal Outcome ◽

T Cell Lymphoma ◽

Clinical Activity ◽

Heavily Pretreated ◽

Grade 3

Abstract Background The prognosis of R/R PTCL and ENKTL remains poor. Current therapeutic options are limited, highlighting the need for novel approaches. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. It has demonstrated clinical activity in different hematological malignancies. Preclinical synergistic anti-tumor effects are confirmed when combined with gemcitabine, cisplatin, or etoposide. Method The aim of this study was to evaluate safety and efficacy of ATG-010 plus GemOx or ICE regimen followed by ATG-010 maintenance in patients (pts) with R/R PTCL or ENKTL in China. The study planned to enroll 30 pts with PTCL-NOS, AITL, ALCL, PTCL-TFH, FTL and ENKTL. Pts must have had prior exposure to an anthracycline-based regimen for PTCL or an asparaginase-based regimen for ENKTL, and were relapsed or refractory from the last therapy. ATG-010 was administered orally (60 mg day 1, 8) plus standard-dose of either ICE or GemOx regimen every 3 weeks as per investigator's choice. If response was achieved after initial 2-6 cycles, pts continued to receive ATG-010 maintenance at the dose of 60 mg weekly until disease progression, intolerability or withdrawal of consent. Primary endpoints included safety according to the NCI CTCAE 5.0 and overall response rate (ORR) evaluated by investigators according to the Lugano criteria (2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). This trial was registered at ClinicalTrials.gov (NCT04425070). Results From Aug 18, 2020 to June 25, 2021, 24 pts (20 in GemOx cohort, 4 in ICE cohort) were enrolled and received at least one cycle of treatment. In this abstract, we report results of the GemOx cohort with 9 (45%) PTCL-NOS, 6 (30%) ENKTL, 4 (20%) AITL, and 1 (5%) ALCL ALK-. At study entry, median age was 55 years (range 35-69); 17 (85%) had stage III/IV disease. Five (36%) pts with PTCL had IPI score ≥3, and 5 (83%) ENKTL pts with had PINK-E score ≥2. Median number of prior regimens was 3.5 (range 1-7) with 5.5 for ENKTL and 2 for PTCL. All pts were refractory from last therapy; 11 (55%) pts had received gemcitabine-based regimens. Median time from last-line therapy to this trial was 1.5 months (range 1.0-16.7). The most common treatment-emergent adverse events (TEAEs) were hematological toxicities. All grade hematological TEAEs were neutropenia (90%), thrombocytopenia (90%) and anemia (85%). Grade≥3 hematological TEAEs included neutropenia (85%), thrombocytopenia (80%) and anemia (40.0%). The most common (>30%) non-hematological TEAEs were nausea (70%), diarrhea (65%), decreased appetite (65%), asthenia/fatigue (60%), vomiting (50%), pyrexia (40%), and hyponatremia (35%). Grade≥3 non-hematological TEAEs (≥10%) were diarrhea (15%) and pyrexia (10%). Serious TEAEs occurred in 7 (35%) pts with the most common being thrombocytopenia (20%). Three (15%) pts discontinued treatment due to TEAEs. TEAEs with a fatal outcome occurred in 1(5%) patient, who experienced rapid disease progression before death. The majority of adverse events were manageable by dose modification and supportive care. Of 17 efficacy evaluable pts, ORR was 52.9% (9/17), and CR rate was 35.3% (6/17). ORR of PTCL-NOS, ENKTL, AITL, ALCL were 62.5% (5/8), 60% (3/5), 0 (0/3), 100% (1/1); CR rate were 37.5%, 40%, 0, 100%, respectively. At a median follow-up of 6.1months, median PFS, DOR and OS of the whole cohort was 2.9, 3.1 months, and not reached (6-month OS rate 68.9%), respectively. Patients with ENKTL enjoyed a relatively longer median PFS (4.7 months). Conclusions ATG-010 plus GemOx regimen showed a manageable safety profile, and favorable activity with impressive CR rate in refractory pts, potentially offering a new therapeutic option for heavily pretreated pts with refractory PTCL or ENKTL. Disclosures Lou: Antengene Therapeutics Ltd.: Current Employment. Fei: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

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A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820 dimesylate in patients with advanced cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3001 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3001-3001 ◽

Cited By ~ 5

Author(s):

Matthew P. Goetz ◽

Anthony W. Tolcher ◽

Paul Haluska ◽

Kyriakos P. Papadopoulos ◽

Charles Erlichman ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

P38 Mapk ◽

Advanced Cancer ◽

Phase I Study ◽

Single Agent ◽

Clinical Activity ◽

Dependent Manner ◽

Dose Levels ◽

Dose Dependent

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

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