Preliminary Results of the Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Two Phase IIa Dose Expansion Cohorts in Relapsed/Refractory TP53 Wild-Type Peripheral T-Cell Lymphoma

Author:

Shustov Andrei R.1,Horwitz Steven M.2,Zain Jasmine3,Patel Manish R4,Goel Sanjay5,Sokol Lubomir6,Meric-Bernstam Funda7,Shapiro Geoffrey8,Dwivedy Nasta Sunita9,Janakiram Murali10,Weinstock David M11,Korn Ronald12,Payton Marie13,Annis D. Allen13,Pinchasik Dawn13,Aivado Manuel13,Mehta Amitkumar14

Affiliation:

1. University of Washington/Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA

2. Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY

3. Department of Hematology/HCT, City of Hope National Medical Center, Duarte, CA

4. Florida Cancer Specialists, Sarah Cannon Research Institute, Sarasota, FL

5. Montefiore Einstein Cancer Center, Bronx, NY

6. Moffitt Cancer Center, Tampa, FL

7. MD Anderson Cancer Center, The University of Texas, Houston,

8. Dana-Farber Cancer Institute, Boston,

9. University of Pennsylvania, Philadelphia,

10. Department of Hematology and Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY

11. Dana Farber Cancer Institute and Harvard Medical School, Boston, MA

12. Imaging Endpoints, Scottsdale, AZ

13. Aileron Therapeutics Inc., Cambridge, MA

14. University of Alabama at Birmingham, Birmingham, AL

Abstract

Abstract Background: Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of NHL with poor prognosis. Frontline therapy yields a 50-70% overall response rate, but the majority of pts will relapse, which translates to poor overall survival. ALRN-6924, the first-in-class clinical stage stapled peptide, has been structurally stabilized ("stapled") in an α-helical configuration, to mimic the inhibitor-binding region of the tumor suppressor protein, p53. By mimicking this region, ALRN-6924 binds the two most important endogenous inhibitors of p53, murine double minute-X (MDMX) and -2 (MDM2), thereby restoring p53's ability to induce cell cycle arrest and apoptosis in TP53 wild-type (WT) cancer cells. ALRN-6924 is the first known synthetic agent to simultaneously target both of these important p53 inhibitors. A durable CR has been reported in a pt with an angioimmunoblastic subtype of PTCL who is part of the first-in-human study of ALRN-6924 (Meric-Bernstam et al., 2017), providing the rationale for two PTCL expansion cohorts. The PTCL QW cohort is receiving treatment at the recommended Phase 2 dose (QWx3 every 28 days). Preclinical data suggest that more frequent dosing may enhance efficacy (Carvajal et al., 2018; Ng et al., 2018) and this hypothesis is being evaluated in a second PTCL cohort, treated TIWx1 every 21 days. Methods: Pts with relapsed or refractory PTCL are receiving treatment with 3.1 mg/kg of ALRN-6924 IV over 1 hour, on Days 1, 8, and 15 of a 28-day cycle (QW) or Days 1, 3, and 5 of a 21-day cycle (TIW). Treatment continues until symptomatic progressive disease (PD), unacceptable toxicity, or other indication for treatment withdrawal. Due to documented cases of pseudoprogression, continuation beyond radiographic PD is permitted at the investigator's discretion. Response is evaluated by investigators according to IWG 2014. Additionally, an independent radiologist reviews response using IWG 2014 and modified Cheson 2007. Adverse events (AEs) are assessed per CTCAE V4.03. Results: As of 13 July 2018, 26 PTCL pts have been treated (16 QW, including one from Phase 1, 10 TIW) with a median age of 63 years (31-82). Here, we report safety from the QW and TIW cohorts as well as efficacy from the QW cohort. Accrual to TIW continues; its efficacy data as well as updated safety data will be presented at the meeting. Median number of prior systemic therapies is 3 (1-10). Pts have received 1-34 cycles. Of the 16 QW-pts and 10 TIW-pts, 2 and 6 pts remain on therapy, respectively. Treatment-related AEs have been reported in 76.9% of 26 PTCL pts dosed QW or TIW. Fatigue (50.0%), nausea (42.3%), anemia (19.2%), diarrhea (15.4%), headache (15.4%), vomiting (15.4%), and hyperbilirubinemia (11.5%) are most frequent. 46.2% have experienced grade 3 AEs, most commonly fatigue (7.7%), anemia (7.7%), and hyperbilirubinemia (7.7%). No related grade 4 or 5 AEs have been reported. SAEs have been reported in 10 pts, including 3 treatment-related SAEs: a grade 3 lung infection, a grade 3 nausea/vomiting, and a grade 3 hyperbilirubinemia, which is a known transient effect of ALRN-6924 and has not been associated with liver injury. Treatment has been discontinued due to related AEs in 2 pts, for a grade 1 infusion-related reaction and a grade 3 lung infection (pneumonia). Main reasons for treatment discontinuation include disease progression (46.1%; objective PD 19.2%, clinical PD 26.9%) and AE (7.7%). Pts receiving QW treatment who received at least one dose of ALRN-6924, had TP53 WT, and a post-baseline assessment or evidence of clinical disease progression were evaluated for efficacy. Table 1 shows responses determined by IWG 2014 (investigator-reported) and modified-Cheson 2007 (independent radiologist-determined) for the evaluable QW patients. One pt was not evaluable per IWG 2014. Cases of pseudoprogression during treatment of PTCL pts with ALRN-6924 have been documented. Several pts with new FDG-avid lesions and/or transient lymph node enlargement on CT have benefitted from treatment continuation, including pts who went on to achieve a subsequent response. Conclusion: ALRN-6924 has shown activity against PTCL and has an acceptable safety profile across QW and TIW dosing. The potential for pseudoprogression was not initially recognized, hence raising the possibility that the true response rate for QW may be higher. These early data support continued development of ALRN-6924 for the treatment of PTCL. Disclosures Shustov: Seattle Genetics: Research Funding. Horwitz:Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Spectrum: Research Funding; Millennium/Takeda: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Trillium: Consultancy; Corvus: Consultancy. Sokol:Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. Meric-Bernstam:Genentech: Consultancy; Inflection Biosciences: Consultancy; Pieris Pharmaceuticals: Consultancy; Clearlight Diagnostics: Consultancy; Darwin Health: Consultancy; Bioepis: Consultancy; Novartis: Research Funding; AstraZeneca: Research Funding; Taiho Pharmaceuticals: Research Funding; Genentech: Research Funding; Calithera Biosciences: Research Funding; Debiopharm: Research Funding; Bayer: Research Funding; Aileron Therapeutics: Research Funding; PUMA Biotechnology: Research Funding; CytomX Therapeutics: Research Funding; Zymeworks: Research Funding; Curis: Research Funding; Pfizer: Research Funding; eFFECTOR Therapeutics: Research Funding; Abbvie: Research Funding; Sumitomo Group: Honoraria; Dialecta: Honoraria. Shapiro:Roche: Membership on an entity's Board of Directors or advisory committees; Merck/EMD Serono: Research Funding; G1 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck/EMD Serono: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Lilly: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Research Funding; Lilly: Research Funding. Dwivedy Nasta:Roche: Research Funding; Takeda/Millenium: Research Funding; Aileron: Research Funding; Rafael/WF: Research Funding; Merck: Other: DSMC; Debiopharm: Research Funding; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Janakiram:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Weinstock:Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis: Consultancy, Research Funding; Genentech/Roche, Monsanto: Consultancy; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties. Korn:Imaging Endpoints: Employment, Equity Ownership; Aileron Therapeutics Inc.: Other: Client. Payton:Aileron Therapeutics: Employment, Equity Ownership. Annis:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Pinchasik:Aileron Therapeutics Inc.: Employment, Equity Ownership. Aivado:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Mehta:Kite: Consultancy, Speakers Bureau; Celgene: Consultancy; Spectrum: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Incyte: Research Funding; Merck: Research Funding; Gilead: Consultancy, Speakers Bureau; Epizyme: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Carevive: Other: Patient engagement; Medpage: Other: Medical website.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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