Abstract: PR-OS of cHL patients has improved in recent years, likely due to incorporation of novel therapies and more effective use of allo-HCT. Future research should focus on earlier integration of novel therapies for patients with refractory disease to improve outcomes further.

Abstract: Background: CD74 is highly expressed on B cell malignancies, including non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). STRO-001, a novel CD74-targeting ADC was generated using Sutro's cell-free protein synthesis (XpressCF™) and site-specific conjugation (XpressCF+™) platform technologies. STRO-001 contains a potent maytansinoid warhead conjugated to two specific sites (drug-antibody ratio of 2) using a stable non-cleavable linker. This first-in-human Phase 1, open-label, multicenter, dose escalation study was designed to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-001 in adults with B-cell malignancies. Methods: Patients with advanced, relapsed/refractory MM and NHL are eligible for enrollment. STRO-001 is administered as a 60-minute IV infusion on Days 1 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Two cohorts, one for MM and one for NHL patients, were initially enrolled with an accelerated dose titration design (N of 1), but are now being enrolled and analyzed independently with a traditional 3+3 dose escalation design. Results: As of July 15th, 25 patients (14 MM and 11 NHL), have been treated at 7 dose levels: .05, .075, .15, .27, .43, .65 and .91 mg/kg. NHL subtypes include: 3 follicular lymphoma (FL), 1 marginal zone lymphoma, 4 diffuse large B-cell lymphoma (DLBCL), 1 Burkitt's lymphoma, 1 mantle cell lymphoma and 1 composite DLBCL/FL. Ten females and 15 males have been treated to date. Median age is 64 (range 21-82). Median ECOG performance status is 1 (range 0-2). Median number of prior therapies is 6 (range 2-12). Three patients (2-MM and 1-NHL) had received CAR-T therapy. Median number of STRO-001 doses administered is 4 (range 1-12). 21 patients have completed at least one cycle (two doses) of STRO-001 and are evaluable for safety and toxicity for dose escalation recommendation. One MM patient progressed after one dose of STRO-001 and was not evaluable for dose limiting toxicities (DLTs), while 2 patients are currently completing Cycle 1 and not yet evaluable for DLTs. Most AEs are grade 1 or 2 (58%) with the most common grade 1-2 TEAEs of fatigue, chills, pyrexia, cough, nausea, headache and infusion reaction occurring in ≥ 20% of patients. 2 DLTs have been observed, one grade 3 and one grade 5 thromboembolic events, which resulted in a protocol amendment requiring screening for thrombosis at baseline (Doppler US for patients with non-bulky disease, and CT venogram with contrast for patients with bulky disease ≥ 8 cm.) Since implementing this requirement, 3 out of 10 patients enrolled were found to have preexisting thromboses and were allowed on study with anticoagulation and no additional thromboembolic events have been observed. 19 of 21 (90%) of treatment discontinuations have been secondary to disease progression. One patient with DLBCL achieved a complete response after 2 cycles (Figure 1) and progressed after 12 doses (6 cycles). An additional DLBCL patient achieved a partial response at Cycle 3. A patient with MM has stable disease after 6 doses (3 cycles). Four patients remain on treatment and dose escalation is ongoing. PK and anti-drug antibody (ADA) analyses are ongoing. Preliminary PK analysis of ADC shows exposure increased (Cmax from 0.39 to 8.2 µg/mL) and (AUC0-tlast from 0.41 to 21 h*µg/mL) as dose increased from 0.05 to 0.65 mg/kg. Summary/Conclusion: STRO-001 is the first ADC generated with novel cell-free protein synthesis technology and site-specific conjugation with the non-natural amino acid pAMF to be tested in the clinic. STRO-001 has been well-tolerated. No ocular toxicity signals have been observed and the MTD has not been reached. Preliminary anti-tumor activity observed in 2 patients with DLBCL is encouraging. The study continues to enroll patients in dose escalation. This study is registered with clinicaltrials.gov identifier NCT03424603. Disclosures Shah: Oncosec: Equity Ownership; Cell Vault: Consultancy, Equity Ownership; Exelexis: Equity Ownership; Geron: Equity Ownership; Incyte: Consultancy; Celgene: Other: Advisory Board; Lentigen: Honoraria, Research Funding; Kite Pharma: Other: Advisory Board. Krishnan:Takeda: Research Funding; Celgene, Z Predicta: Other: Stock Ownership; Celgene, Janssen, Sanofi, BMS: Consultancy; Sutro BioPharma, zPredicta: Consultancy; Amgen, Takeda: Speakers Bureau. Shah:University of California, San Francisco: Employment; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding. Burke:Celgene: Consultancy; Roche/Genentech: Consultancy; Gilead: Consultancy. Melear:DARA: Speakers Bureau; Texas Oncology: Employment. Spira:Virginia Cancer Specialists: Employment; MedImmune: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Research Funding; BMS: Consultancy; Newlink Genetics: Research Funding. Popplewell:City of Hope: Employment. Andreadis:University of California, San Francisco: Employment; Celgene: Research Funding; Genentech: Consultancy, Employment; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Juno: Research Funding; Kite: Consultancy; Merck: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Roche: Equity Ownership. Sharman:Acerta: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Kaufman:Janssen: Honoraria; AbbVie: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Celgene: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Winship Cancer Institute of Emory University: Employment. Cohen:Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Janssen Pharmaceuticals: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Genentech, Inc.: Consultancy, Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. DiLea:Aclairo Pharmaceutical Development Group, Inc.: Employment. Kuriakose:Sutro Biopharma: Employment, Equity Ownership. Matheny:Sutro Biopharma: Employment, Equity Ownership. Leonard:AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy; BeiGene: Consultancy; Gilead: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy. Molina:Sutro Biopharma: Employment, Equity Ownership.

Abstract: Background: Sutro’s cell-free antibody production system was used to generate STRO-001, a novel CD74 targeting antibody drug conjugate. CD74 is expressed on B cells throughout differentiation and is an attractive target for treatment of B cell malignancies (Zhao et al, J Path Clin Res, Jan 2019). STRO-001 demonstrates potent cytotoxicity in non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) cell lines and anti-tumor activity in xenograft models. Toxicology studies demonstrate dose-dependent B-cell depletion and reversible hematologic toxicity when STRO-001 is administered at up to 10 mg/kg (Solis et al, Proc AACR 2018, Abs 742). Methods: This study (NCT03424603) is a first-in-human Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), recommended phase 2 doses (RP2D) and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-001 in adults with B-cell malignancies (MM and NHL) who are refractory to, or intolerant of, all therapy known to provide clinical benefit. STRO-001 is given to all patients on study via intravenous infusion on Day 1 and Day 15 of each cycle until disease progression. Dose limiting toxicities are assessed in the first cycle (Days 1-28) of dose escalation. In Part 1, 2 cohorts (1 for MM and 1 for NHL) will enroll 30 patients each to determine the MTD and RP2D for expansion while Part 2 will enroll 4 dose expansion cohorts based on disease subtypes (MM, diffuse large B cell, mantle cell and follicular lymphomas). Efficacy will be evaluated per MM-specific or NHL-specific criteria. Key inclusion criteria include relapsed or relapsed/refractory disease, adequate bone marrow and renal function, and ability to comply with treatment, testing and pharmacokinetic (PK) schedules. NHL patients must have at least one measurable lesion. Key exclusion criteria include leukemic manifestations of lymphoma, need for ongoing anti-coagulants or immunotherapy including systemic corticosteroids and a history of CNS involvement. Samples will be collected to assess the PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US at the following sites: Medical College of Wisconsin, City of Hope, UCSF, Rocky Mountain Cancer Centers, Texas Oncology, Virginia Cancer Specialists, Winship Cancer Institute of Emory University, and the Willamette Valley Cancer Institute and Research Center. Citation Format: Nirav N. Shah, Amrita Y. Krishnan, Nina D. Shah, John M. Burke, Jason M. Melear, Alexander I. Spira, Jonathan L. Kaufman, Jonathon B. Cohen, Ruben Niesvizky, Leslie L. Popplewell, Saurabh Chhabra, Jeff P. Sharman, Thomas G. Martin, Shannon L. Matheny, John P. Leonard, Arturo Molina. A Phase I open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT104.

Abstract: Background: CD74 is highly expressed on B cell malignancies, including non-Hodgkin's lymphoma (NHL). STRO-001, a novel CD74-targeting ADC was generated using cell-free protein synthesis and site-specific conjugation platform technologies. STRO-001 contains a potent maytansinoid warhead conjugated to two specific sites (drug-antibody ratio of 2) using a stable non-cleavable linker. This first-in-human Phase 1, open-label, multicenter, dose escalation study was designed to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-001 in adults with B-cell malignancies (NHL and multiple myeloma). Herein we report preliminary results from the B-cell NHL cohort. Methods: Patients with advanced, relapsed/refractory NHL are eligible for enrollment. STRO-001 is administered as a 60-minute IV infusion. STRO-001 was initially administered on Days 1 and 15 of a 28-day cycle. Starting at 0.91 mg/kg, STRO-001 was administered on Day 1 of a 3-week cycle. Treatment is administered until disease progression or unacceptable toxicity. The study employed a modified 3+3 design with an accelerated dose titration (N=1 per cohort until set specified AEs are observed) for initial dosing cohorts. Results: 18 patients with NHL have been treated at 9 dose levels: .05, .075, .15, .27, .43, .65, .91, 1.27 and 1.78 mg/kg. NHL subtypes include: 6 diffuse large B-cell lymphoma (DLBCL), 5 follicular lymphoma (FL), 2 mantle cell lymphoma (MCL), 2 marginal zone lymphoma, 1 Burkitt's lymphoma, 1 composite DLBCL/FL and 1 composite DLBCL/CLL. Median age is 64.5 (range 21-82). Median ECOG performance status is 1 (range 0-2). Median number of prior therapies is 4 (range 1-12). Three patients received prior CAR-T therapy. Median number of STRO-001 doses administered is 2 (range 1-12). 17 patients have completed at least one cycle of STRO-001 and are evaluable for safety and toxicity for dose escalation recommendation. One patient at the 1.78 mg/kg dose level is currently completing Cycle 1 and not yet evaluable for DLT assessment. Most AEs are grade 1 or 2 (90%) with the most common grade 1-2 TEAEs of chills, fatigue, nausea, anemia, headache, pyrexia, infusion reaction, decreased appetite, and abdominal pain occurring in ≥ 20% of patients. There was one DLT in the NHL cohort, a grade 3 thromboembolic event at the 0.91 mg/kg dose level. 16 patients are evaluable for response. The preliminary clinical benefit/disease control rate for all patients is 25% (4/16) including 1 patient with complete response (CR) 2 with partial response (PR) and 1 with stable disease (Table). One patient with DLBCL treated at .075 mg/kg achieved a CR after 2 cycles (4 doses) and progressed after 12 doses (on study 24 weeks). A DLBCL patient treated at 0.65 mg/kg achieved a PR at Cycle 3 and progressed after 8 doses (on study 15 weeks). A DLBCL patient treated at 1.27 mg/kg who achieved a PR has received 10 cycles and remains on study after 27 weeks. Preliminary PK analysis of ADC shows exposure increased (Cmax from 0.39 to 19 µg/mL) and (AUC0-tlast from 0.6 to 71 h*µg/mL) as dose increased from 0.05 to 0.91 mg/kg. Summary/Conclusion: STRO-001 is the first ADC generated with novel cell-free protein synthesis technology and site-specific conjugation to be tested in the clinic. STRO-001 has been well-tolerated. No ocular or neuropathy toxicity signals have been observed and the MTD has not been reached. Preliminary anti-tumor activity has been observed in this heavily pre-treated patient population, including two DLBCL patients who had previously progressed after a CAR-T (Table). The study continues to enroll patients in dose escalation. Next planned dose levels are 2.5 mg/kg and 3.5 mg/kg. This study is registered with clinicaltrials.gov identifier NCT03424603. Table Disclosures Shah: Verastim: Consultancy; Kite Pharma: Consultancy, Honoraria; Lily: Consultancy, Honoraria; Cell Vault: Research Funding; TG Therapeutics: Consultancy; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy. Popplewell:Pfizer: Research Funding; Novartis: Research Funding; Roche: Research Funding. Andreadis:Gilead/Kite: Consultancy; Merck: Research Funding; Incyte: Consultancy; Karyopharm: Honoraria; Jazz Pharmaceuticals: Honoraria; Genentech: Consultancy, Current equity holder in publicly-traded company; BMS/Celgene/Juno: Honoraria, Research Funding; Novartis: Research Funding. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau. Spira:Cardiff Oncology: Research Funding; Takeda: Consultancy; Novartis: Consultancy; Merck: Consultancy; BMS: Consultancy; Incyte: Consultancy; Janssen: Consultancy; ADCT: Research Funding. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Burke:Roche: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Verastem: Consultancy; Morphosys: Consultancy; Adaptive: Consultancy; Epizyme: Consultancy; Kura: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau. Sharman:TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding. Krishnan:Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Takeda: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Janssen: Consultancy; Regeneron: Consultancy; Z Predicta: Membership on an entity's Board of Directors or advisory committees. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Kuriakose:Sutro Biopharma: Current Employment. Berman:Sutro Biopharma: Current Employment. Matheny:Sutro Biopharma: Current Employment. Leonard:Miltenyi: Consultancy; BMS/Celgene: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy; GenMab: Consultancy; Sutro: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Bayer: Consultancy; Gilead/Kite: Consultancy; ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy. Molina:Sutro Biopharma: Current Employment.