Faculty Bibliography

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 (XpressCFTM) and site-specific conjugation (XpressCF+TM) 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. XXMethod(s): 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. XX, 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 microg/mL) and (AUC0-tlast from 0.41 to 21 h*microg/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. [Formula presented] 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.XXCopyright

Background: The Bruton's tyrosine kinase inhibitor ibrutinib is highly effective as a monotherapy in relapsed/refractory mantle cell lymphoma (MCL) with an overall response rate of 68% (Wang et al, NEJM 2013), but the duration of response is shorter than what is seen in chronic lymphocytic leukemia, and the survival of patients who progress after receiving ibrutinib is as short as 3 months (Martin et al, Blood, 2016). In addition, the complete response (CR) rate is only 21%. Ibrutinib-containing combinations may improve depth and duration of response in patients with relapsed/refractory MCL. While use of the proteasome inhibitor, bortezomib, can be limited due to the development of peripheral neuropathy, it has an ORR of 33% (CR rate 8%) in MCL, and preclinical models suggest a synergism between proteasome inhibitors and ibrutinib in MCL cell lines (Axelrod et al, Leukemia 2014). We developed a phase 1/2 trial of ibrutinib combined with the oral proteasome inhibitor ixazomib in patients with relapsed/refractory MCL. XXMethod(s): PrE0404 will be open at 18 sites nationwide and is registered at clinicaltrials.gov (NCT03323151). It is currently enrolling patients with relapsed/refractory MCL who have received at least 1 prior line of combination therapy. Patients receiving prior BTK or proteasome inhibitors are eligible, and patients may have received prior autologous or allogeneic transplantation as long as they do not have active graft versus host disease. Patients must have <= grade 1 peripheral neuropathy. For phase 1, patients are required to have been off of a BTK inhibitor for 3 months. Starting dose of ibrutinib for all patients is 560mg daily, and dose levels of ixazomib for the phase 1 trial range from 3mg to 4mg days 1, 8, and 15 of a 28 day cycle. Patients continued therapy until disease progression or unacceptable toxicity. For the phase 1 portion of the study, patients are monitored for a dose limiting toxicity (DLT) during cycle 1, defined as grade 3 thrombocytopenia with significant bleeding, select grade 3 non-hematologic toxicities, grade 4 thrombocytopenia, grade 4 febrile neutropenia, grade 4 non-hematologic toxicity, or any grade 5 toxicity. In addition, any toxicity-related dose delay > 7 days of ibrutinib or ixazomib or an inability to receive all 3 doses of ixazomib during cycle 1 are considered DLT's. The maximum tolerated dose/recommended phase 2 dose will be the dose at which fewer than 1/6 patients experience a DLT, with the maximum dose of ixazomib will be 4mg. The primary endpoint for the phase 2 portion of the study is CR rate, and patients will be assigned to one of two cohorts based on prior BTK-inhibitor exposure. For ibrutinib-naive patients, we will target a CR rate of 40% (based on a historical CR rate of 21% for ibrutinib), and for ibrutinib-pretreated patients, we will target a CR rate of 23% (based on a historical CR rate of 8% for bortezomib). There is 86% statistical power & a one-sided 10% alpha to test each hypothesis. We will accrue 31 patients to each cohort in order to detect this difference. Secondary and exploratory endpoints will include progression-free and overall survival, overall response, toxicity, frequency of BTK mutations, and response based on molecular risk stratification. As of July 2019 the study is open to accrual at 14 sites and is expected to move to phase 2 in fall 2019, at which time it will be expanded to 18 sites. Disclosures: Cohen: Hutchison: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; Astra Zeneca: Research Funding; LAM Therapeutics: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; UNUM: Research Funding; Gilead/Kite: Consultancy; Takeda Pharmaceuticals North America, Inc.: Research Funding. Portell: Infinity: Research Funding; Roche/Genentech: Research Funding; Xencor: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; Bayer: Consultancy; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; BeiGene: Consultancy, Research Funding. Hamadani: ADC Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Otsuka: Research Funding; Celgene: Consultancy; Merck: Research Funding; Medimmune: Consultancy, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy. Diefenbach: Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Landsburg: Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Triphase: Research Funding; Takeda: Research Funding; Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau. Kahl: Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Ixazomib is not currently approved for mantle cell lymphoma.XXCopyright

Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after >=4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2.5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.XXCopyright

Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score 90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

The role of magnetic resonance imaging in evaluating shoulder arthropathies is evolving. This article reviews 4 of the major arthropathies: septic arthritis, rheumatoid arthritis, calcium pyrophosphate dihydrate (CPPD) deposition disease, and hydroxyapatite disease (HAD), with special attention to their magnetic resonance imaging features. Comfort with identifying these entities allows appropriate and prompt treatment, which is critical for joint preservation in the case of infection, for maximal therapeutic efficacy of disease-modifying drugs in the case of rheumatoid arthritis, and for expediting symptomatic relief in the cases of CPPD deposition disease and HAD.

The purpose of this study was to investigate the association of aortic arch calcification, a surrogate marker of atherosclerosis, with rotator cuff tendinosis and tears given the hypothesis that decreased tendon vascularity is a contributing factor in the etiology of tendon degeneration. A retrospective review was performed to identify patients ages 50 to 90 years who had a shoulder MRI and a chest radiograph performed within 6 months of each other. Chest radiographs and shoulder MRIs from 120 patients were reviewed by two sets of observers blinded to the others' conclusions. Rotator cuff disease was classified as tendinosis, partial thickness tear, and full thickness tear. The presence or absence of aortic arch calcification was graded and compared with the MRI appearance of the rotator cuff. The tendon tear grading was positively correlated with patient age. However, the tendon tear grading on MRI was not significantly correlated with the aorta calcification scores on chest radiographs. Furthermore, there was no significant correlation between aorta calcification severity and tendon tear grading. In conclusion, rotator cuff tears did not significantly correlate with aortic calcification severity. This suggests that tendon ischemia may not be associated with the degree of macrovascular disease

OBJECTIVE: Femoroacetabular impingement is an important entity with well-described radiographic findings. One of the criteria of the cam type of femoroacetabular impingement is femoral head-neck dysplasia, denoted mathematically as the 'alpha angle.' Several observers have reported that direct measurement of the angle may not be necessary because subjective appraisal may yield similar results. We sought to scientifically determine the accuracy of a subjective assessment, using the calculated angle as the gold standard. MATERIALS AND METHODS: At 1.5 T, 50 consecutive patients' hips were evaluated on sets of oblique axial images. Two musculoskeletal radiologists recorded their subjective opinion as to the alpha angle using a confidence scale of 1-5. Direct mathematic measurement of the alpha angle was done by a third independent observer and correlated with the subjective results. Correlations between the subjective and measured angles and interobserver variation were calculated. RESULTS: Statistically, significant variability was seen in the subjective assessment of the alpha angle. When the alpha angle was > 55 degrees, the area under the receiver operating characteristic curve (AUC) was 0.606, indicating that visual assessment is a poor predictor of a wide alpha angle. Even in patients with a measured normal alpha angle (< 55 degrees), slightly fewer than half were subjectively thought to possibly, likely, or definitely have abnormal angles. Similarly, more than half of the abnormal cases (alpha angles > 55 degrees) were subjectively thought to possibly or probably be normal. CONCLUSION: Subjective assessment of alpha angles is suboptimal unless one is quite confident of a bone abnormality

PURPOSE: The quantitative assessment of muscle atrophy has a degree of importance in prognosticating rotator cuff treatment. However, it has been conjectured that muscle fat increases with aging. Therefore, we thought that the quantitative assessment of the supraspinatous would be better if made in comparison with a standard of reference such as the deltoid. Consequently, we performed a two-part study, first evaluating supraspinatous changes compared with the deltoid in 'normals' with aging, and second, determining if in patients with cuff tears the supraspinatous fat exceeds that of the deltoid. MATERIALS AND METHODS: In part 1, we studied 50 patients stratified by decade. In the first sitting, two blinded independent observers quantitatively graded the deltoid (with the supraspinatous obscured) and in the second sitting the same two observers quantitatively graded the supraspinatous (with the deltoid obscured). In part 2 of the study, we evaluated patients with moderate rotator cuff tears (>2 cm) and performed the same blinded, two-sitting, quantitative assessment (with the comparison muscle obscured). RESULTS: We found that muscle atrophy increases with age in patients without tears (0.011/0.028 U/year), although to a greater degree in the deltoid (p = 0.032). Also, in similarly aged patients, quantitative scores of the deltoid closely matched those of the supraspinatous (p = 0.071). Notably, however, in patients with large tears, the supraspinatous showed significant changes disproportionate to those of the deltoid, regardless of patient age (p = 0.044). CONCLUSION: In the presence of a normal rotator cuff, fatty infiltration increases with age. Age-related changes occur more frequently in the deltoid, verifying this muscle's potential as a standard of reference. With cuff tears, supraspinatous atrophy was disproportionate to that of the deltoid. Therefore, systematic assessment of supraspinatous muscle atrophy may be more reliable using the deltoid as a control for comparison than assessing it in isolation