Faculty Bibliography

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m² IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m² IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.

Evaluation of tolerability is increasingly relevant for patients with haematological malignancies treated with chronically administered therapies. Adverse events from these agents might affect the ability of patients to tolerate treatment over time. Conventional toxicity tables that include the incidence of high-grade adverse events, defined by the Common Terminology Criteria for Adverse Events, do not provide information on the time profile of these adverse events or reflect the continuous, lower grade symptomatic toxicities that are particularly relevant to treatment tolerability for patients living with indolent disease. Modern approaches to the evaluation and reporting of toxicity that capture the tolerability of treatment to the patient are imperative. In this Viewpoint, we present a focused, pilot, and longitudinal Toxicity over Time analysis of adverse events from lenalidomide and lenalidomide with rituximab in patients with follicular lymphoma treated in the CALGB 50401 (Alliance; NCT00238238) trial to define the trajectory of adverse events and quantify the burden of continuous, low-grade events. Toxicity over Time analyses provided clinically relevant descriptions of neutropenia and fatigue trajectories caused by lenalidomide that were not identified by standard analysis of the maximum grade events defined by the Common Terminology Criteria for Adverse Events. Systematic, rigorous incorporation of patient-reported outcomes in clinical trials will be crucial to our understanding of the tolerability of chronically administered therapies in patients with haematological malignancies.

BACKGROUND:Diabetes places patients with cancer at an increased risk of infections, hospitalizations, and mortality. The objective of the current study was to characterize diabetes care management patterns among patients with cancer in the year before and, separately, after cancer diagnosis. The authors hypothesized that diabetes care declines after a diagnosis of cancer. METHODS:The Surveillance, Epidemiology, and End Results (SEER) cancer registry linked to Medicare claims data was used. The authors included diabetic beneficiaries aged ≥65 years who were diagnosed with incident, nonmetastatic breast, prostate, or colorectal cancer between 2008 and 2013. Controls were diabetic Medicare beneficiaries in SEER regions who did not have cancer. Cases were matched to controls based on age, sex, Charlson Comorbidity Index, and diabetes severity. Primary outcomes were diabetes care received over 12 months: 1) hemoglobin A1c testing; 2) eye examination; and 3) low-density lipoprotein testing. Using a difference-in-difference (DID) approach, the authors examined use differences 12 months before to after diagnosis for patients with cancer and controls. To avoid capturing testing related to diagnosis and not diabetes management, the authors implemented a 90-day washout period (45 days before and/or after diagnosis). RESULTS:A total of 32,728 diabetic patients with cancer and 32,728 matched noncancer controls were included. After diagnosis, patients with cancer were found to have modest, but significantly lower, rates of diabetes care use compared with controls. Patients with cancer had greater declines in hemoglobin A1c testing (DID, 2.4%; 95% CI, 1.7%-3.0%), low-density lipoprotein testing (DID, 4.3%; 95% CI, 3.6%-5.0%), and receipt of all diabetes indicators (DID, 2.7%; 95% CI, 1.8%-3.5%) 12 months before to after diagnosis. CONCLUSIONS:Compared with controls, less diabetes care use was observed among patients with cancer in the year after diagnosis. Understanding and addressing the reasons for this may improve outcomes in this population.

BACKGROUND:ClinicalTrials.gov is used by clinicians and patients to identify clinical trials. We assessed the ease with which users could identify relevant trials related to lymphoma using the short and official titles. We hypothesized that lymphoma titles frequently lack important information. MATERIALS AND METHODS:We performed 2 searches on ClinicalTrials.gov. The first search was performed before June 2017, when ClinicalTrials.gov underwent updates to improve usability. The second was performed after 2017. We assessed whether the short and official titles of each trial provided information on the study phase, eligible disease status, lymphoma histologic subtype, study intervention, primary objective, and the presence of randomization and placebo control. RESULTS:Of the pre-overhaul lymphoma trials, the official versus short titles included information regarding study intervention (99% vs. 96%), study phase (82% vs. 14%), lymphoma histologic subtype (78% vs. 72%), disease status (46% vs. 35%), randomization (13% vs. 2%), presence of placebo (6% vs. 2%), and primary objective (38% vs. 26%). Of the post-overhaul trials, the official versus short titles included information regarding study intervention (97% vs. 96%), lymphoma histologic subtype (83% vs. 78%), study phase (78% vs. 8%), disease status (64% vs. 50%), primary objective (38% vs. 23%), presence of placebo (11% vs. 0%), and randomization (18% vs. 0%). CONCLUSION:The official titles were more informative than were the short titles on ClinicalTrials.gov. However, the short and official titles both often lacked the basic information needed to understand a clinical trial. This has persisted despite updates to the platform. These results highlight the need for standardization of the format and content included in study titles.

PURPOSE:Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers. PATIENTS AND METHODS:This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen. RESULTS:Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response. CONCLUSIONS:The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.

In mantle cell lymphoma (MCL), cyclin D1 combines with CDK4/6 to phosphorylate Rb, releasing a break on the G1 to S phase cell cycle. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. The proteasome inhibitor bortezomib is approved by the US Food and Drug Administration for treatment of mantle cell lymphoma. Palbociclib-induced pG1 appears to sensitize MCL cells to killing by low-dose bortezomib, potentially improving its activity and tolerability. We conducted a phase 1 trial of palbociclib plus bortezomib in patients with previously treated MCL (NCT01111188). Patients received palbociclib at 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) on days 1-12 of each 21-day cycle in addition to intravenous bortezomib 1.0 mg/m² (dose levels 1, 2, 3) or 1.3 mg/m² (dose level 4) on days 8, 11, 15 and 18. A total of 19 patients with a median age of 64 and an average of 2 prior therapies were enrolled. Two subjects experienced dose limiting toxicity (DLT): thrombocytopenia (dose level 1) and neutropenia (dose level 3). Although no DLTs were seen at dose level 4, all patients required dose delays during cycle 2 due to cytopenias, and the study team decided to stop the trial. Four of 19 patients achieved a clinical response, including one patient with a complete response. Three patients received treatment for more than one year, including one patient receiving single-agent palbociclib for more than 6 years. The combination of palbociclib 125 mg on days 1-12 plus bortezomib 1.0 mg/m² on days 8, 11, 15, and 18 of a 21-day cycle is feasible and active in previously treated MCL, with the primary toxicity being myelosuppression. The regimen may be worthy of further evaluation in patients with non-blastoid MCL following failure of other newer agents.

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

Five-year follow-up of S1106 demonstrates similar efficacy, MRD negativity, and 5-year survival with RH or RB, but RH was more toxic than RB. RB showed excellent efficacy and survival and less toxicity compared with a cytarabine-based regimen in transplant-eligible MCL patients.