New WHO guidelines for cancer pain in adults and adolescents

In this article we performed publication analysis devoted to pain medicine in oncology during anticancer therapy and in palliative setting. Until recently, the main WHO guidelines for pain management in oncology were the recommendations of 1996, which included only pain relievers, as well as adjuvant and symptomatic drugs, which were applied according to the WHO analgesic ladder. These recommendations were based on the collective expert opinion of leading clinicians and scientists. The new WHO clinical guidelines were published in 2019. They are based on the principles of evidence-based medicine, including modern concepts of the etiology and pathogenesis of tumor pain syndrome. This recommendations contain sections on the analgesic efficacy of radiation therapy and antitumor drug therapy. The new WHO recommendations have not yet been published in Russian and are not sufficiently available for a wide range of oncologists and palliative specialists in our country. The purpose of this publication is to present within one volume a concise but complete and comprehensible discussion of the latest trends in pain therapy in oncology, published by WHO experts.

Safety and efficacy of VIP152, a CDK9 inhibitor, in patients with double-hit lymphoma (DHL).

7538 Background: PTEFb/CDK9-mediated transcription of short-lived anti-apoptotic survival proteins and oncogenes like MCL-1 and MYC plays a critical role in a variety of cancers. VIP152 (formerly BAY 1251152), a potent and highly selective CDK9 inhibitor, has been evaluated in a Phase 1 dose-escalation study in patients with advanced cancer. The maximum tolerated dose was 30 mg once weekly administered in consecutive 21-day cycles, based on neutropenia as the dose-limiting toxicity (JCO 2018;36:2507; NCT02635672). DHL is defined as dual rearrangement of the MYC gene and either the BCL2 or BCL6 genes; the resulting overexpression of MYC and BCL2/BCL6 make it particularly difficult to treat. Patients with DHL have a poor prognosis and no standard of care. Considering the impact of CDK9 inhibition on MYC, an exploratory cohort of patients with DHL was added to the study. Methods: Patients with refractory or relapsed DHL were eligible. VIP152 was administered once weekly as a 30-minute IV infusion on Days 1, 8 and 15 of a 21-day cycle. Tumor response was assessed according to the revised Cheson criteria (2007). Results: To date a total of 7 patients have been enrolled and were evaluable at the time of data cutoff (24NOV2020). The patients were mostly men (6/7 pts, 86%) with a median (range) age of 70 (58-84) years. All patients received ≥2 prior therapies, including 2 patients with bone marrow transplant. Three of 7 patients (29%) had ≥3 prior therapies. The median time on treatment was 22 days (range 8-1361 days). The most common adverse events of any grade were: constipation, fatigue, nausea (each 3/7 pts, 43%) and abdominal pain, diarrhea, lymphocyte count decrease, neutrophil count decrease, skin infection, tumor pain, and vomiting (each 2/7 pts, 29%). Most were Grade 1 and Grade 2. The Grade 3 adverse events were fatigue, lymphocyte count decrease, neutrophil count decrease (each 1/7 pts, 14%) and tumor pain (2/7 pts, 29%). One Grade 4 lymphocyte count decrease was reported. Two patients had a serious adverse event (Grade 3 syncope and Grade 3 tumor pain). Two patients had dosing held for an adverse event; however, no patient withdrew from treatment due to any adverse events. One death occurred due to disease progression. Pharmacodynamic biomarker analysis showed significant reduction of MYC, PCNA, and MCL-1 mRNA in all patients across multiple timepoints. Antitumor activity consisted of 2 complete metabolic responses in 7 patients (29%) based on investigator-assessed FDG-PET scans. Due to the COVID pandemic, the patients withdrew consent after 3.7 and 2.3 years, respectively, of treatment. Both patients were in complete metabolic response. Conclusions: VIP152 had a manageable safety profile, on-target pharmacodynamic activity and signs of durable monotherapy antitumor activity in patients with DHL. These encouraging results warrant further evaluation of VIP152 in patients with MYC-driven lymphoma and solid tumors. Clinical trial information: NCT02635672.

Phase Ib study of a novel bivalent IAP antagonist APG-1387 in combination of pembrolizumab for patients with advanced solid tumors.

3508 Background: APG-1387 is an IAP (inhibitor of apoptosis proteins) antagonist that has strong antitumor activity in multiple xenograft cancer models and acts as a host immune modulator, supporting its exploration for use in combination with checkpoint inhibitors for cancer therapy. Methods: This “3+3” dose escalation and dose expansion study evaluated APG-1387 combined with pembrolizumab in patients with refractory or intolerant advanced solid tumors (NCT03386526). APG-1387 was administered IV once weekly with pembrolizumab 200 mg on day 1 of a 21-day cycle. Study aims were to assess safety/tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of December 25, 2019, total 28 patients had been treated in 3 dose cohorts of APG-1387: 20 mg (n = 4), 30 mg (n = 3), and 45 mg (n = 21, 18 in dose expansion). The median line of prior systemic cancer therapies was 3.0 (1-12). No dose-limiting toxicity was observed. The most common treatment-related adverse events (TRAEs; ≥10%) were fatigue (28.6%), arthralgia (14.3%), headache (14.3%), and tumor pain (10.7%). One patient in the 45-mg cohort had grade 2 Bell’s Palsy. G3+ TRAEs were autoimmune colitis, hypoxia, increased lipase, mucosal inflammation, pneumonitis, and tumor pain in 1 patient each (3.6%). Treatment-related SAEs were 1 G3 autoimmune colitis, 1 G2 myocarditis, and 1 G3 pneumonitis. The maximum tolerated dose (MTD)/RP2D for APG-1387 was 45 mg. Among 25 efficacy-evaluable patients, 1 with ER+, HER2‒ breast cancer receiving APG-1387 30 mg after failing 5 lines of therapy (PD-1 treatment-naïve, microsatellite stable) achieved confirmed PR (-79.2%) for 6 cycles but discontinued due to pneumonitis; another patient with PD-L1‒ non‒small-cell lung cancer treated at 45 mg had confirmed PR (-65.0%) for 6 cycles (ongoing). Other 11 patients had SD for 2-11 cycles. The disease control rate was 52%. Preliminary PK data showed a dose-proportional increase in APG-1387 exposure from 20 mg to 45 mg. Preliminary PD data showed that APG-1387 induced rapid degradation of cellular IAP1 and X-linked IAP in peripheral blood mononuclear cell samples; Increased serum release of interleukins (IL-12, IL-10) and monocyte chemotactic protein 4 was dose and time dependent. Conclusions: APG-1387 combined with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in patients with several tumor types. The ongoing study will further evaluate the efficacy of this combination. Clinical trial information: NCT03386526 .

Study on the Clinical Effect and Safety of Oxycodone Hydrochloride Sustained-release Tablets in the Treatment of Advanced Malignant Tumor Pain

Objective: To investigate the clinical effect and safety of oxycodone hydrochloride sustained-release tablets in the treatment of advanced malignant tumor pain. Methods: From January 2016 to November 2016, 128 patients with advanced malignancy, 42 patients with gastric cancer, 18 patients with hepatocellular carcinoma, 35 patients with esophageal cancer and 33 patients with breast cancer were selected. All patients were randomly divided into study group and control group, 64 cases in each group, the study group of 42 male patients, 22 females, aged 32-68 years, mean 52.1 ± 1.8 years; control group of 38 male patients, female the patients in the study group received endoscopic therapy and antibiotics to prevent infection. The control group received only endoscopic therapy. Results: The pain relief rate of the study group was significantly lower than that of the control group andthe quality of life was higher than that of the control group. The incidence of adverse reactions was less in the study group than in the control group (P<0.05). Conclusion: The oxycodone hydrochloride sustained-release tablets has a significant clinical effect and a small side-effect in the treatment of advanced malignant tumor pain. It is of high clinical value.

Phase 1 Study of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody, in Patients with CD20+ B-Cell Malignancies Previously Treated with CD20-Directed Antibody Therapy

Introduction: REGN1979 is a hinge-stabilized CD20xCD3bispecific full-length antibody (Ab) based on an IgG4isotype modified to reduce Fc binding. It is designed to bind T cells (via CD3) and CD20-expressing cells. Cross-linking results in specific, local T cell activation and engagement ofcytolytic functions, independent of T cell receptor mediated recognition. This mechanism of action (MOA) is distinct from approved anti-CD20 Abs, and may provide additional therapeutic benefit. This report describes safety and clinical outcomes in 25 patients (pts) treated with REGN1979. Methods: The study uses a 3+3 design to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and activity of REGN1979 inpts with NHL and CLL, in separate dose escalation cohorts. REGN1979 is administered IV over 1-4 hours, weekly (QW) for 4 doses followed by every 4 weeks (Q4W) for 5 doses. Each dose level (DL) consists of an initial starting dose followed by a higher (step-up) dose.Pts with either progressive disease (PD) after initial response or suboptimal initial response could be retreated. Results: As of clinical cut-off, 25pts had been enrolled and treated with REGN1979 at flat doses ranging from 0.03 - 3.0 mg: 20pts with NHLand 5pts with CLL. NHL subtypes included DLBCL (n=12), FL (n=6), and MCL (n=2). Allpts hada medianof3 (range 1-7) prior regimens, and received a median of 5 (range 2-9) doses of REGN1979. Sixpts remained on initial treatment, 3pts completed treatment, and 16pts discontinued treatment (14 for PD; 2 subject decision). Of 4pts who entered retreatment, 2pts remained ongoing. The most common treatment-related treatment-emergent AEs (TR-TEAEs) were pyrexia (56%), infusionrelated reaction (IRR) (40%), chills (36%), cytokine release syndrome (CRS) (28%), fatigue (24%), tachycardia (24%), hypomagnesaemia (20%) and hypotension (20%). Grade >= 3 TR-TEAEs occurred in 8 pts(32%): IRR (12%), CRS (8%), hypotension (8%), and pyrexia, tachycardia, dyspnea, anemia, hypoxia, hypertension, tachypnea, transaminases increased, and tumor pain each in 1 pt(4%). All were grade 3 with the exception of 1 ptwith grade 4 hypotension. There were no protocol-defined DLTs, nor grade 5 TEAE. No ptsdiscontinued REGN1979 due to TR-TEAE. IRR and CRS events were most commonly reported with the first administration of both initial and step-up dose with incidence and severity decreasing with increasing exposure. Tenptsreported at least one TR-SAE: CRS (24%), IRR (20%), and increased AST and tumor pain, each in 1pt(4%). Threeptswith aggressive lymphoma who discontinued REGN1979 due to PD died of their disease within 30 days of their last dose. Notably, modifications to pre-medication(s) and drug administration instructions have improved tolerability (fewer and less severe IRR/CRS). No clinically significant CNS TEAEs have been observed. CT-based (Cheson, 2007) anti-tumor activity was observed in 11 ptswith NHL: PR [n=4,median duration of 50d];SD [n=7, median duration of >196d]. The overall response rate (ORR) in NHL ptsacross DLs was 20%. In 2 highest dose levels, ORR was 27% (Fig 1). Of the 14pts evaluated by PET, 4pts had a partial metabolic response, withmedian duration of 244d perLugano Criteria. Twopts with CLL attained SD as best overall response. PK: REGN1979 concentrations in serum increased with increasing DL and were variable across pts. Variability was less at higher DLs and also decreased over time during therapy. At DLs tested, REGN1979 concentrations did not notably increase over time during treatment. PD/Cytokines: At the lowest dose tested, 0.03 mg, transient B-cell depletion was observed inpts with measurable circulating B cells.Samples from 12pts were available for cytokine analysis. Interim analysis indicates REGN1979 induces cytokine release as expected based on MOA. An increase in IL-6, IL-10 and to lesser extent IFN-γ was observed. The magnitude of cytokine response generally correlated with symptomatic IRR/CRS. Conclusion: REGN1979 demonstrated an acceptable safety profile at flat doses of 0.03 - 3.0 mg (< 1% of rituximab dose) inpts with NHL and CLL. Most TEAEs were associated with IRR/CRS, and were managed with supportive therapy and modification to REGN1979 administration. No clinically significant neurological toxicity was observed. Preliminary antitumor activity demonstrates increased activity at higher doses. Dose escalation and treatment schedule optimization continue. Disclosures Brown: Acetylon, Gilead: Research Funding; Celgene, Roche/Genentech, Gilead, Infinity, Janssen, Pharmacyclics, ProNai, Sun BioPharma: Consultancy. Arnason:Gilead: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Chavez:Janssen: Speakers Bureau. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Topp:Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Roche: Honoraria, Other: travel; Boehringer: Consultancy, Other: Travel, Research Funding; Jazz: Consultancy; Pfizer: Consultancy, Other: Travel. Adriaens:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Kostic:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Paccaly:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Gao:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Trail:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Brownstein:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership.