First-in-human study of TAS3681, an oral androgen receptor (AR) antagonist with AR and AR splice variant (AR-SV) downregulation activity, in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) refractory to abiraterone (ABI) and/or enzalutamide (ENZ) and chemotherapy (CT).

5031 Background: Second-generation AR signaling inhibitors have improved outcomes from mCRPC; drug resistance, however, invariably evolves with AR overexpression, AR mutation, or AR-SVs and continued AR signaling. TAS3681 is an oral and selective AR antagonist with AR and AR-SV down-regulation and has antitumor efficacy in AR-SV+, ENZ-resistant CRPC models. We report the dose escalation part of the first-in-human trial of TAS3681 in pts with mCRPC (NCT02566772). Methods: mCRPC pts with progressing disease after ABI and/or ENZ, and ≥1 additional CT, received TAS3681 in a 3+3 dose escalation design; QD or BID tablets were given in 28-day cycles; BID dosing at ≤600 mg was introduced to increase daily exposure while limiting Cmax. Primary endpoints: incidence of dose limiting toxicities (DLTs) and adverse events (AEs); other endpoints: pharmacokinetics (PK), and antitumor activity per Prostate Cancer Clinical Trials Working Group 3 (PCWG3). Results: As of January 22, 2021, 56 pts in 10 cohorts were dosed (QD: 25, 50, 100, 200, 400, 600, 800, and 1000 mg; and BID: 300 and 400 mg). Median age was 66 (56–79) yrs; pts had a median of 6 prior lines of systemic therapy. Of 41 pts evaluable for DLTs, 3 had confirmed DLTs: 1/10 DLT evaluable pts at 600 mg QD (QT prolongation >480 ms) and 2/3 DLT evaluable pts at 400 mg BID (1 pt with QT prolongation >480 ms, 1 pt with G3 hypertension). The most common treatment-related AEs (TRAEs) were: nausea (32 pts, 57.1%), hyperbilirubinemia (21 pts, 37.5%), fatigue (18 pts, 32.1%), vomiting (17 pts, 30.4%) and diarrhea (16 pts, 28.6%); AEs of QT prolongation were seen in 11 pts (19.6%). TRAEs ≥G3 were reported in 12 pts (21.4%). TAS3681 exposure increased dose-dependently up to 600 mg QD and then plateaued. Steady state was reached by Day 8 and accumulation ratios of AUC were approximately 2 to 6 times. Confirmed PSA declines of >50% from baseline were seen in the 600 mg QD (2 pts) and 300 mg BID cohorts (1 pt). Antitumor activity was observed; tumor response rate was 23.1% in the 600 mg QD cohort (3 confirmed partial responses (cPRs) in 13 dosed pts), 22.2% in the 300 mg BID cohort (1 cPR and 1 unconfirmed complete response in 9 dosed pts), and 14.3% in the 400 mg BID cohort (cPR in 1/7 dosed pts). Responses occurred after 2–4 cycles of treatment. The longest duration of response (DoR) to date is 16.2 mo. The 5 pts with cPR had DoR >6 mo with the exception of 1 pt who had a short follow-up period. 300 mg BID was found to be the best tolerated dose with antitumor activity. Conclusions: The recommended phase 2 dose is 300 mg BID. TAS3681 has a manageable safety profile and has antitumor activity against heavily pretreated, multi-drug resistant mCRPC. The study expansion phase is enrolling pts who have progressed on ABI or ENZ +/- taxane CT. Clinical trial information: NCT02566772.

Usefulness of carbon-11-labeled methionine positron-emission tomography for assessing the treatment response of primary central nervous system lymphoma

Background Primary central nervous system lymphoma (PCNSL) responds relatively quickly to chemotherapy or radiotherapy. However, determination of a complete response after treatment is often difficult because of extremely light residual contrast enhancement on magnetic resonance images due to the effects of microhemorrhages and scar tissue formation. These small enhancing lesions define an unconfirmed complete response. The aim of this study was to investigate the usefulness of carbon-11-labeled methionine (11C-Met) positron-emission tomography (PET) for determining the treatment response of PCNSL. Methods Data for 36 patients who were treated for PCNSL between 2011 and 2015 and underwent magnetic resonance imaging and 11C-Met PET were reviewed. Magnetic resonance imaging findings were classified as complete response, unconfirmed complete response, and tumor mass (a composite of partial response, stable disease and progressive disease). PET images were evaluated, standardized uptake values were quantified, and the tumor-to-normal tissue count ratio (TNR) was calculated. Receiver operating characteristic curves were generated to determine the optimal cutoff TNRs. Results The optimal TNRs for differentiating complete response and unconfirmed complete response from tumor mass were 1.83 (area under the curve, 0.951) and 1.80 (area under the curve, 0.932), respectively. The corresponding sensitivity and specificity values for the diagnosis of tumor mass were 82.4 and 100%, respectively, in the complete response group and 85.3 and 85%, respectively, in the unconfirmed complete response group. Conclusions A TNR of ≥1.80 can aid in the detection of active PCNSL using 11C-Met PET. Thus, 11C-Met-PET may be a useful tool for accurate evaluation of the treatment efficacy in PCNSL.

A Phase I Trial of the Anti-Inhibitory KIR Antibody, IPH2101, and Lenalidomide in Multiple Myeloma: Interim Results

Abstract 4058 Introduction: Multiple myeloma (MM) cells upregulate MHC class I antigens which serve as ligands to inhibitory Killer Immunoglobulin-like Receptors (KIR) as a means of evading natural killer (NK) cell immunity. IPH2101 is a human, IgG4 monoclonal antibody against common inhibitory KIR that prevents KIR-ligand interaction and augments NK cell cytotoxicity against MM. A prior, single-agent, phase I study of IPH2101 demonstrated acceptable safety and tolerability with 34% of heavily pretreated patients achieving disease stabilization. Lenalidomide expands and activates NK cells, thus, pairing this agent with IPH2101 may represent a novel, steroid-free therapeutic option. Our preclinical data suggest that IPH2101 and lenalidomide combine to enhance NK cell function against MM. Herein, interim results of a phase I clinical trial of IPH2101 and lenalidomide are presented. Methods: A 3+3 design includes dose escalation over 4 planned cohorts: Cohort 1 = IPH2101 0.2mg/kg & lenalidomide 10mg, Cohort 2 = IPH2101 0.2mg/kg & lenalidomide 25mg, Cohort 3 = IPH2101 1mg/kg & lenalidomide 25mg, Cohort 4 = IPH2101 2mg/kg & lenalidomide 25mg. A 6-patient extension cohort is planned at the maximally tolerated dose. Lenalidomide is administered orally days 1–21 and IPH2101 is given intravenously on day 1 of a 28-day cycle for 4 cycles. Responding patients may continue therapy for 4 additional cycles and are maintained on lenalidomide alone thereafter. The primary objective of the study is to determine the safety and tolerability of IPH2101 and lenalidomide with secondary endpoints including: response rate, progression-free survival, pharmacodynamics, pharmacokinetics, and biologic correlates. Adult patients with relapsed MM following one or two lines of prior therapy are eligible to participate. Prior exposure to lenalidomide is allowed; however, patients must not have been resistant to, or intolerant of, lenalidomide. Patients must have measurable disease, ECOG performance status 0–2, and adequate organ function and bone marrow reserve. Thromboprophylaxis is mandatory for all patients. Results: To date, n=13 patients have been enrolled in the first 3 cohorts who have received a median number of 4 cycles of therapy to date (range 1–8). Adverse events have been generally low grade and self-limited. Two potential dose-limiting toxicities (DLT) have been observed (cohort 1 and cohort 3). Both patients experienced grade 3 infusion reactions associated with pyrexia and transient, grade 4 leucopenia following cycle 1, day 1 treatment. Clinical cytokine release syndrome was observed, and high levels of IFN-gamma, IL-6, TNF-alpha, and MIP-1beta were documented. Infusion reactions were treated with supportive care, including intravenous fluids and anti-pyretics; steroids were not administered. Leucopenia resolved without intervention, and both patients were subsequently treated in cycle 2 without recurrence of DLT. Both patients appear to have disproportionally greater KIR binding of IPH2101 on T cells relative to NK cells. Cohort 1 was expanded to n=6 patients without recurrence and expansion of cohort 3 is ongoing. An amendment is now included for pre-medication of patients with an anti-pyretic and anti-histamine prior to dosing. Co-administration of lenalidomide does not appear to alter the IPH2101 pharmacodynamic profile observed in the prior, single-agent phase I study. To date, responses include: 1 (unconfirmed) complete response, 3 partial responses, 2 minor responses and 1 stable disease. Conclusions: In addition to direct anti-MM effects, lenalidomide promotes NK cell activation, and IPH2101 prevents inhibitory signaling to augment NK cell immunity against MM. Results suggest the combination has activity with manageable toxicity in relapsed MM. At present, ongoing unconfirmed complete response has been > 12 months and ongoing partial responses have been > 18 months, > 8 months, and > 1 month in duration. This combination may represent the first steroid-free, “dual immunotherapy” for MM and further development is justified. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without dexamethasone, IPH2101 not FDA approved yet. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment.

Results of a phase 2 study of bortezomib in patients with relapsed or refractory indolent lymphoma

This study evaluated the efficacy and safety of single-agent bortezomib in indolent B-cell lymphoma that had relapsed from or was refractory to rituximab. Sixty patients enrolled: 59 were treated with bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles; responders could receive 4 additional cycles; maintenance was optional. Fifty-three evaluable patients completed more than 2 cycles. The median age was 70 years, 53% female, Ann Arbor stage III-IIIE (28%) and IV (65%); 43 patients (72%) had more than 2 prior regimens; and 6 patients went on to maintenance. Overall responses are as follows: 1 complete response (1.9%), 3 unconfirmed complete response (5.7%), 3 partial response (5.7%), 34 stable disease (64.2%), and 12 progressive disease (22.6%). Median time to response = 2.2 months (range, 1.2-5.3 months); duration of response = 7.9 months (2.8-21.3 months); 1-year survival was 73% and 2-year survival was 58%; median survival = 27.7 months (range, 1.4-30.9 months); median progression-free survival = 5.1 months (range, 0.2-27.7 months), median time to progression = 5.1 months (range, 0.2-27.7 months), and median event-free survival = 1.8 months (range, 0.2-27.7 months). Treatment-related grade 3 or 4 adverse events included: thrombocytopenia (20%), fatigue (10%), neutropenia (8.5%), and neuropathy and diarrhea (6.8% each). This study demonstrates that bortezomib has modest activity against marginal zone and follicular lymphoma; it has the potential for combination with other agents in low-grade lymphomas. Maintenance therapy should be explored further.

A phase I study of oxaliplatin (OXA) and irinotecan (IRN) in pediatric patients with refractory solid tumors: A Children's Oncology Group study

9546 Background: Platinum analogues in combination with topoisomerase 1 inhibitors have been shown in in vitro studies to have synergistic anti-tumor activity. This study estimated the maximum tolerated dose (MTD) of OXA in combination with a protracted schedule of IRN in children with refractory solid tumors. Methods: OXA was administered over 2 hrs on days 1 and 8 in combination with IRN iv over 1 hr on days 1–5 and 8–12 of a 21-day cycle. An oral cephalosporin was administered daily to ameliorate IRN-associated diarrhea. Pharmacokinetic studies of OXA and UGT1A1 genotyping were performed during course 1 in consenting patients. Results: 13 patients (median age 16 yrs, 4 M) were enrolled. Dose-limiting diarrhea (n=3), serum lipase elevation (n=3), serum amylase elevation (n=2), colitis (n=1), abdominal pain (n=1) and headache (n=1) occurred at the 1st dose level (60 mg/m2/dose OXA; 20 mg/m2/dose of IRN) in the first 3 patients. Only 1/7 patients treated with reduced doses of both agents (40 mg/m2/dose OXA; 15 mg/m2/dose IRN) experienced DLT, diarrhea. When the OXA dose (60 mg/m2) was increased with the reduced IRN dose (15 mg/m2) 2/3 patients had DLT (1 diarrhea, 1 hypokalemia). Myelosuppression was minimal at all dose levels. One patient with alveolar rhabdomyosarcoma previously treated with irinotecan (dose level 2: 40 mg/m2/dose OXA; 15 mg/m2/dose IRN) had an unconfirmed complete response of her breast metastases and one patient with refractory neuroblastoma had disease stabilization through 6 courses of therapy. The frequency of 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes were 5/10, 4/10, and 1/10, respectively. Conclusions: The MTD using this schedule with oral cephalosporin support was oxaliplatin 40 mg/m2/dose with irinotecan 15 mg/m2/dose. There was some evidence of benefit but significant toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was also observed. [Table: see text]

Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial

Lymphocyte-predominant Hodgkin disease (LPHD) is a unique clinical entity characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. The malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late effects than standard therapy. In this phase 2 trial, 22 patients with CD20+ LPHD received 4 weekly doses of rituximab at 375 mg/m2. Ten patients had previously been treated for Hodgkin disease, while 12 patients had untreated disease. All 22 patients responded to rituximab (overall response rate, 100%) with complete response (CR) in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3 had recurrent LPHD, while 2 patients had transformation to large-cell non-Hodgkin lymphoma (LCL). All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR seen in 1 patient and stable disease in 2. Rituximab induced prompt tumor reduction in each of 22 LPHD patients with minimal acute toxicity; however, based on the relatively short response duration seen in our trial and the concerns about transformation, rituximab should be considered investigational treatment for LPHD. Further clinical trials are warranted to determine the optimal dosing schedule of rituximab, the potential for combination treatment, and the possible relationship of rituximab treatment to the development of LCL.