Number Of Prior Treatment Regimens Research Articles

The lymphocyte/monocyte ratio predicts the efficacy of isatuximab plus pomalidomide in multiple myeloma patients

BackgroundIsatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab.ObjectiveWe tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment.MethodsWe retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment.ResultsAmong the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/μL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen.ConclusionWe found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results.

Clinical Outcomes of Tucidinostat Therapy for Relapsed/Refractory Adult T-Cell Leukemia-Lymphoma (ATL) in Clinical Practice

【Objective】 Tucidinostat, approved for relapsed/refractory adult T-cell leukemia-lymphoma (ATL) treatment in June 2021 in Japan, demonstrated an objective response rate (ORR) of 30.4%, progression-free survival (PFS) of 1.7 months (95% CI: 0.8-7.4), and overall survival (OS) of 7.9 months (95% CI: 2.3-18.0) in a phase IIb trial for 23 cases of relapsed/refractory adult T-cell leukemia-lymphoma (ATL) in Japan. We report the treatment results of this agent in Miyazaki Prefecture. 【Methods】 We retrospectively analyzed the treatment results of relapsed/refractory ATL patients who received Tucidinostat at 6 facilities within the Miyazaki prefecture, and HTLV-1 endemic area in southwest Japan, after its approval. All clinical procedures for patients were part of routine care, and the requirement for written patient consent was waived by the committee in view of the retrospective nature of this study. Approved study protocols were presented on the web site in an opt-out format, ensuring patients had the right to refuse participation in the study. In accordance with these protocols, clinical information was then collected. 【Results】 From October 2021 to July 2023, Tucidinostat was administered to 24 cases of relapsed/refractory ATL. The median age at the start of administration was 72.5 (41-85), with 13 cases of the acute type, 7 cases of the lymphoma type, and 4 cases of poor-prognosis chronic type. The median number of prior treatment regimens was 2 (1-4), with 19 cases of multi-drug combination chemotherapy, 18 cases of mogamulizumab, and 5 cases of oral chemotherapy. There were no cases of transplantation. The period from prior treatment to Tucidinostat administration was 3.2 months (0-27.5 months), and the disease stage at the start of Tucidinostat administration was relapse in 7 cases and refractory in 17 cases. The starting dose was 40mg/day (twice a week) in 19 cases and 20mg/day (twice a week) in 4 cases, with a median number of total treatment courses of 3 (1-20). Of the 24 cases,19 had their dose reduced or treatment suspended because of myelosuppression. The best treatment response was complete response(CR) in 5 cases, parcial response (PR) in 8 cases, Stable Disease(SD) in 8 cases, with an efficacy rate (CR/PR) of 54.2%. The PFS after the start of treatment was 3.7 months (1.8-7.8), and the OS after the start of treatment was 8.6 months. The reason for discontinuation of administration were progression disease in 15 cases, intolerance in 1 case (skin rash in 1 case), and severe complications in 1 case (cryptococcal meningitis). In the Cox proportional hazards model analysis, considering the clinical characteristics at the initiation of Tucidinostat, the initial sIL-2R level negatively impacted PFS. PFS was then stratified using an sIL-2R cutoff of 5000 U/mL, showing a Median Survival Time (MST) of PFS: 0.65 months for those below the cutoff versus 0.15 months for those above it, p=0.006 (log-rank).“A similar trend was observed for OS (Median OS: not reached vs. 0.53 months, p=0.032 (log-rank)). 【Conclusion】 In relapsed/refractory ATL, Tucidinostat achieved treatment results similar to those in the phase IIb trial in clinical practice. In particular, for cases with an sIL2-R value of less than 5000, it was suggested that Tucidinostat may be a meaningful treatment option.

Preliminary Biomarker Data from a Phase 1/2 Study of Golidocitinib Demonstrates Targeting JAK/STAT Pathway to Treat Peripheral T-Cell Lymphoma

Background Peripheral T-cell lymphoma (PTCL) is a group of heterogenous non-Hodgkin lymphomas originating from mature T lymphocytes. There is no consensus on treatment for patients with PTCL who failed 1st line treatment (r/r PTCL). It has been well documented that many PTCL patients have elevated JAK/STAT pathway activities. Golidocitinib (AZD4205) is an orally available, JAK1-specific inhibitor currently in late-stage clinical development. We previously reported encouraging efficacy data from an ongoing phase 1/2 multicenter global study (#NCT04105010, JACKPOT8). Here we presented safety and efficacy data and the biomarker analysis of the samples collected from this study. Method JACKPOT8 is a single arm, multicenter, multi-cohort global study. Patients with r/r PTCL were enrolled to receive golidocitinib at either 150 mg or 250 mg, once daily until disease progression or meeting pre-defined termination criteria. Antitumor efficacy was assessed according to Lugano criteria. All patients were requested to provide archived or freshly obtained tumor and plasma samples during the screening. Genome level mutation detection was carried out using next generation sequencing (NGS). JAK/STAT pathway activation was assessed according to pSTAT level. Result At the cut-off date on May 31, 2021, 51 patients with r/r PTCL (21 PTCL-NOS, 20 AITL, 4 ALCL ALK-, 4 NKTCL, 2 MEITL) had been enrolled into the study and treated with golidocitinib at 150 mg (n = 35) or 250 mg (n = 16). Median number of prior treatment regimens was 2; 10 patients had a prior stem cell transplant. Overall, golidocitinib showed an acceptable safety profile. Grade 3 or above adverse events occurring in 10% or more of patients included neutropenia (29.4%), thrombocytopenia (15.7%), and pneumonia (11.8%). The majority of AEs were reversible or clinically manageable with dose modifications. Of all 49 patients who completed at least one investigator-based tumor response assessment, 21 achieved tumor response (ORR 42.9%), including 11 complete responses (CRs, 22.4%). Tumor samples from 20 patients were determined suitable for pSTAT3 IHC analysis. A positive trend between clinical activity and high level of pSTAT3 was observed (Table 1). Targeted genomic sequencing was carried out in samples from 19 patients. No genetic mutations associated with JAK/STAT pathway (including JAK1/2/3, STAT3/5A/5B/6) were identified in the tested samples. Conclusion Golidocitinib demonstrated its promising potential as a novel targeted therapy for the treatment of PTCL. Clinical activity was observed across different subtypes. No apparent correlation between mutations in JAK/STAT pathway and clinical response was observed while baseline high pSTAT level seems to predict clinical benefit. Larger sample size is needed to confirm the findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase II trial of gemcitabine and nab-paclitaxel for recurrent osteosarcoma: A report from the National Pediatric Cancer Foundation.

10042 Background: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. A retrospective study of 35 such patients has reported an objective response rate of 17% and 4-month progression-free survival (PFS) of 56% with this combination (BMC Cancer 2016;16:280). Nab-paclitaxel is a nanoparticle taxane that has activity against osteosarcoma xenografts and may have less myelosuppression than docetaxel. The combination of gemcitabine and nab-paclitaxel is now frontline therapy for pancreatic cancer. We conducted a prospective multi-institutional phase II trial of this drug combination for patients with recurrent osteosarcoma. Methods: Patients with relapsed/refractory osteosarcoma with measurable disease and age ≥ 12 years and adequate organ function were included. A Simon’s two-stage design was used to identify a 4-month progression-free survival (PFS) of &gt; 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 weekly x 3 in 4-week cycles. Results: Eighteen patients with a median age 16 years (range 12- 26) received a total of 56 total cycles.(median 2, range 1 - 12). The median number of prior treatment regimens was 3 (range 1-7). Two patients (11%) experienced a partial response, and 6 (33%) received more than 2 cycles. The 4-month PFS was 30% (95% CI 14-62 %). Six patients required dose reductions for neutropenia (n = 4), pleural effusion (1), or neuropathy (1). Two patients were removed from study secondary to neutropenia despite dose reduction and myeloid growth factor support, and one patient came off study due to severe peripheral edema. Conclusions: In this prospective study, the combination of gemcitabine and nab-paclitaxel administered on this schedule showed only limited activity for patients with heavily pretreated recurrent osteosarcoma. Toxicity led to dose modifications in 33% and discontinuation in 17% of patients. When compared to a historical retrospective study, the substitution of nab-paclitaxel for docetaxel did not appear to increase activity or decrease toxicity for this patient population. Clinical trial information: NCT02945800.

Interim safety and efficacy results from a phase 1 study of NT219 in adults with advanced solid tumors.

3096 Background: NT219 is a small molecule, effecting IRS1/2 degradation and inhibiting STAT3 phosphorylation. IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, altered during epithelial to mesenchymal transition (EMT) and drug resistance, and play an important role in the tumor and its microenvironment. A Phase 1/2 study (NCT04474470) includes a dose escalation of NT219 administered weekly for the treatment of relapsed and/or refractory cancer patients. Methods: In the dose escalation part of the study involving a conventional 3+3 design, patients with recurrent and/or metastatic solid tumors were administered intravenously with NT219 at 3, 6, 12 and 24mg/kg. Safety was assessed according to CTCAE v5 and anti-tumor activity was assessed by the investigators according to RECISTv1.1 using CT/MRI. The primary objectives of this part of the study are to evaluate safety, tolerability, PK and determine the recommended Phase 2 dose (RP2D). The study includes evaluation of potential biomarkers including measurements of STAT3, IRS1/2 phosphorylation, and TILs in biopsy specimens. Results: As of data cutoff date of February 8, 2022, a total of 13 patients were enrolled to 4 NT219 dose levels (3 - 24mg/kg) in the dose escalation phase, of which 11 were evaluable for dose limiting toxicity (DLT) determination, including 4 with colorectal cancer (CRC), 2 with pancreatic cancer, 2 with breast cancer, and one of each of the following cancers: gastroesophageal junction (GEJ), esophageal, appendiceal, papillary thyroid, and mesothelioma. Median number of prior treatment regimens for metastatic disease was 4 (2-11). Six Grade 3 adverse events (AEs) were observed, including alkaline phosphatase increase, aspartate aminotransferase increase, toxic encephalopathy, worsening back pain, abdominopelvic ascites, closed displaced fracture of right femoral neck, with the first 2 considered as possibly related to NT219. No Grade 4 AEs or treatment related deaths were reported. For the 11 evaluable patients, best overall response included one confirmed PR (GEJ patient, 5.5 months duration of response), and 3 SD (3 of 4 CRC patients; duration of 5.2, 4, and 2 months with ongoing follow up) with two patients awaiting follow up MRI/CT scans. As of the cutoff date, 9/11 patients that completed the DLT period are either on treatment or in follow up (range 1.1 to 14.7 months). Conclusions: Interim analysis of safety results obtained in 4 NT219 dose levels found NT219 to be well tolerated without DLTs in advanced cancer patients. The observed durable PR in a GEJ patient and SDs in 3 CRC patients are an encouraging initial signal of efficacy. Combination treatment of cetuximab with escalating NT219 doses in patients with recurrent/metastatic CRC and squamous cell carcinoma of the head and neck (SCCHN) has begun. An expansion cohort in patients with recurrent/metastatic SCCHN will be initiated at the conclusion of this part. Clinical trial information: NCT04474470.

Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide.

Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts.

Coastal: A Phase 3 Study of the PI3Kδ Inhibitor Zandelisib with Rituximab (R) Versus Immunochemotherapy in Patients with Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

Coastal: A Phase 3 Study of the PI3Kδ Inhibitor Zandelisib with Rituximab (R) Versus Immunochemotherapy in Patients with Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

Updated Results from a Phase Ib Study of Isatuximab Plus Pomalidomide (Pom) and Dexamethasone (dex) in Relapsed/Refractory Multiple Myeloma (RRMM)

Updated Results from a Phase Ib Study of Isatuximab Plus Pomalidomide (Pom) and Dexamethasone (dex) in Relapsed/Refractory Multiple Myeloma (RRMM)

Initial Results of KD025-208: A Phase 2a Open Label Trial of KD025 for Steroid-Dependent Chronic Graft Versus Host Disease

Introduction: cGVHD occurs in approximately 50% of patients undergoing allogeneic hematopoietic stem cell transplantation and it remains a leading cause of post-transplant morbidity and mortality. cGVHD typically exhibits features of both autoimmune and fibrotic diseases and can affect single or multiple organ systems. Corticosteroids are the primary treatment modality and while not uniformly effective, often cause additional adverse effects in patients with prolonged use. Despite major advances in the understanding of cGVHD biology, no targeted therapy has been approved for cGVHD. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor currently in Phase 2 clinical development for autoimmune and fibrotic indications. KD025 has been shown to downregulate pro-inflammatory T helper 17 cells and T follicular helper cells while upregulating anti-inflammatory regulatory T cells, which may potentially correct the immunological imbalance seen in cGVHD.Methods: Seventeen adult patients were enrolled in KD025-208, a Phase 2a, open-label study. Enrollment is planned for three cohorts (200 mg QD, 200 mg BID, and 400 mg QD) of 16 steroid-dependent cGVHD patients per cohort. The primary activity endpoint is the percentage of patients who meet the NIH Consensus Conference-defined overall response criteria (Partial Response (PR) + Complete Response (CR)) at 24 weeks. Secondary efficacy endpoints include changes in corticosteroid and calcineurin inhibitor dose and changes in cGVHD severity using the Physician-Reported Global cGVHD Activity Assessment. Exploratory endpoints include changes in symptom burden/bother using the Lee cGVHD Symptom Scale.Results: Seventeen patients with a median age of 50 years, median time from transplant to cGVHD diagnosis of 9.1 months, median time from initial cGVHD diagnosis to KD025 treatment initiation of 25.9 months, and median number of prior treatment regimens of three were enrolled in the 200 mg QD cohort. KD025 demonstrated an overall response rate (PR or CR at any evaluation time point) of 71% (12/17). Three patients discontinued KD025 treatment prior to 24 weeks (one cancer relapse, one cGVHD progression, and one adverse event of headache). Each of the three discontinued patients had demonstrated responses (PR) prior to study discontinuation. Fourteen of 17 (82%) patients remained on treatment at 24 weeks. At week 24, KD025 demonstrated clinical responses (CR or PR) in 57% (8/14) of the remaining evaluable patients. In addition to the eight responders, four patients had stable disease (SD) at 24 weeks; therefore, CR, PR or SD occurred in 86% (12/14) of patients. Importantly, of patients remaining on treatment at 24 weeks, 57% (8/14) had a reduction in steroid dose and 67% (4/6) had a reduction in tacrolimus dose. Moreover, 57% (8/14) of patients had a reduction in symptoms as measured by the Lee cGVHD Symptom Scale score. Patients with PR or SD were permitted to remain on KD025 for an additional 24 weeks. Eleven of 14 patients elected to remain on KD025 treatment after 24 weeks. Two patients were discontinued due to lack of response at 24 weeks and one patient with stable cGVHD was discontinued due to an unrelated adverse event of nephrotic syndrome.In addition, KD025 demonstrated an overall clinical benefit rate (PR or CR at any evaluation time point or SD at 24 weeks) of 88% (15/17) in all cGVHD patients.No treatment-related serious adverse events (SAEs) have been reported and no definitive treatment-related elevations in liver function tests (LFTs) (ALT, AST, ALP, and Bili) have been observed. Elevations in LFTs were commonly observed prior to KD025 dosing and may be attributable to cGVHD liver involvement. KD025 has been well tolerated and the overall adverse event profile appears consistent with cGVHD. Other low-grade treatment emergent adverse events seen in three or more patients were anemia (24%), diarrhea (24%), and nausea (24%).Conclusions: Treatment of cGVHD with KD025 demonstrated encouraging clinical responses and a favorable safety profile in patients with steroid-dependent cGVHD when administered at 200 mg QD. Eight of 14 patients (57%) demonstrated a 2014 NIH Consensus Conference-defined PR. No drug-related SAEs were reported. Enrollment in the dose-escalating cohorts is ongoing. DisclosuresLee:Kadmon: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Mallinckrodt: Honoraria. Salhotra:Kadmon: Consultancy. Jagasia:Mallinckrodt: Consultancy; Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding. Schueller:Kadmon: Employment, Equity Ownership.

EPCT-01. A NOVEL PEPTIDE VACCINE DIRECTED TO CMV PP65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL

IntroductionThe cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma. MethodsVaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly. ResultsTo date, 22 patients have been enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=12), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=3), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 45% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 1.7,4.5) and median OS is 6.5 months (95% CI 3.3, 7.9). Immune response to pp65 as determined by ELISpot was found in 75% of patients. On MRI 6 of the 11 evaluable patients have had at least stable disease with three of those having a partial response. ConclusionsPreliminary results demonstrate that PEP-CMV is well-tolerated and elicits an immune response in heavily pretreated, multiply recurrent patients. A multi-institutional Phase II trial is scheduled to open fall 2021.

Coastal: A phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL).

TPS7573 Background: Patients (pts) with iNHL treated with front-line immunochemotherapy may benefit from an alternative, chemotherapy-free regimen at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3Kδ inhibitor, achieved an 87% response rate, with median duration of response not reached in iNHL when given as a monotherapy or in combination with R. A low rate ( &lt; 10%) of Grade ≥ 3 immune-mediated adverse events of special interest associated with PI3kδ inhibitors is observed in patients administered zandelisib on an intermittent schedule (IS) (JCO 2020 38:15_suppl, 8016). An open-label, phase 2 study (TIDAL, NCT03768505) of zandelisib as monotherapy is ongoing in pts with relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: The COASTAL study is a randomized, open-label, controlled multicenter phase 3 trial to investigate the safety and efficacy of zandelisib in combination with R versus standard immunochemotherapy in pts with iNHL. Key eligibility criteria: adults with relapsed or refractory FL or MZL who received ≥1 prior lines of therapy which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide (L); at least one bi-dimensionally measured lesion &gt; 1.5 cm; adequate bone marrow, renal and hepatic function; ECOG performance status score of 0 to 1. Key exclusion criteria: histologically confirmed diagnosis of FL grade 3b or transformed disease; administration of 2 prior immunochemotherapy regimens; prior PI3K inhibitor therapy; known lymphomatous involvement of the central nervous system. Subjects will be randomized 1:1 to receive R-zandelisib or immunochemotherapy (R-CHOP or R-B) and stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy. Zandelisib will be given in a 28-day cycle comprising of daily dosing for 2 cycles followed by IS dosing on days 1-7 of each 28-day subsequent cycle for a duration of 2 years. Rituximab or immunochemotherapy will be given for a total of 6 cycles. Disease response will be assessed by an Independent Response Review Committee according to the modified Lugano Classification. Radiographic tumor assessment will be performed approximately every 12 weeks for the first 9 months, every 16 weeks for the next 12 months, and every 24 weeks thereafter. The primary efficacy endpoint is progression-free survival. The major secondary endpoints include ORR, complete response rate, overall survival, and safety. The trial will enroll approximately 534 pts in ̃200 sites globally and will begin enrollment in mid-2021. Clinical trial information: NCT04745832.

Outcome of patients with recurrent/refractory osteosarcoma enrolled in three recent phase II trials: A report from the Children’s Oncology Group.

11530 Background: Based on seven prior Phase 2 Children’s Oncology Group (COG) trials, the 4-month event-free survival(EFS) and associated confidence interval for relapsed osteosarcoma with measurable disease according to RECIST was determined to be 12% (95% CI 6 - 19%). Three prospective clinical trials were conducted using this historical benchmark to detect activity defined by an EFS improvement of double the upper confidence interval. This report summarizes the outcome of these studies, describes whether the historical data remains an accurate baseline, and considers implications for future phase II trial study design in relapsed osteosarcoma measurable according to RECIST. Methods: We conducted an analysis of outcome for patients with recurrent/refractory osteosarcoma enrolled in three recent prospective COG phase II trials; AOST1321 (unresected cohort), AOST1322 and AOST1521 that used EFS at 4 months as the primary endpoint. Patients were eligible if they had osteosarcoma that had recurred or become refractory after standard therapy and had measurable disease according to RECIST. We assessed whether risk of an EFS event is modified by age, sex, race/ethnicity, number of prior chemotherapy regimens, or time to first relapse. Results: In each of the three phase II trials (unresected group of AOST1321, AOST1322, AOST1521), the drugs tested (denosumab, eribulin and glembatumumab) were concluded to be not effective due to a failure of the patient populations to meet the prespecified active 4-month progression free survival endpoint. The 4-month EFS for the 57 evaluable patients enrolled on these trials was 7% (95% CI 2 – 16%), similar to the 4-month EFS for 96 patients in the previous seven phase II trials of 12% (95% CI 6 - 19%). The combined EFS at 4 months for all 10 studies is 10% (95% CI 6 – 15%).There was no significant difference in EFS across trials based on age, sex, ethnicity, number of prior treatment regimens, consistent with prior analysis. Data from AOST1321 and AOST1521 were analyzed to determine the impact of time to first recurrence on EFS. Two different quantifications were applied: 1 year or less versus 2 or more years; and 2 years or less versus 3 years or more. Neither categorization was statistically significant. Conclusions: The EFS at 4 months in the three new phase II trials is similar to the previous seven phase II single arm trials. The combined analysis of 153 patients from 10 trials tightens the confidence interval, moving the upper 95% CI to 15%. Modification to future study designs could be considered based on this updated analysis. EFS at 4 months remains a robust primary endpoint. Single-arm trials using this endpoint based on the historical benchmark have accrued rapidly and allowed assessment of multiple novel agents in osteosarcoma. The negative trial results and continued poor outcome highlight the need for new approaches for relapsed osteosarcoma. Clinical trial information: NCT02097238, NCT02470091, NCT02487979.

CTIM-21. PEPTIDE VACCINE DIRECTED TO CMV pp65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL

INTRODUCTIONThe cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma.METHODSVaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly.RESULTSTo date, 17 patients have been enrolled. Diagnoses include medulloblastoma (n=1), glioblastoma (n=9), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=2), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 41% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 0.8, not estimable) and median OS is 6.5 months (95% CI 1.8, not estimable). Interim analysis of immune monitoring bloodwork and perfusion MRI to quantify responses to PEP-CMV has been delayed due to COVID-19. However, adults with GBM who received PEP-CMV (NCT02864368) had significant (p≤0.05) increases in GCSF, GM-CSF, IFN-γ, IL-10, IL-2, IL-8, MIP1-α, and TNF-α levels.CONCLUSIONSPreliminary results demonstrate that PEP-CMV is feasible and well-tolerated in heavily pretreated, multiply recurrent patients.

Haploidentical Mbil-21 Ex Vivo Expanded NK Cells (FC21-NK) for Patients with Multiple Relapsed and Refractory Acute Myeloid Leukemia

Haploidentical Mbil-21 Ex Vivo Expanded NK Cells (FC21-NK) for Patients with Multiple Relapsed and Refractory Acute Myeloid Leukemia

Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma.

Pediatric low-grade gliomas (pLGGs) are the most common CNS tumor of childhood and comprise a heterogenous group of tumors. Children with progressive pLGG often require numerous treatment modalities including surgery, chemotherapy, rarely radiation therapy and, more recently, molecularly targeted therapy. We describe our institutional experience using the MEK inhibitor, trametinib, for recurrent/progressive pLGGs. We performed a retrospective, IRB-approved, chart review of all pediatric patients treated with trametinib for recurrent/progressive pLGGs at Dana-Farber/Boston Children's Cancer and Blood Disorder Center between 2016 and 2018. Eleven patients were identified, of which 10 were evaluable for response. Median age at commencement of trametinib treatment was 14.7years (range 7.3-25.9years). Tumor molecular status included KIAA1549-BRAF fusion(n = 4), NF1 mutation(n = 4), FGFR mutation(n = 1) and CDKN2A loss (n = 1). Median number of prior treatment regimens was 5 (range 1-12). Median duration of treatment with trametinib was 19.2months (range 3.8-29.8months). Based on modified RANO criteria, best responses included partial (n = 2), minor response (n = 2) and stable disease (n = 6). Two patients remain on therapy (29.8 and 25.9months, respectively). The most common toxicities attributable to trametinib were rash, fatigue and gastrointestinal disturbance. Five patients required dose reduction for toxicities. Two patients experienced significant intracranial hemorrhage (ICH) while on trametinib. While it is unclear whether ICH was directly attributable to trametinib, therapy was discontinued. Trametinib appears to be an effective treatment for patients with recurrent/progressive pLGG. The toxicities of this therapy warrant further investigation, with particular attention to the potential risk for intracranial hemorrhage. Early phase multi-institutional clinical trials are underway.

A phase I, open-label, multicenter study to assess the safety, pharmacokinetics, and preliminary antitumor activity of AZD4635 both as monotherapy and in combination in patients with advanced solid malignancies: Results from prostate cancer patients (NCT02740985).

5518 Background: AZD4635 inhibits adenosine 2a receptor (A2aR) signaling and improves immune activation and anti-tumor activity in preclinical models. This phase I study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of AZD4635 monotherapy (mono) and in combination (combo) with durvalumab (durva) in patients (pts) with refractory solid tumors. Here we present data for immune checkpoint-naïve pts with metastatic castrate-resistant prostate cancer (mCRPC). Methods: Pts with refractory mCRPC received AZD4635 mono (75 mg or 100 mg QD oral nanosuspension [(RP2D]) or in combination (75 mg or 100mg QD) with durva 1.5g IV q4wk. Results: Between 30Aug16 and 20Jun19 (data cutoff [DCO]) 94 mCRPC pts were treated with mono (n = 49) or combo (n = 45): median age 70.5 yrs; ECOG 0-1 = 99%. The median number of prior treatment regimens was 5 (range = 1-10); 61% of pts (57/94) had prior chemotherapy, 90% had prior new hormonal therapy. PK data suggest AZD4635 concentrations at 75-100 mg QD are above the in vitro IC50 for A2aR inhibition throughout the dosing interval. Modeling predicts 80-90% A2aR occupancy at steady state for doses at ≥75 mg QD. Most common treatment-related AEs ( &gt; 10%) were nausea, vomiting, fatigue, decreased appetite, dizziness, and diarrhea. At the DCO in this ongoing study, 70 pts were evaluable for response by RECIST v1.1 (mono = 33, combo = 37). Confirmed response occurred in 8 pts: mono = ORR 6.1% (2PRs) and combo = 16.2% (2CRs, 4PRs). The duration of response across cohorts ranged from 1-18.5 mo (5 pts ongoing). PSA response (defined as ≥50% decrease from baseline of ≥1ng/ml) was observed in 6.4% (3/47 pts; 95% CI, 1.3-17.5) of mono-treated patients and 20% (9/45 pts; 95% CI, 9.6-34.6) of combo-treated patients. Patients with high adenosine (ADO) gene expression signature (N = 46) in peripheral blood, showed a median PFS of 21 weeks v. 8.7 weeks in ADO signature low patients (N = 46) (HR 0.5, CI 0.3-0.9) (DCO 20Jun19). In addition, baseline TCR clonality and diversity were linked with response. Conclusions: In mCRPC pts, AZD4635 alone or in combination with durva was tolerable and associated with clinical benefit. A mCRPC phase II trial is ongoing with continued exploration of predictors of response to treatment. Clinical trial information: NCT02740985 .

Phase III trial of sitravatinib plus nivolumab vs. docetaxel for treatment of NSCLC after platinum-based chemotherapy and immunotherapy (SAPPHIRE).

TPS9635 Background: Sitravatinib is an oral spectrum-selective tyrosine kinase inhibitor that targets the TAM (TYRO3/AXL/MERTK) and split (VEGFR2/KIT) family receptor tyrosine kinases (RTKs), as well as MET. Inhibition of TAM RTKs may promote the depletion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) and repolarize tumor associated macrophages towards the pro-inflammatory M1 phenotype. Inhibition of the split RTKs may reduce immunosuppressive regulatory T cells in addition to MDSCs within the TME. Given these pleiotropic immune-stimulating effects, sitravatinib may reverse resistance to checkpoint inhibitor therapy (CIT) and augment the antitumor immune response of nivolumab in patients (pts) with non-small cell lung cancer (NSCLC). An ongoing Phase 2 study (MRTX-500) demonstrates clinical activity of this combination in pts with metastatic non-squamous NSCLC after progression on or after CIT. Methods: Global, randomized, open-label, Phase 3 study of sitravatinib in combination with nivolumab vs docetaxel in pts with advanced non-squamous NSCLC who have progressed on or after CIT. Pts must have also received platinum-based chemotherapy either in combination with CIT or prior to CIT. Pts are randomized (1:1) to receive oral sitravatinib 120 mg once daily in continuous 28-day cycles combined with nivolumab IV 240 mg every 2 weeks or 480 mg every 4 weeks vs treatment with docetaxel 75 mg/m2 IV every 3 weeks. Patients are stratified based on number of prior treatment regimens in the advanced setting, ECOG performance status, and presence of brain metastases. Key eligibility criteria include duration of treatment of CIT of at least 4 months, discontinuation of prior treatment with CIT &lt; 90 days prior to the date of randomization, and absence of symptomatic or uncontrolled brain metastases. The primary endpoint is overall survival (OS). Key secondary endpoints include safety and tolerability, ORR, PFS, PROs, and PK. OS will be analyzed using Kaplan-Meier methods and the stratified log-rank test to estimate and compare the median OS between the two treatment arms with 95% CI. An IDMC will review safety at regular intervals and efficacy at a planned interim analysis based on OS. Enrollment is ongoing. Clinical trial information: NCT03906071 .

Selinexor, daratumumab, and dexamethasone in patients with relapsed/refractory multiple myeloma (MM).

8510 Background: Selinexor is a first-in-class oral Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates exportin 1 (XPO1). Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with relapsed/refractory MM (RRMM). Single agent daratumumab has demonstrated an ORR of 29% in MM reftactory to proteasome inhibitors (PIs)/immunomodulatory drug (IMiDs). We evaluated the safety, tolerability and preliminary efficacy of the combination of Sel-dex and daratumumab (SDd) in pts with MM refractory to PIs/IMiDs. Methods: This is a multicenter, open-label, phase 1b/2 dose escalation and expansion study. Pts were eligible if they had received ≥ 3 prior lines of therapy, including a PI and an IMiD, or whose MM was refractory to a PI and an IMiD. In the expansion phase, pts were required to be anti-CD38 monoclonal antibody-naïve. One dose level was tested at each schedule: selinexor once-weekly (QW at 100 mg) or twice-weekly (BIW at 60 mg) with dexamethasone 40 mg. Daratumumab 16 mg/kg IV was administered per label. Primary objective was to determine the maximum tolerated dose and recommended phase 2 dose (RP2D), and assess safety, tolerability and efficacy of SDd in pts with RRMM. Results: A total of 34 pts were enrolled; 3 in the 60 mg BIW and 31 in the 100 mg QW cohorts. Median age was 69 and median number of prior treatment regimens was 3 (range, 1–10). Out of 34 pts, 62% and 65% were refractory to bortezomib and lenalidomide respectively. Common treatment related adverse events (all grades, grades 3/4) included: thrombocytopenia (71%, 47%), fatigue (62%, 18%), nausea (71%, 9%), anemia (62%, 32%) and neutropenia (50%, 26%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: Grade 3 thrombocytopenia and Grade 2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort (n = 6), no DLTs occured. 32 patients were evaluable for efficacy. The ORR was 73% (11 VGPR, 11 PR) for 30 daratumumab-naïve pts. Median progression-free survival was 12.5 months in both groups. Conclusions: Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dexamethasone 40 mg, administered QW. In pts with PI and IMiD refractory MM, weekly SDd demonstrated promising activity with an ORR of 73% in daratumumab-naïve pts and a median PFS of 12.5 months. This supports further development of a novel non-PI, non-IMiD backbone in earlier lines of therapy. Clinical trial information: NCT02343042 .

DCEP and bendamustine/prednisone as salvage therapy for quad- and penta-refractory multiple myeloma.

Multiple myeloma (MM) almost invariably progresses through novel therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (additional refractoriness to daratumumab) have few treatment options. Two chemotherapy regimens, bendamustine/prednisone (BP) and dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP), are often used in quad- and penta-refractory MM, but there are limited data on outcomes in this heavily pre-treated population. We conducted a single-center retrospective study to identify all patients who received DCEP and/or BP for quad- or penta-refractory MM. Disease response and refractoriness were defined by International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). We identified 27 patients who received BP for quad- or penta-refractory MM. The median number of prior lines of therapy was 6. The ORR for BP was 26%. The median PFS for BP was 1.4months (95% CI 1.1-1.6) and median OS was 8.7months (95% CI 2.3-15.0). Patients treated with cyclophosphamide had less response to BP. Thirty-one patients received DCEP for quad-refractory or penta-refractory MM. The median number of prior treatment regimens was 8. The ORR to DCEP was 35%. The median PFS was 2.7months (95% CI 1.5-3.8) and median OS was 6.2months (95% CI 4.4-7.8). DCEP and BP retain efficacy in quad- and penta-refractory MM. Our analysis supports prospective study of these regimens, possibly in combination or in comparison with other agents in this area of unmet need.

Abstract GS1-03: [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01)

Abstract Background [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a HER2 antibody, peptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. In a phase 1 trial, the objective response rate (ORR) was 59.5% (66/111) and median progression-free survival (PFS) was 22.1 mo in subjects with HER2-positive metastatic breast cancer (BC) previously treated with T-DM1 (Tamura, Lancet Oncol, 2019). DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 registration study of T-DXd in subjects with centrally confirmed HER2-positive metastatic BC. Methods Part 1 of this 2-part study was performed in 2 stages (pharmacokinetics and dose finding; T-DXd 5.4, 6.4, 7.4 mg/kg) and served to identify the recommended Part 2 dose (RP2D). In Part 2, subjects were treated at the RP2D. Subjects in Parts 1 and 2a were required to have metastatic BC that progressed on or after T-DM1. Subjects in a small additional cohort (Part 2b) had discontinued T-DM1 for reasons other than progression. The primary endpoint was ORR (complete response [CR] + partial response [PR]) per independent central review (ICR). Additional endpoints included disease control rate (DCR; CR + PR + stable disease [SD]), duration of response (DOR), and PFS. Abstract results represent 6 mo of follow-up from the date the last subject enrolled in the study. Results As of data cutoff (March 21, 2019), 253 subjects were enrolled and 184 received the RP2D (5.4 mg/kg), 4 of which were enrolled in Part 2b. All subjects were female, 55% were white, and 38% were Asian. Median age was 55 y (range, 28-96 y; ≥ 65 y, 24%); 53% were hormone receptor (HR) positive and 45% were HR negative. Median number of prior treatment regimens was 6 (range, 2-27), including trastuzumab (100%), T-DM1 (100%), pertuzumab (66%), and other HER2-targeted regimens (54%). The reported best response to T-DM1 before enrollment was 22% CR or PR, 21% SD, and 36% progressive disease (PD); 21% were not evaluable. At data cutoff, 60% of subjects remained on T-DXd treatment; primary reasons for discontinuation were PD (21%) and treatment-related adverse events (TEAEs, 8%). The confirmed ORR by ICR in subjects treated at the RP2D in Parts 1, 2a, and 2b was 60% (111/184 [95% CI, 53%-68%]). ORRs were consistent across subgroups, including those with prior pertuzumab (64%) and those with ≥ 3 prior regimens (59%). The DCR was 97% (95% CI, 94%-99%); only 5 of 184 subjects did not have SD or better at the time of first post-baseline scan. As of the data cutoff, median DOR and PFS had not been reached; median duration of follow up was 7.2 mo (range, 0.7-17.2 mo). In the 184 subjects, the median treatment duration was 6.9 mo (range, 0.7-16 mo); 70% had &amp;gt; 6 mo of treatment. TEAEs occurred in 99% of subjects (grade ≥ 3, 51%); the most common any-grade TEAEs were gastrointestinal (nausea [77%], vomiting [45%], constipation [34%], decreased appetite [29%], and diarrhea [27%]), alopecia (48%), fatigue (48%), and hematologic (decreased neutrophil count [31%] and anemia [26%]). Most common grade ≥ 3 AEs were decreased neutrophil count (17%), nausea (7.6%), anemia (6.5%), decreased lymphocyte count (5.4%), and fatigue (5.4%). 15 subjects (8.2%) had interstitial lung disease (ILD) adjudicated as ILD related to T-DXd by an independent adjudication committee; ILD was primarily grade 1 or 2 (6.0%; no grade 3 or 4; 2.2% grade 5). [Additional follow up and first DOR/PFS data will be presented at the meeting.] Conclusion Overall, T-DXd treatment demonstrated clinically meaningful and durable activity in a heavily pretreated patient population with HER2-positive metastatic BC. T-DXd had a generally manageable safety profile, with ILD identified as a risk warranting proactive awareness and management. Citation Format: Ian E Krop, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice André, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Shanu Modi. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-03.