Best Response Of Stable Disease Research Articles

A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma

BackgroundN-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR–MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity.ResultsThirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1–20). Grade 3–4 adverse events (AEs) were reported in seven (54%; 95% CI 25–81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0–36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29–539) days and 33 (95% CI 9.7– > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39–91%). PK analysis demonstrated proportional dose–concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months.ConclusionsNMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR–MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.

CTIM-35. A PHASE II STUDY OF GITR AGONIST INCAGN01876 AND PD-1 INHIBITOR RETIFANLIMAB IN COMBINATION WITH STEREOTACTIC RADIOTHERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract BACKGROUND We evaluated the combination of retifanlimab, INCAGN01876, and FSRT in patients with recurrent GBM. METHODS Phase II, single-center, 2 cohort study (A: single-arm non-surgical cohort; B, two-arm neoadjuvant/surgical cohort). Cohort A patients received pre-FSRT one-time doses of retifanlimab (500mg) and INCAGN01876 (300mg), FSRT (8 Gy x 3 fractions), and post-FSRT 28-day treatment cycles (retifanlimab, day 1; INCAGN01876, days 1, 15). Cohort B patients received pre-surgery doses of retifanlimab + INCAGN01876; subsequently, patients either went directly to resection (Sub-Arm 1) or to FSRT followed by resection (Sub-Arm 2). All patients resumed immunotherapy post-operatively. Primary endpoint: ORR in Cohort A. Data cut-off for this analysis was June 30, 2022. RESULTS Thirty-two evaluable patients: Cohort A, n=16; Cohort B, n=16 (Sub-Arm 1, n=8, Sub-Arm 2, n=8). Median follow-up time: Cohort A, 13.6 months; Cohort B, 8.8 months. Forty-four percent women, median age 64 (IQR, 55–65), 56% MGMT unmethylated. Most common grade 3/4 treatment-related AEs included cerebral edema (25%), lymphopenia (16%), and cognitive disturbance (13%). Efficacy in Cohort A: no objective responses observed, best response of stable disease achieved in 9/16 patients (56%), median PFS 3.9 months (95% CI 2.1 – 6.2 months), median OS 9.8 months (95% CI 8.3 months – not reached [NR]). Efficacy in Cohort B: median PFS NR, median OS 15.1 months (95% CI 8.5 months – NR). Median PFS and OS are longer in Cohort B Sub-Arm 2 compared to Cohort B Sub-Arm 1 (PFS, NR vs. 2.2 months, p = 0.009; OS, NR vs. 8.5 months, p=0.026). Results of tissue and blood-based immune correlative analyses will be presented. CONCLUSIONS The combination of retifanlimab, INCAGN01876, and FSRT is generally well-tolerated in patients with recurrent GBM when administered with or without surgical resection. Survival outcomes in the neoadjuvant cohort are encouraging, largely driven by patients that received neoadjuvant FSRT.

Intermittent MEK inhibition for the treatment of metastatic uveal melanoma.

IntroductionUveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity.MethodsWe conducted a phase Ib trial of selumetinib using an intermittent dosing schedule in patients with metastatic UM. The primary objective was to estimate the maximum tolerated dose (MTD) and assess safety and tolerability. Secondary objectives included assessment of the overall response rate (RR), progression-free survival (PFS) and overall survival (OS). Tumor biopsies were collected at baseline, on day 3 (on treatment), and between days 11-14 (off treatment) from 9 patients for pharmacodynamic (PD) assessments.Results29 patients were enrolled and received at least one dose of selumetinib across 4 dose levels (DL; DL1: 100 mg BID; DL2: 125 mg BID; DL3: 150 mg BID; DL4: 175 mg BID). All patients experienced a treatment-related adverse event (TRAE), with 5/29 (17%) developing a grade 3 or higher TRAE. Five dose limiting toxicities (DLT) were observed: 2/20 in DL2, 2/5 in DL3, 1/1 in DL4. The estimated MTD was 150 mg BID (DL3), with an estimated probability of toxicity of 29% (90% probability interval 16%-44%). No responses were observed; 11/29 patients achieved a best response of stable disease (SD). The median PFS and OS were 1.8 months (95% CI 1.7, 4.5) and 7.1 months (95% CI 5.3, 11.5). PD analysis demonstrated at least partial pathway inhibition in all samples at day 3, with reactivation between days 11-14 in 7 of those cases.ConclusionsWe identified 150 mg BID as the MTD of intermittent selumetinib, representing a 100% increase over the continuous dose MTD (75 mg BID). However, no significant clinical efficacy was observed using this dosing schedule.

Abstract CT168: Randomized phase 2 trial of sunitinib or cediranib in alveolar soft part sarcoma

Abstract Background: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few effective treatment options. Cediranib (C) and sunitinib (S) are potent oral inhibitors of all 3 VEGF receptors. Cediranib showed substantial single-agent activity (objective response rate [ORR] = 35%) in our previous trial in patients (pts) with metastatic ASPS (NCT00942877). Here we report a phase 2 randomized multicenter trial of single agent C or S in pts with ASPS (NCT01391962). Methods: We conducted a multicenter phase 2 trial with an optimal 2-stage design targeting an ORR of 40%. Enrolled pts were >16 years with metastatic ASPS, previously not treated (N) and unresectable, or previously treated (T), who have progressed per RECIST 1 within the 6-month period preceding enrollment. Pts were randomized to receive C (30 mg) or S (37.5 mg) orally, once a day, in 28-day cycles and could crossover to the other treatment arm at disease progression. ORR (primary endpoint), median progression-free survival (mPFS), and PFS rate at 24 weeks for the 2 arms (C and S) were evaluated; T and N cohorts were assessed separately in each arm. Arm accrual closed if ≤ 1 of the first 10 enrolled pts responded to the first treatment. Results: Thirty-four pts (47% white, 29.4% black, 17.6% Asian, 5.8% Pacific Islander) were enrolled; 29 pts were evaluable for response. One pt on each of the initial treatment arms had a confirmed partial response (PR), rates of 6.7% (1/154) and 7.1% (1/14) for C and S tx or tx-naive, respectively. Among pts who crossed over, there was 1 PR in a pt receiving C after initially responding (PR) on S (1/9; ORR 11.1%). Twenty-four pts had a best response of stable disease (86.7% and 78.6%) for C and S, respectively. The mPFS was 7.6 months (mo) (95% CI: 3.7-9.9 mo) and 5.5 mo (95% CI: 1.8-14.5 mo) for C and S, respectively administered as first therapy (p=0.92). PFS rate at 24 weeks was 62.5% (95% CI: 29.5-76.2%) and 50% (95% CI: 25.9-70.1%) for pts receiving C and S respectively, as initial therapy. There was no difference in mPFS between T or N pts in the C (6.7 mo [95% CI: 1.4-9.9 mo] vs 8.3 mo [95% CI: 2.7 - 16.6 mo]; P=0.35) arm, but some evidence of a potential difference in the S (4.8 mo [95% CI: 0.9-7.9 mo] vs 14.7 mo 95% CI: 1.8 - 21.6 mo]; P=0.058) arm. Overall, 43.7% (C) and 77.8% (S) of pts experienced grade ≥3 adverse events (AEs) at least possibly related to the study drug. Common grade ≥3 AEs included: diarrhea (C), neutropenia (S), hypertension (C and S). AEs were in line with the known safety profiles of each agent. As of August 2021, 1 pt (unevaluable for ORR) remains on study. Conclusions: The study did not meet its endpoints for ORR. There were no differences in mPFS for the 2 treatment arms. The selection of pts with more aggressive disease, who had progressed in the 6 months prior to enrollment, may account for the low patient response rates compared to our previous study of cediranib in ASPS. Funded by NCI Contract No. HHSN261200800001E. The study was a collaboration between NCI and Pfizer. Citation Format: Naoko Takebe, James Nguyen, Shivaani Kummar, Albiruni Abdul Razak, Sant P. Chawla, Suzanne George, Shreyaskumar R. Patel, Mary Louise Keohan, Sujana Movva, Geraldine O’Sullivan, Khanh Do, Larry Anderson, Lamin Juwara, Brooke Augustine, Seth Steinberg, Laura Kuhlmann, S. Percy Ivy, James H. Doroshow, Alice P. Chen. Randomized phase 2 trial of sunitinib or cediranib in alveolar soft part sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT168.

A phase 1 dose-escalation and -expansion study of IMP7068, a WEE1 inhibitor, in patients with advanced solid tumors.

e15052 Background: WEE1 kinase is a cell-cycle regulator that is important in DNA repair, and a validated antitumor target. IMP7068 is a potent and selective WEE1 inhibitor that has demonstrated antitumor activity in preclinical pharmacological models. A first-in-human, multicenter, open-label study was conducted to evaluate the safety, tolerability, pharmacokinetic (PK) characteristics, pharmacodynamic (PD) profiles and preliminary antitumor activity of IMP7068 in patients (pts) with advanced solid tumors. Methods: This phase 1 study included both a dose-escalation and dose-expansion stage. The dose-escalation stage was designed with 6 dose cohorts of IMP7068 at 30, 60, 120, 200, 300, and 400 mg (administered orally, once daily [QD] for 3 days, followed by 4 days off weekly for 21-day cycles). An accelerated titration design was used for the 30- and 60-mg dose levels, and an i3+3 design for all doses > 60 mg. Pts were adults (age ≥18 years) with confirmed advanced solid tumors that were refractory or intolerant to standard treatment, or for which no standard treatment exists. The objectives of the dose-escalation stage were to evaluate the safety and tolerability, PK and PD profiles, and antitumor activity (per RECIST v1.1) of IMP7068. Results: As of Jan 7, 2022, 9 pts were enrolled in the dose-escalation phase (average age, 56 years). An additional cohort of IMP7068 160 mg was recommended by the Safety Monitoring Committee based on PK data from the 120-mg cohort. Pts received escalating doses at 30 mg (n = 1), 60 mg (n = 1), 120 mg (n = 3), and 160 mg (n = 4). No dose-limiting toxicities (DLTs) were observed. Treatment-related adverse events (TRAEs) occurred in 4 pts, most frequently alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and diarrhea (all in 2 pts each). Most TRAEs were grade 1 or 2 in severity; and only 1 patient had grade 3 TRAEs (AST and ALT increased). Time to reach the maximum plasma concentration of IMP7068 was approximately 2–6 hours following administration of 30–160 mg doses, respectively. Following repeated QD administration for 3 days, the accumulation ratios for IMP7068 exposure parameters Cmax and AUC0-tau were 1.74–2.49 and 3.17–3.46, respectively, across the dose levels. The elimination half-life was approximately 10–28 hours after administration of 60–160 mg IMP7068. PD data showed that levels of phosphorylated cyclin-dependent kinase 1 decreased by ≥50% after treatment in the 160-mg cohort. Five of 8 evaluable pts had a best tumor response of stable disease (SD); 1 patient with colorectal cancer maintained a best response of SD for 22 weeks. Four pts remain on study. Conclusions: IMP7068 was well-tolerated with no DLTs, and conferred a meaningful PD effect and preliminary antitumor activity at doses of up to 160 mg in pts with advanced solid tumors. Dose escalation to establish the recommended phase 2 dose and/or maximum tolerated dose is continuing. Clinical trial information: NCT04768868.

A phase 1 study of TPST-1120 as a single agent and in combination with nivolumab in subjects with advanced solid tumors.

3005 Background: TPST-1120 is a first-in-class oral therapy that inhibits PPARα, a transcription factor that regulates fatty acid oxidation (FAO). TPST-1120 has diverse mechanisms of anti-tumor activity in preclinical studies, including inhibiting tumor proliferation, increasing the anti-angiogenic factor thrombospondin 1, and reducing T cell exhaustion. Methods: Subjects with advanced solid tumor malignancies received escalating doses of TPST-1120 as a single agent or in combination with nivolumab 480 mg IV every 4 weeks (combination cohort limited to RCC, cholangiocarcinoma [CCA] and HCC). Study objectives included evaluation of safety, pharmacokinetics, MTD, RP2D and anti-tumor activity as monotherapy and in combination with nivolumab. AEs were assessed per CTCAE v5 and efficacy per RECIST v1.1 Results: As of 14-Jan-2022, 35 subjects have been dosed (20 with TPST-1120 monotherapy at doses from 100 mg to 600 mg PO BID and 15 in combination with nivolumab at doses from 200 mg to 600 mg PO BID). Median prior lines of systemic therapy were 3 (2-11) in monotherapy and 2 (2-6) in combination cohorts. An MTD was not reached in monotherapy or combination, and the TPST-1120 RP2D was 600 mg PO BID for both cohorts. For TPST-1120 monotherapy, the most common treatment related AEs (TRAEs) were nausea (20%), fatigue (15%), and diarrhea (10%), all Grade 1-2. One monotherapy subject (5%) experienced a Grade 3 TRAE (hypertension). In the combination cohort the most common TRAEs related to either drug were fatigue (40%), diarrhea (27%) and nausea (20%), all Grade 1-2. Three combination subjects (19%) experienced Grade 3 TRAEs (one each arthralgia, hepatic enzyme increased, muscle spasms). A best response of stable disease was observed in 53% (10/19) of subjects treated with monotherapy. In combination, the ORR was 23% (3/13, all PRs) across all dose levels and 38% (3/8) at TPST-1120 dose levels ≥400 mg BID. These responses included 2 subjects with late-line RCC (2/2 RCC subjects enrolled, both with progression on prior anti-PD1 therapy) and one subject with heavily pre-treated CCA. At data cut off, 2 of 3 responding patients (CCA and one RCC) remained in PR and on study at 8.4 and 14 mo, respectively. Conclusions: TPST-1120 is a novel therapy designed to inhibit tumor proliferation and angiogenesis and stimulate anti-cancer immunity through inhibition of PPARα, a key regulator of FAO. The drug is well tolerated as a single agent and in combination with nivolumab. Promising objective responses have been observed in combination with nivolumab in subjects previously refractory to anti-PD-1 therapy, including 2/2 responders in late-line RCC, and a subject with heavily pretreated CCA, a tumor type generally not responsive to anti-PD-1 alone. Notably, all responders were treated at the two highest doses of TPST-1120 (ORR 38%). Updated study results including exploratory biomarkers will be presented. Clinical trial information: NCT03829436.

Safety, pharmacodynamic, and clinical response evaluation of nilotinib and paclitaxel in adults with refractory solid tumors.

3026 Background: The combination of the BCR-Abl kinase inhibitor nilotinib and the anti-tubulin agent paclitaxel was identified in the NCI-ALMANAC study to have greater-than-additive activity in the NCI-60 cell line panel and greater-than-single-agent antitumor activity in xenograft models, in which this combination induces tumor epithelial-mesenchymal transition (EMT). A phase 1 study was initiated to establish the safety, tolerability, and recommended phase 2 dose (RP2D) of this combination in patients (pts) with advanced solid tumors and to examine the pharmacokinetic (PK) and pharmacodynamic (PD) effects of the combination to understand the mechanism of action (NCT02379416). The dose escalation phase established the RP2D as 300 mg oral nilotinib twice daily and 80 mg/m2 intravenous paclitaxel on days (D) 1, 8, and 15 of each 28-day cycle. Here, we report the safety, preliminary PD, and efficacy data for this combination. Methods: Nilotinib and paclitaxel were administered as noted above, with a 1-day (escalation cohort) or 2-day (expansion cohort) paclitaxel-only run-in during the first cycle to enable comparison of the PK and PD effects of the combination vs. single-agent paclitaxel. Paired biopsies to assess tumor molecular response were collected from expansion cohort pts at baseline, cycle (C) 1 D2, and C1D28, with an optional biopsy at progression; accrual continued until ≥ 12 sufficient-quality paired biopsies were obtained. Blood specimens to assess molecular responses in circulating tumor cells (CTCs) were obtained at several timepoints during C1 and longitudinally every cycle thereafter. EMT biomarkers were measured in tumor and CTC specimens using quantitative immunofluorescence microscopy assays. Results: A total of 44 pts were enrolled. Three pts had partial responses (PR), and 1 had an unconfirmed PR (9%); 23 pts (52%) had a best response of stable disease (SD), including 7 pts on study for ≥ 10 cycles. The most common grade (Gr) 3-4 treatment-related adverse events were hematologic and hypophosphatemia. No pts experienced Gr ≥ 3 peripheral neuropathy. The median time on treatment was 67 days. Two pts with granulosa cell ovarian carcinoma had durable responses, completing 74+ and 64 cycles. Multiple patient biopsies and corresponding CTC specimens exhibited treatment-induced EMT. Longitudinal analysis of CTC EMT phenotypes in the 2 pts with extended PR revealed a substantial increase in mesenchymal-like CTCs prior to progression for the pt on study for 64 cycles; such increases were not observed in the pt still on study after 74+ cycles. Further PD analyses are ongoing. Conclusions: The combination of nilotinib and paclitaxel demonstrates promising disease control with durable response in select patients. Tumor PD analyses to discover the underlying pharmacology of this active regimen are ongoing. Funded by NCI Contract No. HHSN261201500003I. Clinical trial information: NCT02379416.

A phase I study to evaluate the safety, tolerability, and pharmacokinetics of MSB0254 in Chinese patients with solid tumors.

3023 Background: MSB0254 is a humanized vascular endothelial growth factor receptor 2 (VEGFR-2) monoclonal antibody. MSB0254 inhibits angiogenesis induced by either VEGF-A or –C. This trial is a phase I study to evaluate MSB0254’s safety, tolerability and PK profiles, as well as early anti-cancer activities in Chinese patients with advanced solid tumors. Methods: In this phase I study (NCT04381325), locally advanced or metastatic solid tumor patients failed previous standard treatments were enrolled. In the dose escalation phase, following 3+3 rules, MSB0254 was given intravenously Q2W (every 2 weeks) at 4mg/kg, 8mg/kg, 12mg/kg, 16mg/kg, and Q3W at 20mg/kg. In the dose expansion phase, patients with selected tumor types will be treated with MSB0254 at 16mg/kg Q2W or 20mg/kg Q3W. Primary objectives were to evaluate the safety and tolerability and to identify maximum tolerable dose (MTD) and/or Recommended Phase 2 Dose (RP2D). Secondary objectives included the assessment of pharmacokinetics, immunogenicity, and preliminary efficacy per RECIST1.1. Results: As of 10th Jan, 2022, a total of 22 Chinese patients have been enrolled into the dose escalation phase and treated with MSB0254 at different dose levels from 4-16mg/kg Q2W or 20mg/kg Q3W. MTD was not reached. One DLT was reported in 12mg/kg Q2W dose cohort. A subject with intra-cholangial carcinoma developed G3 (grade 3) upper gastrointestinal hemorrhage on the C1D13. The adverse event was resolved after symptomatic treatment. The most common treatment-emergent adverse events (TEAEs) (>10%) included: hypertension (27.3%), AST increased (27.3%), γ-GGT increased (22.7%), neutrophil count decreased (18.2%), proteinuria (18.2%), WBC count decreased (13.6%), platelet count decreased (13.6%) and anemia (13.6%). Three subjects (13.6%) experienced G3 TEAEs: 1 upper gastrointestinal hemorrhage, 1 anemia and 1 Hypertriglyceridemia. No G4/5 TEAE was observed. And three subjects (13.6%) experienced 3 SAEs: 1 upper gastrointestinal hemorrhage, 1 G2 intestinal obstruction caused hospitalization and 1 G2 fatigue caused hospitalization. MSB0254 displayed a dose proportional pharmacokinetic profile between 4-16 mg/kg Q2W with calculated T1/2 of 6-9 days. Eighteen subjects had at least one tumor assessment per RECIST 1.1 after MSB0254 treatment. Eleven subjects (61.1%) had best response of stable disease (SD). Four of them had stable disease for more than 6 months, including a neuroendocrine tumor (NET), a gastric cancer, an epithelioid hemangioendothelioma (EHE) and a submaxillary gland carcinoma patient. Conclusions: MSB0254 demonstrated a manageable safety profile and preliminary antitumor activity in patients with advanced solid tumors. 16mk/kg Q2W is recommended as RP2D. 20mg/kg Q3W is still under investigation. The study of MSB0254 on the expansion phase in selected tumor patients is ongoing. Clinical trial information: NCT04381325.

Tazemetostat in patients with tumors with alterations in EZH2 or the SWI/SNF complex: Results from NCI-COG Pediatric MATCH trial Arm C (APEC1621C).

10009 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients, age 1-21 years, with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms based on genetic alterations detected in their tumor. Arm C evaluated the EZH2 inhibitor tazemetostat in patients whose tumors harbored EZH2 hotspot mutations or SMARCB1 or SMARCA4 loss by immunohistochemistry. Methods: Tazemetostat 1200 mg/m2/dose PO BID was administered to the first 13 patients; after study amendment due to second malignancy noted in the pediatric phase 1 trial, the dose for patients with non-CNS tumors was reduced to 520 mg/m2/dose PO BID. Patients were treated for 28-day cycles until PD or intolerable toxicity (max 26 cycles); response assessments occurred every 2-3 cycles. Primary and secondary endpoints were ORR and PFS, respectively. Results: Twenty eligible and evaluable patients (median age 5 years; range 1-21) were enrolled between Nov 2017 and Sept 2020. SMARCB1 loss was detected in 16/20 (80%) tumors: atypical teratoid rhabdoid tumor (ATRT, n = 8), malignant rhabdoid tumor (MRT, n = 4), epithelioid sarcoma (ES, n = 2), renal medullary carcinoma (RMC, n = 1) and hepatocellular carcinoma (HCC, n = 1). EZH2 mutations were identified in 3/20 (15%) tumors: Ewing sarcoma (n = 2), ependymoma (n = 1). One patient with Langerhans cell histiocytosis (LCH) had SMARCA4 loss. Centrally reviewed, one objective response (PR) was observed (LCH [SMARCA4], 26 cycles at 1200 mg/m2/dose BID). Five other patients had a best response of stable disease (ES [SMARCB1], 26 cycles, 520 mg/m2/dose BID; ATRT [SMARCB1], 13 cycles,1200 mg/m2/dose BID; RMC [SMARCB1], 12 cycles, 520 mg/m2/dose BID; ES [SMARCB1], 9 cycles,1200 mg/m2/dose BID; ATRT [SMARCB1], 6 cycles, 1200 mg/m2/dose BID). No other patients received > 2 cycles. Six-month PFS was 35% (95% CI 15.7%, 55.2%); OS was 45% (95% CI 23.1%, 64.7%). Treatment-related adverse events were consistent with AEs previously reported with tazemetostat, including anemia, thrombocytopenia, elevated LFTs, abdominal pain, dyspnea, infection, and intracranial hemorrhage. Three patients had bromide elevations. Conclusions: In this cohort of children with relapsed tumors harboring EZH2 mutations or loss of SMARCB1 or SMARCA4, tazemetostat did not produce significant objective responses (ORR: 5%, 90% CI 1%, 20%). However, we observed prolonged stable disease of > 6 months (range: 6-26 cycles) in 33% of patients across different histologic diagnoses, including two patients who received the full two years of study therapysuggesting a potential effect of tazemetostat on disease stabilization. Future studies will incorporate tazemetostat in combination with chemotherapy or immunologic agents for patients with these aggressive and difficult to treat tumors. Clinical trial information: NCT03213665.

Primary efficacy and safety of letetresgene autoleucel (lete-cel; GSK3377794) pilot study in patients with advanced and metastatic myxoid/round cell liposarcoma (MRCLS).

11500 Background: Lete-cel is an autologous T-cell therapy targeting NY-ESO-1 tumors using a genetically modified, high-affinity T-cell receptor. MRCLS is a sarcoma with poor response to current immunotherapy approaches and limited treatment options. The cancer testis antigen NY-ESO-1 is expressed in 80‒90% of MRCLS tumors, making this a promising target. This report summaries the primary efficacy and safety results of a pilot study of lete-cel in patients (pts) with advanced or metastatic MRCLS. Methods: This is an open label, study of lete-cel in pts with advanced or metastatic MRCLS following reduced-dose (Cohort 1 [C1]; 30 mg/m2 fludarabine [flu] x 3d + 600 mg/m2 cyclophosphamide [cy] x 3d) or standard dose (Cohort 2 [C2]; 30 mg/m2 flu x 4d + 900 mg/m2 cy x 3d) lymphodepletion (LD). Key eligibility criteria were: age ≥18 y; HLA-A*02:01; A*02:05, or A*02:06; advanced or metastatic NY-ESO-1+ MRCLS (≥30% of cells 2+/3+ by IHC); prior anthracycline treatment, and measurable disease. The transduced T cell dose range was 1– 8 × 109. Response was assessed at weeks 4, 8, 12, 24, then every 3 months (mo) until disease progression, death, or withdrawal. Investigator-assessed (IA) ORR by RECIST v1.1 was the primary efficacy endpoint. Secondary endpoints included safety, independently assessed ORR by RECIST v1.1, time to response (TTR), duration of response (DOR), progression-free survival (PFS). Overall survival (OS) was an exploratory endpoint. Results: 23 pts enrolled from March 2017 to February 2020. The median age was 47.0 yrs (range 33 to 72). 20 pts were dosed with T cells, 10 in each cohort with a median transduced T cell dose of 4.6 x 109. 8 of 20 pts (40%) had 1 line of prior therapy, 6 pts (30%) had 2 lines, and 6 pts (30%) had ≥3 lines. The median follow-up was 5.6 (C1) and 12.9 (C2) mo. In C1 the IA ORR was 20%, with best response (BR) of partial response (PR) in 2 pts and BR of stable disease (SD) in 8 pts. The median TTR was 1.9 mo, median DOR was 5.3 mo (95% CI: 1.9-8.7), and median PFS was 5.4 mo (95% CI: 2.0-11.5). In C2 the IA ORR was 40%, with BR of PR in 4 pts and BR of SD in 5 pts. The median TTR was 1.9 mo, median DOR was 7.5 mo (95% CI: 6.0-NE), and median PFS was 8.7mo (95% CI: 0.9-NE). OS is not yet mature. All pts experienced at least 1 treatment-emergent adverse event (TEAE). 55% of pts experienced serious TEAEs. 90% of pts had Gr ≥3 TE neutropenia, with 83% probability of resolution of initial Gr ≥3 occurrence by Day 30. Cytokine release syndrome occurred in 80% of pts, of which 25% were Gr 3, with 1st onset within 5d of infusion and median duration 7.5d. No Graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, Guillain-Barré Syndrome were reported. Conclusions: Treatment with a single dose of lete-cel showed anti-tumor activity, including response and long median PFS with an acceptable safety profile in pts with advanced and metastatic MRCLS. Clinical trial information: NCT02992743.

Dose escalation of a phase 1b/2 study of modakafusp alfa, an immune-targeting attenuated cytokine, in patients (pts) with metastatic solid tumors.

2503 Background: Modakafusp alfa (TAK-573) is a first-in-class immune-targeting attenuated cytokine designed to deliver attenuated interferon alpha-2b (IFNα2b) moieties to CD38-expressing cells. It consists of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody. Specificity for CD38 and reduced IFN receptor binding affinity of the attenuated IFNα2b molecules significantly reduces the potential for off-target binding and toxicity. Modakafusp alfa has demonstrated immune cell activation and antitumor activities in preclinical mouse models, including tumor models that do not express CD38, and has shown strong clinical responses and immune activation in pts with refractory/relapsed multiple myeloma. The dose-escalation phase of this phase 1b/2 study (NCT04157517) investigated safety, pharmacokinetics, immunogenicity, pharmacodynamics (PD), and preliminary efficacy of modakafusp alfa in metastatic solid tumors. Methods: Adult pts with advanced/metastatic solid tumors received modakafusp alfa IV on day 1 of a 21-day cycle (Q3W). Dose escalation started at 0.1 mg/kg and proceeded based on cycle 1 safety data via a Bayesian model with overdose control principles. Results: Twenty-one pts were dosed in the escalation phase at 0.1 (n = 3), 0.2 (n = 3), 0.4 (n = 3), 0.75 (n = 3), 1.0 (n = 3), and 1.5 mg/kg (n = 6) Q3W; median age 63 y (range 42–80); male 57.1%; GI malignancies 71.4%; median prior lines of therapy 3 (range 2–7). Two pts had dose-limiting toxicities in cycle 1 at 1.5 mg/kg; 1 pt with baseline bone infiltration had grade 4 thrombocytopenia and 1 pt had grade 3 confusion. As of Nov 2021, across all doses, pts received a median of 2 treatment cycles (range 1–11). Modakafusp alfa treatment-related adverse events (TRAEs) reported in 81% of pts included infusion-related reactions (52.4%), chills (47.6%), and nausea (33.3%). Grade ≥3 TRAEs reported in 42.9% of pts included neutropenia (14.3%) and hypertension (9.5%). There was a greater than dose proportional exposure increase in the dose range 0.1–1.5 mg/kg, with no exposure accumulation after Q3W dosing. Incidence rate of post-treatment anti-drug antibody (ADA) was 100%. PD data suggested saturation of peak IFN pathway modulation at ≥0.2 mg/kg in the peripheral blood with duration of modulation increasing with dose. Among the 14 response-evaluable pts, 7 had best response of stable disease, including 1 with cutaneous melanoma who had 21% target lesion reduction. Conclusions: Modakafusp alfa had a manageable safety profile in the dose range 0.1–1.5 mg/kg in pts with solid tumors. Proof of mechanism was validated. The recommended phase 2 dose was determined as 1.0 mg/kg Q3W based on assessment of holistic data and will be tested in combination with a checkpoint inhibitor in selected tumor types. Characterization of ADA and its impact is ongoing. Clinical trial information: NCT04157517.

Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001).

339 Background: Hypoxia inducible factor-2 alpha (HIF2a) is a transcription factor and key tumorigenic driver of clear cell renal cell carcinoma (ccRCC). Normally, HIF2a is expressed at low levels and targeted for degradation by the von Hippel-Lindau ( VHL) tumor suppressor protein. VHL inactivation, the causative event of ccRCC, induces tumorigenesis through uncontrolled accumulation of HIF2a and constitutive expression of downstream target genes implicated in cell survival, cell proliferation and angiogenesis. ARO-HIF2 is a synthetic double-stranded RNAi trigger with an alpha-v beta3 targeting ligand, designed to silence HIF2a expression. Herein, we present initial results from a phase 1 clinical trial of ARO-HIF2 in advanced ccRCC (NCT04169711). Methods: Advanced ccRCC patients (pts) (ECOG ≤ 1), with progressive disease on prior anti-VEGF and checkpoint inhibitor therapy, were enrolled into three escalating dose cohorts (up to 10 per cohort) to receive 225, 525 or 1,050 mg i.v. weekly of ARO-HIF2 until progression or unacceptable toxicity. The primary endpoint was incidence and severity of AEs. Secondary endpoints included tumor response based on RECIST. All pts underwent tumor biopsy at baseline and post-dose for analysis of changes in HIF2a mRNA (qPCR) and protein expression (IHC). Results: At the time of data cut, twenty-three pts (median age 66.5) were enrolled across 3 cohorts. Seventy four percent of pts received ≥ 3 prior lines of therapy. The most common treatment emergent AE was fatigue (39%). Three SAEs in 3 pts were reported by investigators as possibly drug related including, myocarditis (in a pt with a history of TKI induced cardiomyopathy and NSTEMI requiring stent placement), demyelinating neuropathy (in a pt with autoimmune sequelae secondary to checkpoint inhibitors), and hypoxia (in a pt with a pulmonary infiltrate treated with antibiotics). No cases of drug related anemia were reported. Among pts with adequate biopsy for qPCR (n=7), mean (max) reductions in HIF2a mRNA were 38% (47%), 25% (30%) and 28% (28%) in cohorts 1, 2, and 3, respectively. Among pts with adequate biopsy for IHC (n = 12), 8 showed reductions in HIF2a protein with mean (max) reductions of 45% (82%), 57% (90%) and 63% (63%) in cohorts 1, 2, 3, respectively. Across all 3 cohorts, disease control (CR+PR+SD) was seen in 7 (30%) of pts. One pt (cohort 2, with prior sunitinib, nivolumab, axitinib) experienced a partial response with 66% reduction in sum of longest diameters. Six pts had a best response of stable disease. Three pts remain on drug with stable disease and treatment durations between 20 and 32 weeks. Conclusions: HIF2a is a clinically validated driver of ccRCC which can be targeted with a RNAi therapeutic. This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2a expression as well as a favorable safety profile in response to escalating doses of ARO-HIF2. Clinical trial information: NCT04169711.

Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia

BackgroundThe powerful ‘graft versus leukemia’ effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies...

CTIM-29. CLINICAL EVALUATION OF CHLOROTOXIN-DIRECTED CAR T CELLS FOR PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract Chlorotoxin (CLTX), a peptide component of scorpion venom, exhibits selective and broad binding to glioblastoma (GBM) and other tumors with minimal activity against non-malignant cells. We have developed a novel CAR that utilizes CLTX as the tumor targeting domain. Preclinical studies established that CLTX-CAR T cells target GBM through recognition of a receptor complex incorporating membrane-bound matrix metalloprotease-2 (MMP-2). Here, we report initial clinical findings for our phase I trial evaluating safety and bioactivity of CLTX-CAR T cells in patients with MMP2+ recurrent GBM (NCT04214392). Weekly infusions of CLTX-CAR T cells are delivered locoregionally, either directly into the tumor cavity (ICT; Arm 1), or in combination with intracerebroventricular (ICV) delivery (dual ICT/ICV; Arm 2). At this interim analysis, four participants have received at least three cycles of CLTX-CAR T cells ICT (Arm 1; 3-8 cycles) at dose level 1 (DL1; 4M, 20M, 20M CAR T cells per cycle). None of the participants experienced dose limiting toxicity (DLT) during the DLT evaluation period of 28-days, although one participant experienced a serious adverse event of grade 3 cerebral edema, possibly attributed to CAR T cells. Overall, Arm 1-DL1 was well-tolerated, and the next patient cohort will be treated on Arm 2-DL1 (dual ICT/ICV; 8M, 40M, 40M CAR T cells per cycle), as per protocol design. Disease response was assessed by RANO, overall survival, and time to progression; three of four participants achieved a best response of stable disease. Liquid biopsy detected persistent CAR T cells in the tumor cavity throughout treatment, suggesting that the therapeutic cells are not immunogenic. Ongoing studies are evaluating biomarkers of response and resistance, including CAR T cell activation and inflammatory cytokines. This clinical study provides first-in-human evidence for the safety and feasibility of CLTX-CAR T cells as a new class of toxin-based CARs for treatment of GBM.

A Phase 1 Dose-Escalation Study of the Oral CDK Inhibitor Voruciclib in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia (AML): Preliminary Results of the Completed Dose Escalation Stage in AML

A Phase 1 Dose-Escalation Study of the Oral CDK Inhibitor Voruciclib in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia (AML): Preliminary Results of the Completed Dose Escalation Stage in AML

532 First-in-human phase 1 trial of SRK-181: a latent TGFβ1 inhibitor, alone or in combination with anti-PD-(L)1 treatment in patients with advanced solid tumors (DRAGON trial)

BackgroundTransforming growth factor-beta 1 (TGFβ1) plays an important role in mediating the primary resistance to PD-1/PD-L1 [PD-(L)1] blockade. SRK-181 is a fully human monoclonal antibody that selectively inhibits latent TGFβ1 activation. Mouse tumor models (bladder, melanoma, and breast cancer) demonstrated that treatment with SRK-181+anti-PD-1 overcame primary anti-PD-1 resistance. Four-week GLP nonclinical toxicology studies showed that SRK-181 has improved safety profile (no cardiotoxicities) compared to broad TGFβ pathway inhibition.MethodsThe DRAGON trial (NCT04291079) is an ongoing open-label, phase 1 study. Part A of the study follows a standard 3+3 dose escalation design to determine the dose for Part B. Part B (expansion phase) evaluates combination treatment in patients with non-small cell lung cancer (NSCLC), urothelial carcinoma, melanoma, or other advanced solid tumors. SRK-181 is administered IV every 3 or 2 weeks (Q3W/Q2W) alone in patients with advanced solid tumors (Part A1), or in combination with anti-PD-(L)1 in patients who did not respond to prior anti-PD-(L)1 therapy (Part A2/B).ResultsAs of 7 June 2021, 25 patients have enrolled to Part A; median 4 prior lines of therapies (range 1–9). Cancer types: colorectal, ovarian, prostate, and unknown primary (Part A1); liver, melanoma, NSCLC, oropharynx, renal cell carcinoma (RCC) and uterine (Part A2). In Part A1, 15 patients were treated with SRK-181 monotherapy at doses of 80, 240, 800, 1600, 2400, 3000mg Q3W, with no dose limiting toxicity (DLT) observed. The last cohort (2000mg Q2W) remains under evaluation. The most common treatment-related AEs (TRAE, >10%) of any grade were decreased appetite and fatigue (each: 13.3%, n=2). Six patients had stable disease (SD) as best response (2/colorectal cancer, 1/prostate cancer, and 3/ovarian cancer). Three ovarian cancer patients were stable ≥153 days with tumor regressions. In Part A2, 10 patients were treated with SRK-181 at doses of 240, 800 and 1600mg Q3W+pembrolizumab. No DLT was observed up to 800mg. 1600mg Q3W is under evaluation. No TRAE (>10%) of any grade were observed. One confirmed RECIST1.1 partial response (PR) was observed (800mg) in a patient with anti-PD-1 resistant RCC and 2 patients had best response of SD (1/oropharynx cancer, 1/liver cancer). The half-life of SRK-181 ranged from 3.9 to 19.3 days across the doses tested.ConclusionsAs of 7 June 2021, SRK-181 has been well tolerated as monotherapy and in combination with anti-PD-(L)1. One RECIST1.1 PR (800mg) was observed in a patient with anti-PD-1 resistant RCC. Next planned dose in Part A2 will be 2400mg Q3W.Trial RegistrationDRAGON trial (NCT04291079)Ethics ApprovalThe human study was approved by the Massachusetts General Hospital and Beth Israel Deaconess Medical Center (20–286), Sarah Cannon Research Institute (1276118), Mary Crowley Cancer Research (20–06), MD Anderson Cancer Center (2020–0110) Institutional Review Boards with written informed consent obtained from each participant and/or their legal representative, as appropriate.

Abstract CT124: Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor

Abstract Background: The PARP inhibitor rucaparib is approved in the US for pts with recurrent ovarian or metastatic castration-resistant prostate cancer. This phase 1 study (NCT03499444) evaluated safety, pharmacokinetics (PK), and antitumor activity (per RECIST v1.1) of rucaparib in Japanese pts. Methods: Pts were enrolled in a 3+3 dose-escalation phase to establish the recommended dose (RD) in Japanese pts; dose-limiting toxicities (DLTs) were assessed in the first 21 days. Pts must have had an advanced solid tumor that had progressed on standard treatment. A dose-expansion phase enrolled pts at the RD to further assess safety, PK, and efficacy. Results: The visit cutoff was Oct 20, 2020; 29 pts received rucaparib, including 15 in the dose-escalation phase (400 mg BID, n=3; 500 mg BID, n=6; and 600 mg BID, n=6) and 14 in the dose-expansion phase at the RD of 600 mg BID. Median (range) time on treatment was 5.1 (1.3-16.4) months overall and 5.3 (1.4-16.4) months for 600 mg BID pts (n=20).One DLT was reported (treatment interruption >7 days due to grade 1/2 nausea, vomiting, diarrhea, fatigue; 500 mg BID cohort). Across all doses, the most frequent any-grade treatment-emergent adverse events (TEAEs) were alanine aminotransferase/aspartate aminotransferase increased (82.8%), anemia (82.8%), and nausea (69.0%); the most frequent grade ≥3 TEAE was anemia (51.7%). Among 600 mg BID pts, 25.0% (5/20) had a TEAE leading to treatment interruption or dose reduction, most commonly due to anemia (20.0%; 4/20).Steady-state PK was evaluated for the 400, 500, and 600 mg BID cohorts (Table).Most pts with measurable disease had a best response of stable disease (63.0%; 17/27); the confirmed objective response rate was 18.5% (5/27) overall and 21.1% (4/19) among 600 mg BID pts (Table).Conclusions: Rucaparib 600 mg BID had a manageable safety profile for Japanese pts with advanced solid tumors, with a PK profile similar to that of Western pts. These results support further exploration of rucaparib in Japanese pts. 400 mg BID(n=3)500 mg BID(n=6)600 mg BID(n=20)Overall(N=29)Baseline characteristicsAge, median (range), years67.0 (45.0-68.0)61.5 (44.0-73.0)59.5 (43.0-74.0)61.0 (43.0-74.0)Female, n (%)3 (100)6 (100)16 (80.0)25 (86.2)ECOG PS 0, n (%)a3 (100)4 (66.7)15 (75.0)22 (75.9)Tumor type, n (%)Ovarian2 (66.7)1 (16.7)9 (45.0)12 (41.4)Primary peritoneal1 (33.3)2 (33.3)2 (10.0)5 (17.2)Pancreatic004 (20.0)4 (13.8)Breast02 (33.3)1 (5.0)3 (10.3)Other01 (16.7)4 (20.0)5 (17.2)Steady-state PK dataCmax, mean (CV%), ng/mL1,690 (38.7)3,650 (61.9)b2,800 (37.0)cNCtmax, median (range), h1.48 (1.47-2.45)3.95 (2.47-9.95)b2.50 (0.93-9.83)cNCCmin, mean (CV%), ng/mL1,590 (38.7)2,380 (78.5)2,130 (44.4)NCAUClast, mean (CV%), h × ng/mL14,400 (36.6)30,200 (64.7)b23,800 (39.9)cNCCL/F, mean (CV%), L/h26.1 (45.2)22.1 (68.5)d24.3 (34.6)eNCAUC0-12, mean (CV%), h × ng/mL17,200 (35.8)33,900 (78.9)d28,100 (40.8)eNCEfficacy dataORR, n/N (%) [95% CI]1/3 (33.3) [0.8-90.6]0/5 (0) [0.0-52.2]4/19 (21.1) [6.1-45.6]5/27 (18.5) [6.3-38.1]aAll other pts had ECOG PS 1.bn=5.cn=18.dn=3.en=13.AUC0-12, area under the concentration-time curve up to 12 h; AUClast, area under the concentration-time curve up to last time point (10 h) with a quantifiable concentration; CL/F, apparent total clearance of drug after oral administration; Cmax, maximum concentration; CV, coefficient of variation; ECOG PS, Eastern Cooperative Oncology Group performance status; NC, not calculated; ORR, objective response rate; PK, pharmacokinetics; tmax, time to maximum concentration. Citation Format: Kenji Tamura, Koji Matsumoto, Kan Yonemori, Kosei Hasegawa, Jenn Habeck, Eric Jones, Jim Xiao, Aaron Enke, Keiichi Fujiwara. Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT124.

Abstract CT138: Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors, lymphomas, or myelodysplastic syndromes

Abstract Background: NCI ALMANAC, a systematic in vitro combination drug screen study, identified greater-than-additive activity for the combination of the proteasome inhibitor bortezomib and the nucleoside analog clofarabine. The combination also yielded strong, greater-than-single-agent activity in human tumor xenograft models. Our preclinical findings postulate that the activity of this drug pair may be due to modulation of DNA damage and the intrinsic apoptotic cascade. In an ongoing phase I trial, we evaluate the safety and activity of bortezomib and clofarabine in refractory solid tumors, lymphomas, and myelodysplastic syndromes (MDS). Methods: This is an open-label trial with a 3+3 design, enrolling at least one solid tumor/lymphoma and one MDS patient (pt) at each dose level. Starting doses were clofarabine 1 mg/m2 intravenously (IV) on days (D) 1-5 and bortezomib 0.8 mg/m2 subcutaneously (SC) on D1 and D4 of 21-day cycles. Response was determined per RECIST 1.1, Lugano criteria, and IWG, respectively. Exploratory endpoints include markers of DNA damage and epithelial-to-mesenchymal phenotype transition in blood. Once MTD is declared, a biopsy expansion cohort will enroll to evaluate the mechanism of action for the combination using validated apoptosis multiplex and next-generation sequencing assays. Results: As of October 2020, 22 pts were enrolled with advanced solid tumors (n=18), lymphoma (1), and MDS (3). Median pt age is 62 (range 41-80). Median lines of prior therapy is 3 (range 1-8). Three pts had DLTs in the solid tumor/lymphoma cohort: grade 3 anemia at dose level (DL) 3 (clofarabine 1.5 mg/m2, bortezomib 1 mg/m2); grade 4 neutropenia and grade 4 thrombocytopenia at DL 5 (clofarabine 2 mg/m2, bortezomib 1.3 mg/m2); and grade 4 neutropenia at DL 5. In the solid tumor/lymphoma cohort, grade 3 toxicities possibly attributed to study drugs were anemia (3), lymphopenia (3), thrombocytopenia (1), and frequent premature ventricular contractions (1); grade 4 toxicities were lymphopenia (5), neutropenia without infection (2), and thrombocytopenia (1). The only toxicity possibly attributed to study drugs in the MDS cohort was grade 3 febrile neutropenia in one pt. In the solid tumor/lymphoma cohort, 6 pts achieved a best response of stable disease (SD); 3 patients experienced prolonged SD of ≥ 6 months (1 pt each with colorectal adenocarcinoma, pancreatic adenocarcinoma, and cholangiocarcinoma). In the MDS cohort, 2 pts had SD as a best response (8 months in 1 pt following hypomethylating agent failure). Pharmacodynamic analyses in circulating tumor cells are ongoing. Conclusions: Treatment with bortezomib and clofarabine demonstrated prolonged SD in one pt each with colon adenocarcinoma, pancreatic adenocarcinoma, cholangiocarcinoma, and MDS. Hematological DLTs were seen in 2 pts on DL 5. Currently, patients are enrolling on DL 4 for the solid tumor/lymphoma cohort. Funded by NCI Contract No. HHSN261200800001E. Citation Format: James Q. Nguyen, Geraldine O'Sullivan Coyne, Larry Rubinstein, Shivaani Kummar, Lamin Juwara, Jennifer Zlott, Abdul Rafeh Naqash, Murielle Hogu, Jerry Collins, Apurva Srivastava, Brandon Miller, Ralph E. Parchment, Robert Meehan, Christopher S. Hourigan, Steven Pavletic, James H. Doroshow, Alice P. Chen, Naoko Takebe. Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors, lymphomas, or myelodysplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT138.

Abstract CT038: Kinetics of radiographic response for tebentafusp (tebe) in previously treated metastatic uveal melanoma (mUM) patients (pts) achieving prolonged survival

Abstract Background: The phase 3 IMCgp100-202 trial (NCT03070392) (Study 202) in untreated mUM demonstrated improved overall survival (OS), HR=0.51, at the first pre-specified interim analysis. This OS benefit and the promising estimated 12-month OS rate of 62% observed in previously treated mUM pts on the phase 2 IMCgp100-102 trial (Study 102; NCT02570308) is not explained by RECIST responses alone. In this post hoc analysis of Study 102, we describe the tumor kinetics of pts with prolonged survival (OS ≥ 12 mo). Methods: 127 pts with 2L+ mUM received single agent tebe during the expansion phase of Study 102, where treatment beyond RECIST progression was permitted. Analyses of baseline (BL) and on-treatment tumor measurements, best response and time to progression used in this analysis were adjudicated by an independent radiologic committee. Results: With 19.5 mo median follow-up, 59% (75/127) of pts had OS ≥ 12 mo. Of these 75, a minority had RECIST partial response (PR: 8%; 6/75) and the rest had a best response of stable disease (SD: 57%; 43/75), progressive disease (PD: 33%; 25/75), or not evaluable (NE: 1%; 1/75). In contrast, among 41% (52/127) of pts with OS < 12 mo, 27% (14/52) had SD, 67% (35/52) had PD, and 6% were NE (3/52) as best response. Pts with OS ≥ 12 mo were more likely to have a largest liver metastasis of < 3 cm (43% vs 23%). There were no major differences in the use of prior immunotherapy between the two OS groups. Most pts with OS ≥ 12 mo (59%; 44/75) had at least some reduction in the sum of target lesions, regardless of RECIST response. The majority of these 44 pts (64%; 28/44) had durable tumor reduction defined by PFS > 6 mo. In contrast, among OS < 12 mo pts, reduction in the sum of target lesions was infrequent (13%; 7/52), and none were durable. Most pts with tumor growth as best change in target lesions had OS <12 mo (58%; 38/65) compared to OS ≥ 12 mo (42%; 27/65). Among pts with tumor growth, the median BL tumor burden was lower and the rate of increase over time was slower for pts with OS ≥ 12 mo (BL: 59 mm, W8: 68 mm, W16: 68 mm) compared to pts with OS < 12 mo (BL: 113 mm, W8: 129 mm, W16: 143 mm). Interestingly, 42% (25/60) of pts with best response of PD had OS ≥ 12 mo including 4 pts with evidence of tumor shrinkage at 6 months or later. The reason for PD (new lesions or growth in index lesions) was comparable between both OS groups. More pts continued treatment beyond progression in the OS ≥ 12 (81%) compared to OS < 12 mo (56%). Conclusion: Analysis of tumor kinetics while on tebe, the first TCR bispecific to report an OS benefit in a solid tumor, suggests most pts with OS ≥ 12 mo are best described by a new type of immune-related response characterized by durable tumor reduction and slowing rate of tumor growth. RECIST responses therefore capture a minority of patients with OS ≥ 12 mo, while just under half of pts with RECIST PD still had promising OS. Citation Format: Marcus O. Butler, Takami Sato, Richard D. Carvajal, Joseph J. Sacco, Shaad E. Abdullah, Chris Holland, Howard Goodall, Alexander N. Shoushtari. Kinetics of radiographic response for tebentafusp (tebe) in previously treated metastatic uveal melanoma (mUM) patients (pts) achieving prolonged survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT038.

A Phase Ib Study of Isatuximab in Combination with Bortezomib, Cyclophosphamide, and Dexamethasone (VCDI) in Patients with Newly Diagnosed Multiple Myeloma Non-Eligible for Transplantation

Abstract Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. It has demonstrated strong potentiation when combined with bortezomib in a multiple myeloma (MM) xenograft model (Deckert J et al, Clin Cancer Res 2014:20:4754). The combination of bortezomib, cyclophosphamide, and dexamethasone (dex) (VCD) is an effective regimen, commonly used in newly diagnosed MM (NDMM) (Leiba M et al, Br J Haematol 2014:166:702). Here, we report initial data from a Phase Ib study of ISA plus VCD (VCDI) in patients (pts) with NDMM (NCT02513186). Methods: This dose-escalation (DE) and expansion study enrolled pts with NDMM ineligible for transplantation. Treatment consisted of 2 phases: induction and maintenance. Induction (one 6-week cycle [cycle (C)1] followed by eleven 4-week cycles [C2-12]): ISA (10 or 20 mg/kg, sequentially enrolled) weekly during C1, then every 2 weeks; subcutaneous bortezomib (1.3 mg/m2) on Days (D)1, 4, 8, 11, 22, 25, 29, and 32 (C1), then weekly (C2-12); cyclophosphamide (300 mg/m2) weekly (C1) then on D1, 8, and 15 (C2-C12); dex (20 mg) on D1, 4, 8, 11, 15, 22, 25, 29, and 32 (C1) then D1, 2, 8, 9, 15, 16, 22, and 23 (aged Results: Enrolment is now complete; 17 pts were treated with VCDI. During the DE phase, 4 pts were treated at 10 mg/kg and 4 pts at 20 mg/kg. Based on initial safety (no DLTs occurred at either dose; MTD was not reached) and pharmacokinetic (PK) data, ISA 10 mg/kg was chosen as the recommended dose for the expansion cohort and 9 additional pts were treated at this dose (total 13 pts at 10 mg/kg). Median age was 71 (68-80) years. At baseline, 1, 1, and 15 pts were ISS Stage I, II, and III, respectively. At data cut-off (Dec 31, 2016), pts across both doses had been treated for a median of 3.0 (0.5-14.0) months (mo). Two pts discontinued treatment due to an adverse event (AE) (10 mg/kg: Grade [Gr] 3 bronchospasm and Gr 3 infusion-associated reaction [IAR]; 20 mg/kg: sudden death [during C1, not treatment related]) and 1 pt (10 mg/kg) discontinued due to disease progression. ISA dose omission was required in 5/13 (38%) pts at 10 mg/kg (Gr 2 bronchitis, Gr 2 mesenteric vein thrombosis, Gr 3 respiratory tract infection, Gr 3 hypertension, Gr 3/4 neutropenia) and none at 20 mg/kg. Dose omission of bortezomib, cyclophosphamide, and dex was required in 7, 5, and 8 pts, respectively. All pts experienced ≥1 AE. Most frequent AEs across both doses (any Gr; excluding laboratory abnormalities): IARs, 8 pts (47%); back pain, 7 pts (41%); nausea, 5 pts (29%); bronchitis, 5 pts (29%); peripheral neuropathy, hypertension, diarrhea, constipation, peripheral edema, and rash, 4 pts each (24%). Gr ≥3 AEs were reported in 11 (65%) pts and serious AEs (SAEs) in 4 (24%) pts (Gr 3 bronchospasm, Gr 2 mesenteric vein thrombosis, Gr 3 dorsal pain, Gr 5 sudden death). Except Gr 3 bronchospasm, no SAEs were treatment related. Nine IARs occurred in 8 pts, all in the first infusion. IARs were Gr 1/2 in all but 1 pt (Gr 3 bronchospasm). Gr 3/4 hematologic abnormalities (laboratory assessment): lymphopenia (8/16 evaluable pts), leukopenia (3/16), neutropenia (3/16), thrombocytopenia (1/16), anemia (1/16). From 15 efficacy-evaluable pts the ORR was 87% (13/15), including 2 stringent CRs, 3 CRs, 4 very good partial responses (VGPRs), and 4 partial responses. Two pts achieved a best response of stable disease, lasting 5 and 12 cycles, respectively. Median time to first response was 1.5 mo. Median duration of response in the DE phase was 11.1 mo, and 14 (82.4%) pts are continuing on treatment. ISA PK appeared unaffected by co-administration with VCD. Conclusions: These data suggest that VCDI is generally well tolerated with many pts demonstrating at least VGPR. Safety and efficacy data (including minimal residual disease status) with longer-term follow-up will be presented at the meeting. Funding: Sanofi Disclosures Ocio: Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Array Pharmaceuticals: Research Funding; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Janssen: Honoraria. Bringhen: JJ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; BMS: Honoraria. Oliva: Celgene: Honoraria; Takeda: Honoraria. Rodriguez-Otero: BMS: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Kanagavel: Sanofi: Employment. Oprea: Sanofi RD Sanofi: Other: Stock holder. Wei: Sanofi RD Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Janssen: Honoraria.