Experienced Dose-limiting Toxicity Research Articles

Abstract CT206: A phase I study of binimetinib, a MEK inhibitor, in combination with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC)

Abstract Introduction: MEK inhibition combined with PD-1 axis inhibition may achieve a greater clinical response than either inhibitor alone due to increased T-cell infiltration of tumours. We combined binimetinib with pembrolizumab in patients with stage IV advanced non-small cell lung cancer (NSCLC) and PD-L1 tumor proportion score>=50%. Methods: A 3 + 3 dose escalation design was used. Binimetinib at a dose level 1 (DL1; 45 mg) or dose level -1 (DL-1; 30 mg) twice daily orally continuously was given with pembrolizumab 200 mg IV q 21 days. The primary objective was to define the recommended phase II dose (RP2D) of the combination. Secondary outcomes included safety of the combination and response (RECIST 1.1) with a planned Phase Ib expansion in patients with RAS/RAF/MEK dysregulated tumours via next generation gene sequencing. Genomic markers are being explored in tissue and plasma. Results: Eleven patients (3 DL1, 8 DL-1) were enrolled with the following mutations: 7 with KRAS (3 G12C, 2 G12D, 1 G12V, 1 G12A), 2 BRAF (1 G409A, 1 V600E) and 1 STK11 which acts as a tumor suppressor gene encoding for LKB1. Two of 3 patients at DL1 experienced dose limiting toxicity (DLT) including grade 3 elevated amylase, grade 3 diarrhea, grade 4 elevated lipase and severe grade 2 rash requiring dose reduction. Of 8 patients treated at DL-1, 1 progressed in cycle 1, another was noncompliant with treatment. Of the remaining 6 patients, 1 experienced DLT with grade 3 rash with inability to administer binimetinib for >75% of cycle 1. The most common toxicities across all cycles (n=11 patients) were: rash (82%), diarrhea (36%) and pruritis (36%). Nine patients were evaluated for response with partial response in 3 (33%), stable disease in 4 (44%) and progressive disease in 2 (22%). All 3 responding patients had RAS or RAF alterations (KRASG12C, KRASG12V, BRAFV600E) while the patient with STK11 mutant disease had early disease progression. Conclusion: The RP2D of the combination in patients with advanced NSCLC is binimetinib 30 mg BID plus pembrolizumab 200 mg IV q21 days. Updated data from cohort expansion including response and molecular correlates of treatment response and resistance will be presented. Citation Format: Christopher F. Theriau, Jamie Feng, Lawson Eng, Frances A. Shepherd, Mary DeCarolis, Vivian Glenns, Swati Kulkarni, Rachel VanderMeer, Urszula Zurawska-Fortin, Desiree Hao, Lisa Le, Isabel Wozniczka, Aida Al-Kindy, Danny Xie, Tong Zhang, Vasanth Subramanian, Tracy Stockley, Penelope A. Bradbury, Geoffrey Liu, Natasha B. Leighl. A phase I study of binimetinib, a MEK inhibitor, in combination with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT206.

Abstract CT014: Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer

Abstract Background: PSMA-based targeted radionuclide therapy is now a standard of care for mCRPC since approval of 177Lu-PSMA-617. Use of antibodies (e.g., J591) to target PSMA with higher potency radionuclides (e.g., 225Ac) impacts kinetics, biodistribution, clinical efficacy, and toxicities. In our first-in-human ph I dose-escalation study of single dose 225Ac-J591 in patients with mCRPC, no MTD was reached (max dose 93.3 KBq/kg). Following this, we developed ph I/II parallel dose-escalation studies of fractionated (D1, D15) single cycle and multiple (q6w) dose regimens. Here we present safety data from the initial fractionated study in predominantly 177Lu-naive. Methods: Eligible patients had adequate organ function, ECOG performance status 0-2, and progressive mCRPC following potent AR pathway inhibitor (ARPI) and chemo (or unfit/refusing). Prior 177Lu-PSMA was allowed until an amendment developed a separate study for post-177Lu-PSMA. Baseline 68Ga-PSMA PET scans were performed, but not used to determine eligibility. A 3+3 dose-escalation design was used. Phase I primary objective: determination of dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). DLT was defined as within 8 weeks of first dose: neutropenia (Gr 4 or febrile neutropenia), thrombocytopenia (TCP) (Gr 4, or Gr 3 with clinically significant bleeding), any Gr >2 non-hematologic toxicity deemed to be at least possibly related to 225Ac-J591, or any attributable toxicity precluding or delaying the second dose by >2 weeks. Secondary/exploratory objectives: efficacy measures (e.g., PSA decline, radiographic RR, biochemical/radiographic PFS, OS, CTCs, patient reported outcomes), safety (CTCAE v5), and correlatives (plasma and tissue genomics, PSMA imaging). Results: 24 patients were enrolled in phase I. Median age 73.5 (57-91), PSA 25.78 (3.39-2133.41); 53% (n=13) >1 prior ARPI, 58% (n=14) taxane chemo, 8% (n=2) anti-PSMA therapy, 12.5% (n=3) prior 223Ra. CALGB prognostic groups: Good 4 (16%), Intermediate 8 (33%), Poor 12 (50%). No DLTs were observed in Cohort 1 (n=3) or 2 (n=6). In C3, 2/6 subjects experienced DLTs (Gr 3 weakness, Gr 2 TCP with >2 week delay in second fraction). 8 patients were enrolled in an intermediate dose cohort (2.5) with 1 DLT (Gr 4 TCP). Two patients withdrew before the second dose (intercurrent illness; interruption of 225Ac supply). Most common low gr non-hematologic treatment emergent AEs: fatigue (95%), xerostomia (69%), and nausea (57%). Among evaluable patients for PSA change (n=22), 21 (95%) experienced PSA decline with 14 (67%) with decline of 50% and 6 (37%) with decline of 90%. 13/21 patients had CTCs samples collected at baseline and 12 wks; 5 were unfavorable at baseline (≥5/7.5 mL); 10/13 (77%) remained favorable or converted from unfavorable to favorable; 6/12 (50%) had 50% decline in CTC count; and 5/13 (38%) converted from detectable to undetectable. Conclusions: A single fractionated cycle of 225Ac-J591 was delivered with few high grade AEs and with evidence of preliminary efficacy by PSA and CTC changes across all dose levels. Citation Format: Jones T. Nauseef, Michael Sun, Charlene Thomas, Mahelia Bissassar, Escarleth Fernandez, Zachary Davidson, Amie Patel, Angela Tan, Tessa A. Chamberlain, Kara Earle, Rebecca Wunder, Sabrina Guervil, Sandra H. Castellanos, Judith Stangl-Kremser, Peter S. Gregos, Joseph R. Osborne, Karla V. Ballman, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT014.

PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer

BackgroundEpidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC).MethodsTreatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage.ResultsEighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed.ConclusionsThe combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure.Trial registration numberClinicalTrials.gov number: NCT01862003.

MMAP-05 PHASE I STUDY OF CONCURRENT PAXALISIB AND RADIATION THERAPY IN PATIENTS WITH SOLID TUMOR BRAIN METASTASES OR LEPTOMENINGEAL METASTASES HARBORING PI3K PATHWAY MUTATIONS: RESULTS FROM THE DOSE-ESCALATION COHORT

INTRODUCTIONRadiation therapy (RT) is an effective treatment for patients with central nervous system metastases, but disease control is poor in patients with tumors that harbor PI3K pathway alterations. We hypothesized that combining RT with paxalisib, a CNS-penetrant small molecule PI3K/mTOR inhibitor, could abrogate this effect via downregulation of prosurvival pathways. METHODSThis is a single institution, open-label, phase I trial of concurrent paxalisib and RT (NCT04192981) for patients with brain metastases, leptomeningeal metastases, or both with PI3K pathway mutations. Part A comprised a standard 3 + 3 dose escalation of paxalisib at 45mg, 60mg, or 75mg daily for two weeks with concomitant RT. The primary objective was to establish the maximum tolerated dose (MTD) of paxalisib when combined with cranial RT. RESULTSBetween 3/2020-1/2022, 12 patients were enrolled to Part A, of which 9 were evaluable (3 did not complete protocol therapy). Median followup was 4.5 months (0.9-14.9 months). All patients received paxalisib with whole brain RT (30Gy in 10 fractions)- 10 patients for brain metastases, and 2 for leptomeningeal metastases. The most common histology was breast cancer (4 [33%]), and the most common PI3K pathway alterations were PIK3CA mutation (7 [58%]). No patient experienced dose-limiting toxicity (DLT) at 45mg paxalisib daily with concurrent RT, and 2 experienced DLT at 60mg paxalisib: 1 with grade 3 nausea and vomiting and 1 with grade 4 enterocolitis and neutropenia. When combined with cranial RT, the paxalisib MTD was established at 45mg/day. We also observed robust response with all evaluable patients experiencing partial or complete response per RANO-BM within 3 months of protocol therapy. CONCLUSIONA MTD of 45mg/day has been established for paxalisib with concurrent cranial RT in patients with solid tumor brain metastases and leptomeningeal metastases harboring PI3K pathway mutations. Additional patients are being recruited to an expansion cohort at this dose (Part B) to confirm safety and preliminary evidence of activity.

Abstract CT001: Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells

Abstract Background: H3K27M-mutated DMGs are universally lethal central nervous system tumors that express high levels of the disialoganglioside GD2. IV administered GD2-CAR T cells (GD2-CART) regress DMG in preclinical models, and locoregionally delivered CARs demonstrate enhanced activity in xenograft models of brain tumors. Methods: NCT04196413 is a 3+3 Phase I dose escalation trial testing GD2-CART in patients with H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1: 1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART (10-30e6 GD2-CART) administered via Ommaya catheter without LD every 4-8 weeks for a maximum of 12 doses. We previously reported early results from 4 patients treated on DL1, which demonstrated clinical activity and manageable toxicity. Here we provide updated results for DL1 and DL2. Results: Thirteen subjects were enrolled and 11 treated [n=4 DL1 (3 DIPG/1 sDMG); n=9 DL2 (7 DIPG/2 sDMG)]. Two subjects were removed prior to treatment due to rapid progression. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade 4 cytokine release syndrome (CRS), successfully managed with tocilizumab, anakinra, and corticosteroids. CRS occurred earlier on DL2 vs. DL1 (Day 3 vs 7). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN), which was successfully managed with anakinra and, in some cases, CSF drainage and dexamethasone. No DLT due to TIAN has occurred. Ten patients have had adequate follow-up to assess benefit. Nine experienced radiographic and/or clinical benefit after IV infusion, and they received subsequent ICV GD2-CART infusions (median= 4 ICV infusions/pt, range 1-6). ICV infusions were not associated with high-grade CRS, although some subjects developed transient fever, headache, meningismus, nausea, and/or vomiting, and several subjects developed TIAN. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit at 11+, 9.5+, 8+ and 7+ months following enrollment. A 31-year-old with sDMG has experienced a near-complete (>95%) reduction in tumor volume and a 17-year-old with DIPG experienced a near-complete (>98%) reduction in volume of a pontine tumor. Conclusions: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with unacceptable rates of high-grade CRS at 3e6/kg. ICV GD2-CART without LD, administered following a previous course of IV GD2-CART with LD, has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD. Patients are eligible for up to 12 ICV infusions of GD2-CART administered every 4-6 weeks. Clinical benefit will be formally assessed using patient-reported outcomes. GD2-CART has the potential to transform therapy for patients with H3K27M+ DIPG/sDMG. Citation Format: Robbie G. Majzner, Jasia Mahdi, Sneha Ramakrishna, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Valentin Barsan, Rebecca Richards, Cynthia Campen, Agnes Reschke, Angus Martin Shaw Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Ashley Jacobs, Karen Yamabe-Kwong, Lindsey Rasmussen, Esther Nie, Sean Green, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Warren Reynolds, Snehit Prabhu, Katherine E. Warren, Tim Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Michelle Monje, Crystal L. Mackall. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells [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 CT001.

DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells

BACKGROUND: H3K27M-mutated DMGs express high levels of the disialoganglioside GD2 and GD2-CAR T-cells (GD2-CART) regress DMG in preclinical models. METHODS: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CART in patients with biopsy-proved H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1=1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART infusions (10-30e6 GD2-CART) administered via Ommaya without LD. RESULTS: Twelve subjects were treated after standard radiotherapy, 7 of whom began treatment at the time of progression [n=4 DL1 (3 DIPG/1 sDMG); n=8 DL2 (6 DIPG/2 sDMG)]. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade-4 cytokine release syndrome (CRS). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN); no DLT due to TIAN has occurred. Ten subjects experienced radiographic and/or clinical benefit after IV infusion and received subsequent ICV infusions (median=4 ICV infusions/pt, range=1-7). ICV infusions were not associated with high-grade CRS. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit, currently 7-11 months following enrollment. Two patients (one sDMG, one DIPG) have experienced near-complete (>95%) tumor volume reduction. CONCLUSIONS: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with frequent high-grade CRS at 3e6/kg. ICV GD2-CART has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD.

Phase I study of 131I-MIBG with dinutuximab for patients with relapsed or refractory neuroblastoma: A report from the new approaches to neuroblastoma therapy (NANT) consortium.

10038 Background: 131I-metaiodobenzylguanidine (MIBG) is one of the most active salvage therapies for patients with relapsed or refractory (R/R) high-risk neuroblastoma (HRNB). Preclinical neuroblastoma studies show cooperative effects when radiation is combined with anti-GD2 monoclonal antibody (mAb). We hypothesized that MIBG would synergize with the anti-GD2 mAb dinutuximab to provide improved anti-tumor responses. The primary aims of Part A of this study were to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of MIBG administered with dinutuximab in children with R/R HRNB and to define and describe the toxicities. Methods: Patients 1-29 years of age with R/R HRNB who had MIBG uptake in ≥ 1 site were eligible. Prior anti-GD2 mAb therapy was allowed provided it was not administered with MIBG and not permanently discontinued due to toxicity. One prior MIBG therapy was allowed. MIBG was administered on day 1 at one of three dose levels (DLs): 12, 15, and 18 mCi/kg (DL1-DL3, respectively) with an expansion cohort at the RP2D. Doses were escalated using a rolling six design starting at DL1. The primary endpoint was dose-limiting toxicity (DLT) during course 1. Dinutuximab (17.5 mg/m2/dose) was administered intravenously on days 8-11 and 29-32 and GM-CSF (250 mcg/m2/dose) subcutaneously on days 8-17 and 29-38. Autologous peripheral blood stem cells were infused to all patients on day 15 (+/- 2 days). A maximum of 2 courses per patient were allowed. Response rate was defined as the proportion of patients with a complete or partial response. Results: Thirty-one patients were enrolled. Fourteen were evaluable for dose escalation (4 on DL1, 4 on DL2, and 6 on DL3); 5 evaluable patients were treated in the DL3 expansion. The median age was 7.4 years (range: 3.1 – 22.0) and 20 (65%) were male. Twenty-seven (87%) patients had previously received a median of 8.5 cycles of chemoimmunotherapy (range: 2 – 21). Eight patients previously progressed while receiving anti-GD2 mAb including 7 in DL3. Five (16%) patients had previously received MIBG. No patient at any dose level experienced DLT. Common grade 3/4 treatment-related toxicities were expected hematologic toxicities attributable to MIBG and non-hematologic toxicities attributable to dinutuximab or GM-CSF. Among 26 response-evaluable patients, the centrally-confirmed response rate was 31% across all dose levels: 2/6 (33%) in DL1, 3/5 (60%) in DL2, and 3/15 (20%) in DL3. There were 3 minor responses, 1 in DL2 and 2 in DL3. Conclusions: The RP2D of MIBG in combination with standard doses of dinutuximab and GM-CSF is 18 mCi/kg. This radioimmunotherapy regimen is well-tolerated without additive toxicity. Preliminary efficacy data are encouraging in this heavily pre-treated patient population. A phase 2 trial of this regimen is planned in patients with R/R HRNB. Clinical trial information: NCT03332667.

A phase I study of TST001, a high affinity humanized anti-CLDN18.2 monoclonal antibody, in combination with capecitabine and oxaliplatin (CAPOX) as a first-line treatment of advanced G/GEJ cancer.

4062 Background: TST001 is a recombinant humanized IgG1 antibody specifically against human Claudin 18.2 (CLDN18.2) with high affinity and enhanced FcR engaging of NK cells, which can induce strong antibody-dependent cellular cytotoxicity (ADCC) activities. TST001 monotherapy dose-escalation study has been completed (IGCC2022-ABS-1152) and promising anti-tumor activities were observed in advanced gastric cancer patients with CLDN18.2 overexpression who had failed multiple lines of prior therapies. The current study is an open-label, multi-center, multiple cohorts, phase I clinical trial of TST001 monotherapy or in combination with standard treatments in Chinese patients with advanced or metastatic solid tumors (NCT04495296). Methods: This cohort is aimed to determine the recommended phase II dose, evaluate safety, tolerability and preliminary efficacy of TST001 in combination with CAPOX as a 1st line treatment of advanced G/GEJ cancer. A 3+3 design was utilized in the dose escalation phase with treatment naïve advanced G/GEJ cancer patients regardless of Claudin18.2 expression. Claudin 18.2 positive G/GEJ cancer patients were planned to be enrolled in the dose expansion phase in selected dose cohorts. Results: The TST001/CAPOX combination cohort was initiated in August 2021 and is ongoing in multiple sites in China with a data cutoff date of January 27, 2022. 12 subjects were dosed with TST001 with a dose range from 1 to 8mg/kg Q3W in combination with the standard dose of CAPOX in the dose escalation phase and one subject with central lab tested Claudin 18.2 overexpression was dosed in the expansion phase of TST001 at 6mg/kg Q3W with CAPOX. There was no subject experienced dose-limiting toxicity. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (76.9%), anemia (69.2%), vomiting, AST increased (63.8% respectively), hypoalbuminemia, ALT increased (46.2%, respectively). Treatment related grade 3 AEs were hypertension （15.4%）, anemia, hypoproteinemia, WBC count decreased, hypocalcemia aggravated (7.7%, respectively). Among the eight patients from the dose escalation part (with no CLDN18.2 expression selection yet with measurable disease ) with at least one post-treatment tumor assessment, four had achieved partial response, three had achieved stable disease and one had progressive disease as the best tumor response per RECIST1.1. Conclusions: Conclusion: TST001 in combination with CAPOX in first line gastric cancer patients is safe and encouraging anti-tumor activities have been observed. Additional data from the 6 mg/kg dose expansion cohort will be updated at the meeting. Clinical trial information: NCT04495296.

A multicenter phase Ib/II study of liposomal-irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) with nivolumab as second-line therapy for patients with advanced biliary tract cancer (BilT-03).

438 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy and treatment beyond first-line platinum doublet remains largely investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells less sensitive to T cell-mediated lysis, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent anti-PD-1 antibody in BTC provide a rationale for combination chemoimmunotherapy. We conducted a multi-center, phase Ib/II, single-arm study to investigate the role of liposomal-irinotecan, 5FU and LV in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC after progression or intolerance of first-line systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. The limited phase Ib portion evaluated 10 pts to determine the recommended phase 2 dose (RP2D) based on the probability of dose-limiting toxicity (DLT) rate <30% during days 1-29. Study treatment included 5FU 2400 mg/m2 over 46 hrs, LV 400 mg/m2, liposomal-irinotecan 70 mg/m2 at dose level 0 along with nivolumab 240 mg every 2 wks for up to 2 yrs in absence of disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS) rate with an alternative and null hypothesis of 5.0 mo and 2.9 mo (two-sided alpha 0.05, power 80%), respectively. Secondary endpoints included best overall response rate (ORR) per immune related (ir)RECIST, median overall survival (OS), 75th percentile estimates of PFS and OS, and safety. Exploratory objectives include biomarker analysis using include targeted panel exome/transcriptome and immune cell subsets in tissue. Results: 30 eligible pts (60% men, 83% Caucasian) including 10 pts in phase Ib and 20 pts in phase II with a median age of 63.5 yrs (range 36-75) were enrolled across 4 US sites between June 2019 and July 2021. In phase Ib, one pt experienced DLT (grade 3 enterocolitis); RP2D was confirmed at dose level 0. All 30 pts were included in study reported outcomes with a median follow-up time of 10.7 mo. Median PFS was 4.2 mo (95% CI, 1.9-10.2) and failed to reject the null hypothesis. Median OS was 7.5 mo (95% CI, 5.8-21.4). The 75th percentile estimates for PFS and OS are 10.2 mo (95% CI, 5.4-NE) and 21.4 mo (95% CI, 7.8-21.4). ORR estimates and toxicity data are pending and will be presented at the meeting. Conclusions: The observed median PFS is insufficient to reject the null hypothesis. The 75th percentile estimates for PFS and OS are suggestive of prolonged benefit with chemoimmunotherapy in a small fraction of patients with BTC. Clinical trial information: NCT03785873.

Abstract P162: Phase 1 trial of selinexor in children and adolescents with recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium trial

Abstract Introduction: Selinexor is a first-in-class, central nervous system (CNS) penetrant, oral inhibitor of exportin 1 (XPO1), the sole nuclear exporter of many key tumor suppressors. Selinexor is FDA-approved for refractory multiple myeloma and DLBCL and has been evaluated in a phase 1 trial in children with leukemia. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors, including lymphoma (NCT02323880). Methods: A rolling-six design was used to evaluate selinexor (10 or 25 mg tablets) administered twice or once weekly during a 28-day cycle. Dose determination was based on protocol-defined dose limiting toxicity (DLT) using CTCAEv4 during cycle 1. First dose pharmacokinetics (PK) were performed. Results: 43 subjects were enrolled (17 males); median (range) age was 15 (6-20) years. 27 (63%) had CNS tumors, most commonly high-grade glioma (n=12); 16 (37%) had extracranial solid tumors. 42 were evaluable for DLT. At the starting dose (35 mg/m2/dose, twice weekly), no DLTs were observed in 6 subjects, however, 2 subjects had unexpected late myelosuppression delaying initiation of cycle 2. The dosing schedule was amended to twice weekly for 3 weeks followed by a 1 week break. 12 subjects received 35 mg/m2/dose; 4 experienced DLTs [grade 3 fatigue (n=2), grade 3 thrombocytopenia (n=1), or grade 3 ALT increase (n=1)]. The dose was de-escalated to 20 mg/m2/dose, 3 weeks on, 1 week off. 12 subjects enrolled; 3 experienced a DLT [grade 3 increased AST/ALT, acute reversible neurologic changes, or neutropenia (each n=1)]. At the 20 mg/m2 (n=12) and 35 mg/m2 (n=19) dose levels, respectively, the mean ± SD Cmax (ng/ml) was 324±116 and 535±174, and AUC (hr•ng/ml) was 3092 ± 842 and 5156 ± 1227. This was comparable to PK in adults receiving 35 and 50 mg/m2. Based on a desire to achieve a higher Cmax and avoid breaks in schedule, and emerging evidence for similar effectiveness with decreased toxicity in adults receiving continuous once weekly dosing, we evaluated a dosing schedule with once weekly dosing for all 4 weeks of each cycle. At the initial dose level (45 mg/m2 weekly), 2 of 6 subjects had DLTs [prolonged grade 2 thrombocytopenia or grade 3 seizure in a primary CNS tumor patient]. Six subjects received 35 mg/m2/dose once weekly; 1 DLT [grade 3 thrombocytopenia] was observed. Non-dose-limiting toxicity (Grade ≥2 occurring in >10% of subjects during cycle 1) included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. Subjects received a median (range) of 1 (1-9) cycle; 13 received 2-3 cycles, and 6 received 5-9 cycles. Conclusions: Selinexor-related toxicities were primarily hematological and gastrointestinal. The maximum tolerated dose (MTD) of selinexor in children and adolescents with recurrent solid and CNS tumors is 20 mg/m2/dose twice weekly for 3 weeks followed by one week off. On a continuous once weekly schedule, the MTD and recommended phase 2 starting dose of selinexor is 35 mg/m2/dose. Citation Format: Adam L. Green, Charles G. Minard, Xiaowei Liu, Joel M. Reid, Kerice Pinkney, Stephan Voss, Marvin D. Nelson, Elizabeth Fox, Brenda J. Weigel, Julia Glade Bender. Phase 1 trial of selinexor in children and adolescents with recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P162.

Abstract CT112: Initial results from a Phase 1 trial of a first-in-class pan-CDC-like kinase inhibitor (SM08502) with proof of mechanism in subjects with advanced solid tumors

Abstract Dysregulation of alternative pre-mRNA splicing has been identified as a common mechanistic driver of tumor initiation, disease progression, and emergence of therapy resistance. An iterative screening campaign identified SM08502, a potent pan-inhibitor of CDC-like kinases (CLKs), which are known to regulate alternative splicing. In preclinical studies, SM08502 inhibited growth and induced apoptosis in a broad array of tumor models. Study NCT03355066 is a two-part Phase 1 first-in-human study that evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered SM08502 in subjects with advanced solid tumors. In Part 1A of the study, which utilized an accelerated-titration/3 + 3 dose-escalation design, 19 subjects were administered SM08502 at doses ranging from 10 mg to 80 mg; a maximum tolerated dose has not yet been identified. Systemic exposures showed dose-dependent increases from 10 mg to 80 mg and the mean time to maximal concentration (tmax) ranged from 3.3 to 5.9 hours on Cycle 1 Day 1 and from 1 to 24.6 hours on Cycle 2 Day 1. SM08502 had low-to-moderate clearance and a high volume of distribution, which resulted in a long terminal half-life (t½ > 24 hours) and accumulation of approximately 2- to 3.9-fold. Based on preclinical tumor xenograft models, exposures (AUC and Cmax) in the expected therapeutic range were attained. The most commonly reported adverse events (AEs) included nausea (12/19 [63.2%]), diarrhea (10/19 [52.6%]), fatigue (8/19 [42.1%]), and vomiting (7/19 [36.8%]), with the most common grade 3 or greater AEs being diarrhea (3/19 [15.8%]), anemia (2/19 [10.5%]), and decreased lymphocyte count (2/19 [10.5%]). The most common possibly or probably related serious AE (SAE) was diarrhea (2/19 [10.5%]). Two subjects experienced dose-limiting toxicity: one at the 40 mg dose level (elevated liver function tests [ALT and AST]) and a second at the 80 mg dose level (diarrhea). In peripheral blood mononuclear cells, evidence for disruption of alternative splicing was detected through expression changes associated with mRNA splicing and nonsense-mediated decay. Further, direct evidence for CLK1 inhibition was observed at tolerated doses, which provided proof of mechanism. Radiological assessment demonstrated tumor shrinkage in two subjects with endometrial cancer. In addition, stable disease lasting longer than 6 months was observed in four subjects. Further dose finding is planned prior to the Part 2 expansion. Conclusion: In this first-in-human study, PK and PD data demonstrate proof of mechanism for the pan-CLK inhibitor SM08502 at tolerated doses. Citation Format: Anthony Tolcher, Hani M. Babiker, Vincent Chung, Edward Kim, Justin Moser, Raghad Karim, Andre Vandross, David Sommerhalder, Aaron J. Scott, Marwan Fakih, Erminia Massarelli, Jeffrey Adams, Joshua Stewart, Carine Bossard, Long Do, Michael White, Darrin M. Beaupre, Erkut Borazanci. Initial results from a Phase 1 trial of a first-in-class pan-CDC-like kinase inhibitor (SM08502) with proof of mechanism in subjects with advanced solid tumors [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 CT112.

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE)

PurposeTo assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC).MethodsBEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer.ResultsThirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib–apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation.ConclusionsThese results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib–AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC.Trial registration no.NCT02924766 (ClinicalTrials.gov).

A phase I/II study of hydroxychloroquine and suba-itraconazole in men with biochemical relapse of prostate cancer (HITMAN-PC): Dose escalation results.

114 Background: Preclinical data show hydroxychloroquine (HCQ) and suba-itraconazole (SI) together enhance prostate cancer cell death. The proposed mechanism is lysosome dysfunction including sequestration of cholesterol in endosomes and inhibition of gogi-lyosome trafficking. HCQ/SI could delay androgen deprivation therapy (ADT) and its associated morbidity in men with biochemical relapse of prostate cancer. In this phase I/II study, maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of HCQ/SI was investigated in such patients. Methods: Patients received escalating doses of HCQ with fixed SI 150mg BD in rolling 6 design. This will be followed by a planned phase II Simon 2-stage cohort expansion. Results: Eleven men were treated with HCQ/SI. Median age 73 (range 69-77), baseline PSA 4.4 µg/L (1.6-22.4) and doubling time 5.3 months (3.3-15.3). Two experienced dose-limiting toxicity: grade 3 diarrhoea and grade 3 alanine transferase elevation, both at HCQ 600mg BD. Most common treatment-related adverse events (AEs) were hypertension (91% all grade/18% grade 3), QTc prolongation (55%/0%), diarrhoea (36%/9%), and nausea (36%/0%). There were no grade 4 AEs or deaths. While there were no PSA responses (≥50% fall from baseline), PSA PFS by PCWG3 criteria was 5.5 months (2.0-9.0), and PSA doubling time was prolonged at 4 and 12 weeks in 82% and 45% respectively. ADT-free and metastasis-free survival are 14.3 months (95% CI 4.9-23.8) and 15.9 months (95% CI unevaluable) respectively. PK data will be presented. Conclusions: HCQ/SI demonstrated acceptable safety with MTD 600mg BD and RP2D 400mg BD. There is early signal of activity and phase II enrolment is to begin. Clinical trial information: NCT03513211.

A Phase I Dose Escalation Study of Apatinib Combinated with Docetaxel as Second-line Therapy for Advanced Gastric Carcinoma

This study is a phase I clinical trial of 3+3 dose escalation. Three dose escalations of apatinib were employed in this study: 425 mg, 500 mg and 675 mg. Apatinib combined with fixed dose of docetaxel (60 mg/m2, d1, thrice inw). 21 d as one treatment cycle was repeated. Maximum tolerated dose, safety and efficacy were analyzed. From October 2015 to June 2017, a total of eight patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who had failed in the previous first-line treatment were enrolled. One dose-limiting toxicity was observed in patients who received apatinib with the dose of 425 mg combined with docetaxel, but no dose-limiting toxicity was found in additional three patients. Two patients treated with apatinib at the dose of 500 mg combined with docetaxel experienced dose-limiting toxicity, including grade 3 oral mucositis and grade 4 neutropenia respectively. Therefore, Maximum tolerated dose of apatinib was 425 mg. No complete response and partial response were observed; five patients showed stable disease and two had progressive disease. The disease control rate was 71.43 %. The median progression free survival was 4.4 mo (95 % confidence interval, 1.48-7.03) and the median overall survival was 11.5 mo (95 % confidence interval, 3.06-16.56). All patients developed adverse events and treatment-related adverse events. Seven patients (77.78 %) showed treatment-related adverse events greater than or equal to grade 3, mostly including neutropenia and hand-foot syndrome. The combination of apatinib with the dose of 425 mg and docetaxel was well tolerated and support further evaluation for the second-line treatment of advanced gastric cancer.

EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

Safety and Antitumor Effects of CD19-Specific Autologous Chimeric Antigen Receptor-Modified T (CAR-T) Cells Expressing the Inducible Caspase 9 Safety Switch (iC9-CAR19 T Cells) in Adult Acute Lymphoblastic Leukemia (ALL)

Safety and Antitumor Effects of CD19-Specific Autologous Chimeric Antigen Receptor-Modified T (CAR-T) Cells Expressing the Inducible Caspase 9 Safety Switch (iC9-CAR19 T Cells) in Adult Acute Lymphoblastic Leukemia (ALL)

Maximal Tolerated Dose of the BCL-2 Inhibitor Venetoclax in Combination with Daunorubicin/Cytarabine Induction in Previously Untreated Adults with Acute Myeloid Leukemia (AML)

Maximal Tolerated Dose of the BCL-2 Inhibitor Venetoclax in Combination with Daunorubicin/Cytarabine Induction in Previously Untreated Adults with Acute Myeloid Leukemia (AML)

HM43239, a Novel Small Molecule Inhibitor of FLT3, in Acute Myeloid Leukemia (AML) with and without FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1/2 Study

HM43239, a Novel Small Molecule Inhibitor of FLT3, in Acute Myeloid Leukemia (AML) with and without FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1/2 Study

A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation

AbstractProgrammed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti–PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti–PD-1 antibody for post–alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti–PD-1 therapy post–alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT 01822509.

The predictive and prognostic value of low skeletal muscle mass for dose-limiting toxicity and survival in head and neck cancer patients receiving concomitant cetuximab and radiotherapy

PurposeThis study aims to investigate the predictive value of low skeletal muscle mass (SMM) for cetuximab dose-limiting toxicity (DLT) and its prognostic value in head and neck squamous cell carcinoma (HNSCC) patients treated with concomitant cetuximab and radiotherapy.MethodsPatients diagnosed with HNSCC and treated with primary or adjuvant concomitant cetuximab and radiotherapy were included. Clinical and demographic variables were retrospectively retrieved and SMM was measured at the level of the third cervical vertebra using pre-treatment diagnostic computed tomography or magnetic resonance imaging. An optimal cut-off value for low SMM was determined based on the lowest log-likelihood associated with cetuximab DLT. A multivariate linear regression model was used to determine predictive factors for cetuximab DLT. The prognostic value of low SMM for disease-free and overall survival was analyzed using Kaplan–Meier curves.ResultsThe optimal cut-off value for low SMM as a predictor of cetuximab DLT was an LSMI ≤ 45.2 cm2/m2. Of the 91 included patients, 74.7% had low SMM and 30.8% experienced cetuximab DLT. At multivariate analysis, low SMM had no predictive value for DLT (OR 0.83; 95% CI 0.27–2.56; p = 0.74). The Kaplan–Meier curve demonstrated that patients with low SMM had significantly lower overall survival (Log Rank χ2 = 5.87; p = 0.02).ConclusionLow SMM is highly prevalent in HNSCC patients treated with concomitant cetuximab and radiotherapy. Low SMM has no predictive value for cetuximab DLT in HNSCC patients. Low SMM is probably not a prognostic factor for overall survival in highly selected HNSCC patients treated with concomitant cetuximab and radiotherapy and unfit for platin-based chemotherapy.