Preliminary Evidence Of Antitumor Activity Research Articles

DIPG-84. PHASE 1 DOSE-ESCALATION STUDY OF ACT001 IN PEDIATRIC PATIENTS WITH ADVANCED BRAIN AND SOLID TUMORS SHOWS ACTIVITY IN DIFFUSE MIDLINE GLIOMA (DMG)

Abstract BACKGROUND ACT001, an oral parthenolide derivative targeting STAT3 and NF-κB pathways, has shown activity in preclinical models of DMG. We evaluated safety, toxicity and activity of ACT001 in this recently completed, first-in-child study of DMG and other relapsed/refractory brain and solid tumors. METHODS Eligible patients ≥ 1 and ≤ 21 years old were enrolled with dose escalation following a rolling 6 design and tumor lesions evaluated every 8 weeks per RANO/ RECIST criteria. RESULTS A total of 29 patients were enrolled across 5 cohorts, including 19 with DMG (13 with Diffuse Intrinsic Pontine Glioma (DIPG)). Median age was 11 years for the whole cohort and 7 years (3-17) for DMG patients. Safety was evaluated in escalating doses in 188, 533, 700, 875 and 1100 mg/m2,BID cohorts. No DLT nor grade 3 and above TRAE was identified. One SUSAR was noted for a grade 1 pain in extremity event. Peak ACT001 concentration for each dose cohort were estimated based on limited PK sampling time (cycle 1 day 1 at pre-dose, 2 and 4 hours post dose; cycle 1 day 15 and cycle 2 day 1 both at pre-dose). ACT001 peak concentration plateaued at the highest dose levels, fluctuating in the range of 6360, 5430 and 5980 mg/m2 for 700, 875 and 1100 mg/m2 cohorts respectively. The half-life was approximately 3 hours. 8/14 DMG patients treated at ≥ 700 mg/m2 exhibited objective response or stable disease (SD), including one patient with SD for 14 months, another patient with confirmed Partial Response who remained on study for 11-months before disease progression and five other patients with different degrees of tumor burden reduction. CONCLUSION ACT001 was well tolerated and showed preliminary evidence of anti-tumor activity in DMG/DIPG patients dosed at the highest dose levels. A Phase 2 trial is planned using 875 mg/m2 as the RP2D.

Efficacy from the phase 1 study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with head and neck squamous cell carcinoma.

6042 Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) have limited treatment options after progression on first-line immunotherapy with or without platinum-based chemotherapy. Taxanes in this setting have historically demonstrated response rates around 14-27%. FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. This allows the drug to remain in solution until it can enter a cancer cell and preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel. In the phase I study of FID, we determined 125 mg/m2 as the recommended phase 2 dose. Here we present updated safety and efficacy data with emphasis on pts with HNSCC. Methods: The study evaluated the safety, PK, and preliminary efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 160mg/m2 using a 3+3 dose escalation. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and < 3 prior lines of cytotoxic therapy. Results: 46 patients were enrolled, of which 9 had HNSCC (2 nasopharynx, 2 sinonasal, 3 oropharynx, 1 oral cavity, and 1 occult primary). Median age (range) was 60 (53-75). ECOG PS was 1 in all HNSCC pts. Median number of prior therapies was 3 (1-5) and all had received prior immune checkpoint inhibitor. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts included rash (72%), alopecia (52%), leukopenia (46%), pruritus (43%), neutropenia (41%), anemia (37%), fatigue (37%), nausea (28%), and anorexia (28%). Grade 3/4 TRAEs occurring in >1 pt were maculopapular rash (35%), neutropenia (20%), leukopenia (20%), anemia (17%), lymphopenia (7%), and febrile neutropenia (4%). No pts experienced > grade 2 peripheral sensory neuropathy; 20% experienced grade 1-2. Across all solid tumors, the overall response rate (ORR) was 17%. In patients with HNSCC, 5 (56%) had a partial response, 2 (22%) had stable disease, and 2 (22%) had PD. Three out of 5 HNSCC patients previously treated with a taxane achieved a partial response. Median duration of treatment was 4 months (1-15). Conclusions: FID demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated HNSCC pts across different primary tumor sites, with an ORR 56%, including those with prior taxane exposure. A phase 2 study of FID with cetuximab in pts with HNSCC is planned to begin enrollment in 2024. Clinical trial information: NCT03537690 .

ATTAINMENT: A phase Ib trial of MDX-124, a first-in-class annexin-A1 targeting antibody, alone and in combination with anti-cancer treatments, in patients with advanced solid tumors.

TPS2671 Background: Annexin-A1 is a Ca2+-dependent phospholipid binding protein that is secreted from both cancer and immune cells in response to several physiological stimuli. Secreted annexin-A1 activates formyl peptide receptors driving cancer cell proliferation, angiogenesis, migration, and drug resistance, as well as modulating the tumor microenvironment. Annexin-A1 overexpression is observed in multiple cancers, including pancreatic, triple-negative breast, colorectal, lung and prostate, correlating with poor prognosis and decreased overall survival. MDX-124 is a novel, first-in-class humanised monoclonal antibody that targets annexin-A1. It significantly reduces cancer cell growth via cell cycle arrest, inhibits tumour growth in-vivo, reduces metastasis and induces antibody-dependent cellular cytotoxicity in annexin-A1 expressing cancer cells. Additionally, MDX-124 has synergistic activity when combined with chemotherapy and immunotherapy in pre-clinical models. These data indicate blocking the action of annexin-A1 has anti-cancer and therapeutic activity. Methods: ATTAINMENT is a modular, multi-arm, First-in-Human trial to evaluate the safety and tolerability of MDX-124 alone and in combination with anti-cancer treatments, in participants with locally advanced, unresectable, or metastatic solid malignancies. Module 1 is a single agent dose escalation using a Bayesian optimal interval (BOIN) design with an expansion cohort, followed by Module 2, which will evaluate MDX-124 in combination with standard of care in indication-specific arms by using a traditional 3+3 dose escalation scheme. Adult patients (≥18 years) with ECOG performance score 0-1 and histologically/cytologically confirmed solid tumors believed to overexpress annexin-A1 which are not amenable to or refractory to standard therapy, or for which no standard therapy exists are eligible. The primary objective is to determine the recommended phase 2 dose (RP2D) of MDX-124 both as a single agent and in combination with anti-cancer treatments. Secondary objectives will assess the safety and tolerability of MDX-124 when given as a single agent or in combination with anti-cancer treatments, characterize pharmacokinetic parameters and assess evidence of preliminary anti-tumor activity per RECIST v1.1 criteria. Exploratory objectives will assess host immune response to MDX-124 (immunogenicity and immunophenotyping), circulating levels of annexin-A1 at baseline and after dosing to correlate with response and outcome to MDX-124, and the impact of MDX-124 on blood/tissue biomarkers. The study began enrolling patients at sites in the UK in August 2023. Cohorts at 1, 2.5 and 5 mg/kg have been completed without DLT and enrollment to cohort 4 (10 mg/kg) began in January 2024. Clinical trial information: ISRCTN78740398.

Abstract CT095: Phase 1 evaluation of triple therapy with boserolimab (anti-CD27 agonist), pembrolizumab, and chemotherapy in patients with triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) <10: Safety, antitumor activity, and association between biomarkers and response

Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) is an approved therapy for patients (pts) with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) based on results from KEYNOTE-355. However, there is unmet need for effective treatment options in pts with PD-L1 CPS <10. In a first-in-human, open-label, phase 1 study (NCT03396445), treatment with escalating doses of the humanized anti-CD27 agonist boserolimab (MK-5890) alone and with pembro had acceptable safety and preliminary evidence of antitumor activity in pts with advanced solid tumors. We report results for a dose-expansion cohort of this study in pts with metastatic TNBC and PD-L1 CPS <10 tumors who received first-line triple therapy with boserolimab, pembro, and chemo. Exploratory analyses in this cohort assessed the association of baseline T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) with ORR. Methods: This dose-expansion cohort enrolled pts aged ≥18 y with previously untreated locally recurrent inoperable or metastatic TNBC, measurable disease per RECIST v1.1, ECOG PS of 0/1, and tumors expressing PD-L1 at the cutoff of CPS <10 per PD-L1 IHC 22C3 pharmDx (local or central testing). Pts received boserolimab 30 mg IV Q6W plus pembro 400 mg IV Q6W for 18 cycles plus nab-paclitaxel 100 mg/m2 (3 weeks on [days 1, 8, and 15]/1 week off). Primary objectives were safety/tolerability. A secondary objective was ORR per RECIST v1.1 by investigator assessment. Baseline TcellinfGEP was assessed using the NanoString PCI assay (N=31); TMB was assessed using the Illumina TSO500 mutational panel assay (N=21). Results: 41 pts were enrolled in the dose-expansion cohort. Median study follow-up at data cutoff (Apr 25, 2023) was 11.1 (range, 2.2-20.5) mo. The most common treatment-related AEs were fatigue (51.2%), pruritus (51.2%), and alopecia (46.3%). Grade 3/4 treatment-related AEs occurred in 56.1% of pts (23/41); no grade 5 treatment-related AEs occurred. 9.8% of pts (4/41) discontinued ≥1 study treatment due to treatment-related AEs. Confirmed ORR was 46.3% (95% CI, 30.7%-62.6%), with 2 CRs and 17 PRs; 14 pts had SD, 5 had PD, and 3 had no postbaseline assessment at data cutoff. Median PFS was 10.3 (95% CI, 4.2-not reached) mo. No clear association between TcellinfGEP or TMB and confirmed ORR was observed; responses were observed in pts with non-TcellinfGEP-high (less than −0.318) and non-TMB-high (<10 mut/Mb) tumors. Conclusions: In pts with TNBC and tumors expressing PD-L1 at the cutoff of CPS <10, triple therapy with boserolimab, pembro, and chemo had acceptable safety and showed preliminary evidence of antitumor activity regardless of baseline TcellinfGEP expression or TMB status. Citation Format: Carlos Rojas, Bernard Gaston Doger de Spéville, Seock-Ah Im, Ronnie Shapira-Frommer, María De Miguel, Lucía González Cortijo, Margarita Romeo Marin, Maja de Jonge, Mark Ayers, Yiwei Zhang, Song Zhai, Elliot Chartash, Konstantin Dobrenkov, Joohyuk Sohn. Phase 1 evaluation of triple therapy with boserolimab (anti-CD27 agonist), pembrolizumab, and chemotherapy in patients with triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) <10: Safety, antitumor activity, and association between biomarkers and response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT095.

Abstract PR010: Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001

Abstract Background: RMC-6236 is an oral RASMULTI(ON) tri-complex inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. RMC-6236 binds to cyclophilin A, which is abundantly expressed in normal tissues and tumors, resulting in a binary complex that potently binds to RAS(ON) to form a tri-complex, blocking downstream signaling. Preclinical studies with RMC-6236 demonstrated deep and sustained regressions across multiple RASMUT tumor types at well tolerated doses, particularly tumors harboring KRAS glycine-12 substitutions (KRASG12X). Methods: Patients with previously treated, advanced KRASG12X mutant solid tumors were enrolled at escalating doses of single agent RMC-6236 administered once daily (QD). Results: As of May 11, 2023, 54 patients received RMC-6236 at dose levels from 10 to 220 mg QD. The majority of patients had pancreatic cancer (26 [48%]), non-small cell lung cancer (13 [24%]), or colorectal cancer (10 [19%]). The most common (≥10% of patients) treatment-related adverse events (TRAEs) were rash and gastrointestinal (GI)-related toxicities that were all Grade 1 or 2 in severity. Most rashes were acneiform (35%) or maculopapular (13%), consistent with known on-target rash presentation from other RAS pathway inhibitors. Rash frequency, but not severity, was dose-dependent. One patient required a dose reduction due to Grade 2 acneiform rash. The most common GI-related toxicities were nausea (32%), diarrhea (19%), and vomiting (15%) that were manageable with standard supportive care. There were two Grade ≥3 TRAEs in patients with pancreatic cancer: Grade 4 large intestine perforation at the site of an invasive tumor that reduced in size on treatment, and Grade 3 pancreatitis reported at the time of disease progression. Thirty-one patients (57%) remain on treatment, and 23 (43%) discontinued, including 17 (31%) due to progressive disease (PD) per RECIST v1.1, 2 (4%) due to clinical progression, and other reasons due to adverse event (Grade 4 large intestine perforation), death (due to PD), investigator’s decision, or patient withdrawal (1 patient each). RMC-6236 exhibited dose-dependent increases in exposure in patients with no apparent accumulation in the blood following repeated daily dosing. At 220 mg QD, exposure to RMC-6236 was within range of the preclinical exposures in mice that demonstrated significant tumor regressions. Preliminary evidence of anti-tumor activity, including partial responses per RECIST v1.1, was observed in patients across several tumor types and dose levels. Molecular responses were observed with reduction in circulating tumor DNA of the KRAS-mutated allele and other somatic mutations consistent with inhibition of mutant RAS by RMC-6236. Conclusions: RMC-6236 is safe and well tolerated at doses that induce anti-tumor activity in patients with tumors harboring KRASG12X mutations and has favorable pharmacokinetics with oral dosing. A recommended phase 2 dose has not yet been determined and dose escalation is ongoing. Citation Format: Alexander I Spira, Alexander N Starodub, Kathryn C Arbour, David Sommerhalder, Brian M Wolpin, Minal Barve, Ignacio Garrido-Laguna, Salman Punekar, Meredith Pelster, Sumit Kar, Jamie Wong, Tong Lin, Rakesh Raman, Lin Tao, Zeena Salman, Xiaolin Wang, W. Clay Gustafson, David S Hong. Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR010.

A Phase 1A/B Combination Study of Pegargiminase (ADI-PEG 20), Venetoclax and Azacitidine in Patients with Acute Myeloid Leukemia

Background and Significance: Outcomes for adverse-risk acute myeloid leukemia (AML), especially in older and/or unfit patients and those with relapsed/refractory disease, remain poor despite several new drug approvals over the last decade. A promising area for drug development in AML resides in targeting tumor metabolism. The metabolism therapy of pegargiminase (ADI-PEG 20), an agent consisting of the arginine-degrading enzyme arginine deiminase combined with polyethylene glycol, has demonstrated preclinical and clinical efficacy as monotherapy and in combination in AML. ADI-PEG 20 has been shown to be most effective when tumors are deficient in argininosuccinate synthetase (ASS1), the rate limiting step in the urea cycle to form arginine. AML is one such cancer, which appears to be addicted to arginine, with about 90% of AML patient samples being deficient in ASS1 expression. The focus of this phase 1A/B study is to explore combination treatment with ADI-PEG 20 added to standard front-line venetoclax and azacitidine therapy in AML. Study Design and Methods: This study (NCT05001828) is an open label, single arm, multicenter phase 1 trial for patients with newly diagnosed adverse-risk AML unfit for intensive chemotherapy or relapsed/refractory AML. Eligible patients must be ≥18 years old and are ineligible if determined favorable-risk by European LeukemiaNet (ELN) criteria. The primary objective is to determine the recommended phase 2 dose (RP2D) of ADI-PEG 20 administered by intramuscular injection weekly in combination with venetoclax and azacitidine. Secondary objectives include evaluating preliminary evidence of antitumor activity and determining the pharmacodynamics and immunogenicity of ADI-PEG 20 in combination with venetoclax and azacitidine. Patients receive ADI-PEG 20 via intramuscular injection on day -3 and then weekly along with the combination regimen of azacitidine 75 mg/m 2 for 7 days and oral venetoclax on days 1-28 of the first cycle and days 1-21 for subsequent cycles. Subjects may remain on study treatment for a maximum of 24 cycles (96 weeks). The study is designed with a lead-in group exploring 2 dose levels of ADI-PEG 20 and an RP2D expansion group with 18 subjects each in 2 cohorts: Cohort 1 including previously treated (relapsed/recurrent) or refractory AML and Cohort 2 including untreated AML with high-risk features and ineligible for intensive chemotherapy. In total, 48 to 60 subjects are planned across up to 5 centers in the United States. In the RP2D cohorts, the target response rates for the relapsed/refractory and untreated AML with high-risk features are 25% and 55%, respectively. Safety is assessed by comparing adverse events, laboratory results, and physical examination results. A greater than 20% clinically significant drug-related grade 3 or higher toxicity rate occurring in the first cycle is considered unacceptable. To assess efficacy, the number and percent of subjects' objective response rate, duration of response, and overall survival (OS) will be summarized. Pharmacodynamics using peripheral blood arginine and citrulline levels will be summarized for all subjects by time point for the observed value as well as for the change from baseline value and by duration of arginine depletion and citrulline increase. Immunogenicity, determined by antibodies to ADI-PEG 20, will be summarized for all subjects by time point for the observed value as well as for the change from baseline value. Semiquantitative assessment of ASS1 expression by immunoblots and/or immunohistochemistry or other appropriate means will be summarized descriptively. Demographics, clinical characteristics (including duration of response), and safety data of the patients will be summarized using descriptive statistics. For the efficacy analysis, we will estimate the response rate along with the 95% credible interval. The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate. The distribution of time-to-event endpoints, such as OS and others, will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests. The trial is currently enrolling and presents a novel and promising therapeutic strategy for patients with high-risk newly diagnosed and relapsed/refractory AML.

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.

HGG-28. INTERIM ANALYSIS OF THE GCC1949 PHASE 2 TRIAL USING INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH PEDIATRIC BRAIN TUMORS

Abstract Brain tumors are the leading cause of cancer-related death in children. We report interim results of an ongoing multi-institutional phase 2 trial (NCT04049669) of the IDO pathway-inhibitor indoximod utilized in a chemo-immunotherapy regimen for patients 3-21 years of age with either recurrent malignant brain cancer or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Patients are treated with oral indoximod (38.4 mg/kg/day, divided BID) plus oral temozolomide (200 mg/m2/day for 5 days) in 28-day cycles. Patients for whom radiation therapy is planned as standard-of-care receive indoximod during the up-front radiation regimen. During treatment, palliative radiation, surgery, or dexamethasone are allowed as needed for clinical management. To date, 53 patients have been treated. Estimated median follow-up time was 23 months (range 0.2-35.5 months), and indoximod-based therapy was well tolerated. Estimated median overall survival (OS) was 15 months for the entire mixed population (n= 53, 95%-C.I. 11.5-23.2 months); 23.8 months for recurrent ependymoma (n=26); 13.5 months for recurrent medulloblastoma (n=12); 5.8 months for recurrent glioblastoma/diffuse midline glioma (GBM/DMG, n=9, excludes DIPG); and 9.6 months for newly-diagnosed DIPG (n=6). For the 39 response-evaluable patients to date (those with measurable disease and at least one follow-up MRI on-therapy), objective response in any single lesion by pediatric RANO criteria occurred in 20/39 patients (9/17 ependymoma, 9/11 medulloblastoma, 0/6 GBM/DMG, 2/5 DIPG). Lesion response was associated with significantly better overall survival (estimated median OS 23.2 months, n=20) compared to patients without lesion response (median OS 6.6 months, n=19) (p=0.0005). Single-cell RNA sequencing of serial peripheral blood samples allowed identification of expanded T cell clones, which was correlated with survival. Updated results from the first 53 patients will be presented. These data are replicating results of the preceding phase 1 study (NCT02502708) and provide preliminary evidence of anti-tumor activity in pediatric brain tumors.

A phase 1 dose escalation/expansion study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.

3026 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel, with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 160mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and ≤ 3 prior lines of cytotoxic therapy for advanced disease. Results: Thirty-six patients were treated across 7 dose levels. Median age was 61 (39-65). ECOG PS was 2 in 1 patient, 1 in 69% of patients. Median number of prior therapies was 2 (1-5). Median number of cycles was 2.5 (1-30). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and 3 additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 4 WBC decrease at 125 mg/m2, and 1 DLT of G3 febrile neutropenia at 160 mg/m2. There was no MTD. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (56%), leukopenia (47%), pruritus (44%), neutropenia (42%), anemia (42%), fatigue (39%), nausea (33%), anorexia (31%), dysgeusia (25%) and peripheral sensory neuropathy (25%). Grade 3/4 TRAEs occurring in >1 pt were maculopapular rash (25%), anemia, neutropenia, and leukopenia (17% each). Of 36 evaluable patients, 7 (19%) had a partial response by RECIST 1.1 (pancreatic, biliary tract, and HNSCC) and 13 (36%) had stable disease. Three out of 4 HNSCC patients with PR had previously been treated with docetaxel. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and t1/2 is between 18-26 hours. Based on overall tolerability and PK, the dose of 125mg/m2 (dose level 6) has been chosen as RP2D. Conclusions: FID has a manageable safety profile and demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. No high-grade neuropathy has been noted to date. RP2D of FID is set at 125mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. Clinical trial information: NCT03537690 .

Phase I safety and preliminary efficacy of PM1003, a bispecific antibody targeting PD-L1 and 4-1BB, in patients with advanced solid tumors.

e14511 Background: PM1003 is a VHH-based anti-PD-L1/4-1BB bispecific antibody. The anti-4-1BB VHH arm binds to a unique epitope at the CRD4 region of 4-1BB, activating 4-1BB signals through cross-linking in the presence of PD-L1 that is often upregulated in the tumor microenvironment, thus avoiding harm to healthy tissues. This is the First In Human study of PM1003. Methods: This study was conducted with a standard 3+3 dose escalation design (Part A: single doses of 0.02, 0.1, 1, 3, 6, and 10 mg/kg for DLT evaluation after 3 weeks followed by Q2W for further administration) and dose expansion (Part B). For Part A, the primary endpoint was safety and tolerability with secondary endpoint of ORR per RECIST 1.1. For Part B, ORR per RECIST 1.1 was the primary endpoint and the secondary endpoints were safety and PK. Results: As of February 9, 2023, a total of 17 subjects have received at least 1 dose of PM1003, including 16 subjects in Part A (3 subjects in each of the 0.02, 0.1, 1, 3 mg/kg dose levels respectively and 4 subjects in 6 mg/kg), and 1 subject in Part B (1 mg/kg Q2W). In Part A, no DLTs were observed up to 6 mg/kg. Of the 17 patients, TRAEs occurred in 15 subjects (88.2%), ≥ Grade 3 TRAEs occurred in 5 subjects (29.4%). No patient discontinued PM1003 administration due to TRAE. The most common TRAEs were anaemia (35.3%), neutrophil count decreased (29.4%), white blood cell count decreased (29.4%), platelet count decreased (29.4%), fatigue (23.5%). 11 subjects completed at least one efficacy evaluation in part A. The median duration of PM1003 exposure was 9.9 weeks (range, 3.1-31.1 weeks). The ORR per RECIST 1.1 was 9.1% with a DCR of 54.5%. Preliminary evidence of antitumor activity has been observed in 1 subject with gastric cancer (1 mg/kg Q2W) who was enrolled after previous surgery, chemotherapy, anti-PD-1 and anti-HER2-ADC treatment, and had a partial response of 87.8% in target lesion reduction during the first efficacy evaluation (7 weeks) after PM1003 treatment. T1/2 of PM1003 of 1 mg/kg and 3 mg/kg dose level is 6.3 and 12.8 days, respectively. Receptor occupancy of PD-L1 in the 1 mg/kg and 3 mg/kg cohorts reached saturation at 336 hours after the first single dose and maintained at an almost stable state. Conclusions: PM1003 was well-tolerated up to 6 mg/kg and has shown preliminary anti-tumor activity in a patient who was previously treated with multiple drug modalities including anti-PD-1. The dose-escalation at 10 mg/kg and dose expansion are ongoing. Clinical trial information: ChiCTR2100052887 .

Combination L-Glutamine with Gemcitabine and Nab-Paclitaxel in Treatment-Naïve Advanced Pancreatic Cancer: The Phase I GlutaPanc Study Protocol.

Advanced pancreatic cancer is underscored by progressive therapeutic resistance and a dismal 5-year survival rate of 3%. Preclinical data demonstrated glutamine supplementation, not deprivation, elicited antitumor effects against pancreatic ductal adenocarcinoma (PDAC) alone and in combination with gemcitabine in a dose-dependent manner. The GlutaPanc phase I trial is a single-arm, open-label clinical trial investigating the safety of combination L-glutamine, gemcitabine, and nab-paclitaxel in subjects (n = 16) with untreated, locally advanced unresectable or metastatic pancreatic cancer. Following a 7-day lead-in phase with L-glutamine, the dose-finding phase via Bayesian design begins with treatment cycles lasting 28 days until disease progression, intolerance, or withdrawal. The primary objective is to establish the recommended phase II dose (RP2D) of combination L-glutamine, gemcitabine, and nab-paclitaxel. Secondary objectives include safety of the combination across all dose levels and preliminary evidence of antitumor activity. Exploratory objectives include evaluating changes in plasma metabolites across multiple time points and changes in the stool microbiome pre and post L-glutamine supplementation. If this phase I clinical trial demonstrates the feasibility of L-glutamine in combination with nab-paclitaxel and gemcitabine, we would advance the development of this combination as a first-line systemic option in subjects with metastatic pancreatic cancer, a high-risk subgroup desperately in need of additional therapies.

Abstract CT093: Preliminary evidence of antitumor activity of Ipatasertib (Ipat) and Atezolizumab (A) in glioblastoma (GBM) patients (pts) with PTEN loss in the Phase 1 Ice-CAP trial (NCT03673787)

Abstract Background PTEN loss of function is frequent in GBM correlating with poor prognosis, impaired antitumor responses and reduced efficacy of Immune Checkpoint Inhibitors (ICI). Ipat is a potent, selective, small-molecule inhibitor of Akt. Ipat efficiently depletes FOXP3+ regulatory T cells from the tumor microenvironment (TME) resulting in increased infiltration of effector T cells in solid tumors (Lopez 2020, AACR). We hypothesize that Akt inhibition in PTEN loss glioblastomas may deplete the TME of suppressive immune cells, and render malignant brain tumors more responsive to ICIs. Methods Relapsed WHO grade IV GBM pts with stable neurological symptoms ≥5 days prior to enrollment, requiring <3mg Dexamethasone were recruited into a dose determination cohort (A2; n=12) and an expansion cohort (B3; n=11) of this early phase, open-label trial studying the combination of Ipat and A. Primary objectives were to determine the safety and tolerability of the combination (A2) and preliminary efficacy (B3). Results 23 recurrent GBM pts (median age 55 yrs (25-71 yrs; 74% male) were enrolled. Median ECOG PS 1. All pts had surgery followed by radical-chemoradiotherapy. Median prior lines of therapy 1 (range 1-4). 15 pts had PTEN loss by IHC (H<30) indicative of biallelic loss of function, 1 had deleterious PTEN mutations detected by next generation sequencing. No DLTs, no significant treatment-related (TR) serious adverse events (SAEs), or immune-related AEs were observed. Most common TR AEs were G1-2 diarrhea (61%), rash (26%) and mucositis (22%). Clinical benefit rate (CR, PR and SD> 6 cycles) in 19 efficacy evaluable pts was 32% (6/19 overall) and 28.6% (4/14) for pts with PTEN loss. Multiplex IHC of archival samples (n=19) showed PTEN loss tumors had significantly greater numbers of CD3+ infiltrating T-lymphocytes within the TME compared to PTEN wild type tumors (median 53.64/mm2 vs 1.94/mm2; p=0.0021). Within the PTEN loss cohort (n=13), pts with clinical benefit had significantly higher baseline number of CD8+ effector T cells as compared to non-responders (median 46.50/mm2 vs 8.21/mm2; p=0.0336). Two pts with PTEN loss proceeded to re-resection on trial. One exceptional responder, a 58yr male refractory to radical chemo-radiotherapy and Bevacizumab had a resection of enhancing disease after 5 cycles that showed >70% depletion of CD4+ T regulatory cells with an increase in CD8+ lymphocyte infiltration and no residual evidence of tumor (pathological CR). In contrast, a non-responding patient who proceeded to debulking surgery had no change in infiltration of CD8+ lymphocytes, but a marked increase (>27-fold) in CD4+ regulatory T cells. Conclusion The RP2D of 400mg Ipa OD + 1200mg A Q3W was well tolerated in GBM pts. Early efficacy signals were detected with PTEN loss being a promising predictive biomarker for response to combination. Citation Format: Crescens Tiu, Wing Hing Yau, Liam C. Welsh, Timothy L. Jones, Anna Zachariou, Toby Prout, Mona Parmar, Alison J. Turner, Robert W. Daly, Christina Yap, Mateus Crespo, Bora Gurel, Ruth M. Riisnaes, Shaun A. DeCordova, Karen E. Swales, Udai Banerji, Anna R. Minchom, Adam Sharp, Johann S. de Bono, Juanita S. Lopez. Preliminary evidence of antitumor activity of Ipatasertib (Ipat) and Atezolizumab (A) in glioblastoma (GBM) patients (pts) with PTEN loss in the Phase 1 Ice-CAP trial (NCT03673787) [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 CT093.

Abstract CT150: Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib (ATG-008) in HBV+ advanced hepatocellular carcinoma (HCC) subjects who have received at least one prior line of systemic therapy (TORCH)

Abstract Background: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase (PI3K) family, which has been confirmed to be closely related to the development of a variety of human cancers. Onatasertib (ATG-008) is a 2nd generation mTOR inhibitor which inactivates both mTORC1 and mTORC2. Our previous clinical investigation (NCT01177397) has demonstrated preliminary evidence of antitumor activity of onatasertib across multiple solid and hematologic malignancies, with encouraging signals of activity in subjects with hepatitis B virus (HBV)+ unresectable, refractory HCC. Methods: Asian patients with advanced HBV+ HCC who had experienced progressive disease after at least 1 line of systemic therapy were enrolled in this study. Onatasertib was administered orally once a day (QD) at 3 dose levels (15 mg, 30 mg and 45 mg) or 20 mg twice daily (BID). The primary endpoints were pharmacokinetics (PK), safety and efficacy (NCT03591965). Results: As of July 11, 2022, 73 patients were enrolled and evaluated. The median age was 52.0 years and the median follow up duration was 26.5 months. The mean number of prior lines was 1.8. 63 patients (86.3%) had at least one Grade 3-4 treatment emergent adverse event (TEAE), and 25 (34.2%) had at least one serious adverse event (SAE). Among the 73 subjects, 3 achieved confirmed partial response (PR), all in the 45 mg QD cohort. 18 pts were enrolled in the 45 mg QD cohort, in which 11 (61.1%) pts had received at least 2 prior lines of systemic therapy and 15 (83.3%) pts had been exposed to an anti-PD-1/PD-L1 antibody. The overall response rate (ORR) in the 45 mg QD cohort was 16.7%. The median progression-free survival (mPFS) was 3.0 months (95% CI 1.9, 4.6) in the intention to treat (ITT) population and was 5.3 months (95% CI 1.9, 7.6) in the 45mg QD cohort. Median overall survival time (mOS) was not evaluable in the 45 mg QD cohort and the mOS was 13.4 months (95% CI 7.4, 19.8) in the ITT population. Onatasertib demonstrated linear pharmacokinetics between 15 mg QD and 45 mg QD in this Asian population and there was no significant exposure accumulation after multiple dosing, as previously seen in the US population. Conclusion: Onatasertib (ATG-008) showed encouraging single agent antitumor activity in patients with HBV+ advanced HCC after at least 1 prior systemic therapy, notably in the 45 mg QD dose level, in which most patients had been previously exposed to anti-PD-L1/PD-1 therapy. The results indicates that onatasertib has potential efficacy in HBV+ HCC patients who failed prior CPI treatment. Further study may be warranted, particularly in HBV+ HCC patients who have failed prior anti-VEGFR and anti-PDL1/PD-1 therapy. Citation Format: Shukui Qin, Xiaoyan Lin, Zhiqaing Meng, Zhenggang Ren, Yuxian Bai, Shanzhi Gu, Li Zheng, Qiu Li, Sun-Yong Oh, Yabing Guo, Yoong-Koo Kang, Wei-Yu Kao, Wei Li, Jung-Hwan Yoon, Helong Zhang, Pei-Jer Chen, Tsai-Sheng Yang, Jeong Heo, Zhendong Zheng, Hui Xie, Zhinuan Yu. Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib (ATG-008) in HBV+ advanced hepatocellular carcinoma (HCC) subjects who have received at least one prior line of systemic therapy (TORCH) [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 CT150.

Abstract CT121: ARX517, an anti-PSMA ADC targeting mCRPC resistant or refractory to standard therapies: A phase 1 dose escalation and dose expansion study (ARX517-2011, NCT04662580)

Abstract Background: Targeted therapies against prostate-specific membrane antigen (PSMA) have exhibited promising antitumor activity in prostate cancer. With the FDA’s approval of (177) Lu-PSMA-617, PSMA has been validated as a target to treat metastatic castration-resistant prostate cancer (mCRPC). ARX517 is an antibody-drug conjugates (ADC) composed of a fully humanized anti-PSMA mAb site-specifically conjugated to AS269, a potent tubulin inhibitor, yielding a drug-to-antibody (DAR) ratio of 2. After binding to PSMA on the surface of cancer cells, ARX517 is internalized and delivers a cytotoxic payload which inhibits tubulin polymerization and induces cellular apoptosis. ARX517’s site-specific linkage, stable conjugation chemistry, and non-cleavable linker exhibit a homogenous drug-antibody-ratio, mAb-like biophysical properties, and exceptional stability. Therefore, ARX517 promotes highly specific tumor cell apoptosis with minimal off-target bystander activity. Trial Design: The Phase 1 study’s dose escalation and dose expansion evaluates the safety, pharmacokinetics, and preliminary evidence of anti-tumor activity of ARX517 in adults with mCRPC. Patients must have mCRPC which is resistant or refractory to standard therapies, including androgen receptor signaling inhibitors, and show disease progression by Prostate Cancer Working Group 3 (PCWG3) criteria. All patients must have adequate organ function and brain metastases must be radiographically stable. Ascending dose levels of ARX517 administered as a single agent will use an i3+3 design in the dose escalation phase. During the dose expansion phase, ARX517 will be administered at the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD). Exploratory pharmacodynamic assessment includes PSMA-PET/CT imaging. The total number of subjects is dependent on the number of ascending doses and cohort size before dose expansion. Status: ARX517-2011 began enrolling patients in July 2021. With no dose limiting toxicities through dose level 6 (2.0 mg/kg Q3W), dose escalation remains ongoing. As of January 2023, the APEX-01 study is currently enrolling in cohort 7 (2.4 mg/kg) of dose-escalation. Dose expansion will start after RP2D or MTD. Citation Format: John Shen, Richard Pachynski, Luke Nordquist, Nabil Adra, Mehmet Bilen, Rahul Aggarwal, Zachary Reichert, Michael Schweizer, Dong Xu, Manan Patel, Jin Zhang, Wenge Shi, Darryl Z. L'Heureux, Scott Tagawa. ARX517, an anti-PSMA ADC targeting mCRPC resistant or refractory to standard therapies: A phase 1 dose escalation and dose expansion study (ARX517-2011, NCT04662580) [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 CT121.

Inhibition of PRMT5 Increases Sensitivity to BH3 Mimetics in Aggressive B Cell Malignancies

Introduction: Protein Arginine Methyltransferase 5 (PRMT5) is a type II methyltransferase that catalyzes symmetric dimethylation of arginine. PRMT5 is highly expressed in several types of aggressive B cell malignancies, and increased PRMT5 expression has been associated with poor disease prognosis. Several small molecule inhibitors targeting PRMT5 have been developed and showed promising anti-tumor effect in pre-clinical studies including in mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). JNJ-64619178, a potent and specific PRMT5 inhibitor, exhibited broad antiproliferative activity in cancer cell lines from multiple cancer types and cell lines derived xenograft mouse model (Brehmer et al., 2021). In a phase 1 clinical trial of JNJ-64619178 (NCT03573310), patients with advanced solid tumors and non-Hodgkin lymphoma demonstrated manageable toxicity and preliminary evidence of antitumor activity at selected dose levels (Villar et al., 2020). In addition, in patients with lower-risk myelodysplastic syndromes, JNJ-64619178 had manageable hematologic toxicity at the selected expansion dose, but did not have significant clinical activity (Haque et al., 2021). Inhibition of PRMT5 alone could induce cell cycle arrest instead of apoptosis depending on the types of cancer (Zhu et al., 2019), therefore we hypothesized that the combination of PRMT5i and pro-apoptotic BH3 mimetics therapies could be synergistic in aggressive B cell malignancies. Methods: We used dynamic BH3 profiling (DBP) to measure the net pro-apoptotic signaling induced by ex vivo drug treatments (as per Montero et al., 2015). Other standard techniques included shRNA mediated gene knockdown, Western blot, cell viability assays including PI/Annexin V and CellTiter-Glo, and reactive oxygen species (ROS) measurement by flow cytometry with dihydroethidium (DHE) staining. The DLBCL cell lines (HBL1, TMD8, RI-1, OCI-Ly1, Karpas 422, SUDHL4, Toledo), double hit lymphoma (DHL) patient-derived xenograft (PDX) cell lines (DW19), mantle cell lymphoma (MCL) cell lines (Mino, Jeko-1), T cell acute leukemia (T-ALL) cell line (Jurkat) and Burkitt lymphoma (BL) cell line (Raji) were used to investigate the in vitro anti-cancer activity of JNJ-64619178 (Janssen Pharmaceuticals) and BH3 mimetics (venetoclax [BCL2i], S63845 [MCL-1i] and A1331852 [BCL-xLi], Selleckchem). SynergyFinder was used to calculate drug synergism. Results: In all 7 DLBCL cell lines and the DHL-PDX cell line, we found synergistic induction of apoptosis with JNJ-64619178 plus venetoclax (synergy score, 2.82~51.42). The lowest level of synergy was observed in OCI-Ly1 cells, which are intrinsically highly sensitive to venetoclax monotherapy. The combination of JNJ-64619178 with S63845 synergistically induced apoptosis in 5 out of 7 cell lines (synergy score, -1.91~35.64). While the combination of JNJ-64619178 with A1331852 synergistically induced apoptosis in all 7 cell lines (synergy score 1.88~46.73), 4 of them had weak synergy score (1.88~9.4). To confirm the effects we observed with pharmacologic inhibition of PRMT5, we performed shRNA mediated knockdown of PRMT5, which similarly revealed increased sensitivity to venetoclax. In MCL cell lines, combining JNJ-64619178 with venetoclax or A1331852 was more synergistic in inducing cell death than combining with S63845. The T-ALL Jurkat cell line was resistant to JNJ-64619178 and single BH3 mimetic-induced apoptosis. Combining JNJ-64619178 with A1331852 but not venetoclax or S63845 strongly induced apoptosis. The Burkitt cell line Raji was resistant to JNJ-64619178, venetoclax and A1331852, but was sensitive to S63845. The addition of JNJ-64619178 and a single BH3 mimetic in these Raji cells had only a minor synergistic effect. The synergy scores are summarized in Figure 1. Using DBP, JNJ-64619178 was found to increase overall apoptotic priming of DLBCL and MCL cell lines (> 15% increase in cytochrome c loss). By measuring ROS levels, we found increased ROS production (> 2-fold increase in median fluorescent intensity) in response to JNJ-64619178 before the onset of apoptosis, suggesting a possible mechanism by which JNJ-64619178 increases apoptotic priming. Conclusions: The combination of a PRMT5 inhibitor with BH3 mimetics, especially venetoclax, is worthy of further exploration as a potential therapeutic strategy for DLBCL and MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract PR006: Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody

Abstract Background: Elevated circulating growth differentiation factor 15 (GDF15) and increased GDF15 expression in tumor tissues has been observed in patients with advanced pancreatic cancer (APC). These changes were correlated with poor survival. Effects of GDF15 on tumor progression, metastasis and immune escape may play a role. NGM120, a novel antibody to GFRAL that blocks the effects of GDF15, has resulted both in antitumor and anti-cachexia effects in experimental models. Here we report updated findings of the ongoing Phase 1b study with NGM120 in patients with APC. Methods: Metastatic pancreatic cancer patients with elevated serum GDF15 were treated with NGM120 (30 or 100 mg, s.c., q4wks) in a 1st line setting in combination with Gem/nab-paclitaxel. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics, preliminary evidence of antitumor activity (RECIST) and anti-cachexia effects. Results: Eight patients received NGM120 in combination with Gem/nab-paclitaxel. Median age was 67 years, all patients had advanced disease. NGM120 was well tolerated with no dose-limiting toxicities. Most of the AEs or SAEs observed were Gem/nab-paclitaxel related and none of them attributed to NGM 120 treatment. As of data cut off on March 25, 2022, preliminary results include 3 patients with PR (extending >32 wks), 3 patients SD; 2 patients discontinued early (before first post-dose scan) due to toxicity attributed to Gem/nab-paclitaxel. Among the 6 evaluable patients, the disease control rate (DCR) is 100%, mPFS has not been reached, 12-month survival rate (12-month OS) is 83.3%. Over the course of the study, 5/6 of the patients gained or maintained their body weight (BW) and 5/6 of the patients gained or maintained their lean body mass (LBM) based on maximum change from baseline. Conclusions: NGM120 given in combination with Gem/nab-paclitaxel to patients with APC resulted in a 50% ORR (3 PR in 6 evaluable patients), 100% DCR, 83.3% 12-month OS and a “not reached” mPFS. Compared to historical Gem/nab-paclitaxel data, these findings are encouraging and support the potential role of NGM120 in the treatment of patients with APC. The positive effects on BW and LBM is also encouraging compared to the historical cachexia rate of 30% observed within 12 weeks of starting first-line chemotherapy in APC. A sign of NGM120 engages the GDF15-GFRAL pathway in managing body weight regulation. A Ph2a study is ongoing to further evaluate NGM120 in combination with Gem/nab-paclitaxel in the 1st line setting for the treatment of APC. Citation Format: Andrew Hendifar, Efrat Dotan, Benjamin Weinberg, Edward Kim, Peter Hosein, Jian Luo, Jiping Zha, Alex DePaoli, Vladimir Hanes, Cecilia Tranmuchowski, Kefei Zhou, Carol Tseng, Hsiao Lieu. Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR006.

Abstract CT135: Preliminary safety and efficacy of DSP-7888 plus nivolumab (NIV) or pembrolizumab (PEM) in patients (pts) with advanced solid tumors (ASTs): A phase (Ph) 1b/2 open-label study

Abstract Background: DSP-7888—an investigational immunotherapeutic cancer vaccine derived from Wilms’ tumor 1 (WT1)—induced WT1-reactive T cells, the activity of which was maintained and enhanced by anti-PD-1 mAbs (preclinical; Goto, et al. ASH 2016). Results from the Ph 1b dose search cohort of a Ph 1b/2 study of DSP-7888 + immune checkpoint inhibitors (ICIs) NIV or PEM in ASTs (NCT03311334) are presented. Methods: Pts (aged ≥18 y; ECOG PS 0-1; locally advanced/metastatic solid tumors; approved for NIV or PEM) received intradermal (ID) DSP-7888 10.5 mg once weekly (wk) (Q1W) + NIV 240 mg IV Q2W for 4 (Arm 1) or PEM 200 mg IV Q3W for 6 (Arm 2) wks (induction), then DSP-7888 + NIV (Q2W; Arm 1) or PEM (Q3W; Arm 2) (maintenance). A DSP-7888 3.5-mg dose cohort would open if dose limiting toxicities (DLTs) occured in >1 of 6 pts. Primary objectives: evaluate safety (including DLTs) and identify the recommended Ph 2 dose of DSP-7888 + NIV or PEM. Results: At data cutoff (March 30, 2021), 13 pts (mean age 63.8 [range 38-82] y; 61.5% male; median 3 (1-5) lines of prior therapy; 84.6% prior ICIs) were enrolled and treated with DSP-7888 10.5 mg + NIV (Arm 1, n=7) or PEM (Arm 2, n=6). Treatment-emergent adverse events (TEAEs) were reported in 100% (any grade) and 76.9% (grade ≥3; most commonly injection site reactions [ISR; 30.8%]) of pts (Table). No DLTs occurred during the evaluation period (NIV, 4 wk; PEM, 6 wk), establishing 10.5 mg as the recommended dose for DSP-7888 + NIV or PEM. Serious AEs were reported in 7 (53.8%) pts (2 [15.4%] related to DSP-7888). At efficacy data cutoff (May 4, 2020), 2 (15.4%) pts with prior ICIs achieved partial response, which lasted 9.5 and 5.5+ months; 6 pts achieved stable disease (n=4 ≥8 months) and 3 had progressive disease. Conclusions: DSP-7888 + NIV or PEM was generally tolerable at 10.5 mg ID (most common TEAE was ISR) and showed evidence of preliminary antitumor activity. An expansion cohort in ovarian cancer is enrolling. Table. Safety and Efficacy (N=13a) DSP-7888 + NIV (n=7) DSP-7888 + PEM (n=6) Overall (N=13) Patient characteristics Prior lines of therapy, n (%) -1 0 1 (16.7) 1 (7.7) -2 2 (28.6) 1 (16.7) 3 (23.1) -≥3 5 (71.4) 4 (66.7) 9 (69.2) Prior ICI, n (%) 7 (100) 4 (66.7) 11 (84.6) Safety All patients with TEAE grade ≥3, n (%)b — — 10 (76.9) TEAEs grade ≥3 (in ≥2 patients), n (%)b -Injection site reaction — — 4 (30.8) Pts with treatment-emergent SAEs, any grade, n (%)b — — 7 (53.8) Efficacy ORR (CR+PR), n (%) [95% CI] 2 (28.6) [3.7, 71.0] 0 2 (15.4) [1.9, 45.5] Best overall response, n (%) -PRc 2 (28.6) 0 2 (16.7) -SD 3 (42.9) 3 (50.0) 6 (46.2) -PD 0 3 (50.0) 3 (23.1) -Non-CR/Non-PD 1 (14.3) 0 1 (7.7) -NE 1 (14.3) 0 1 (7.7) Disease control rate (CR+PR+SD+Non-CR/Non-PD), n (%) [95% CI] 6 (85.7) [42.1, 99.6] 3 (50.0) [11.8, 88.2] 9 (69.2) [38.6, 90.9] aTumor types included non-small cell lung cancer (n=7), urothelial cancer (n=3), gastroesophageal junction adenocarcinoma (n=1), head and neck squamous cell carcinoma (n=1), and renal cell carcinoma (n=1). For inclusion, patients either progressed on their prior treatment or were being treated with NIV or PEM, achieved at least SD, and could benefit from the addition of DSP-7888 (physician’s judgement). bRegardless of causality. cOf the patients that exhibited a PR, 1 had renal cell carcinoma and 1 had urothelial cancer. Both patients were previously treated with an ICI (NIV and atezolizumab, respectively. DOR w as 9.5 and 5.5 (+) months in the patients with renal cell carcinoma and urothelial cancer, respectively (DOR was defined as the time, in months, from the first documentation of CR or PR to the first documentation of PD or death due to any cause. Patients who were alive and progression-free as of the analysis cut-off date were censored (+) at their last date of response assessment. CI, confidence interval; CR, complete response; ICI, immune checkpoint inhibitor; DOR, duration of response; NE, not evaluable; NIV, nivolumab; ORR, overall response rate; PD, progressive disease; PEM, pembrolizumab; PR, partial response; SAE, serious adverse event; SD, stable disease; TEAE, treatment-emergent adverse event. Citation Format: Wael A. Harb, Makoto Origuchi, Patrick W. Cobb, Trisha Wise-Draper, Natsuko Suginobe, Megumi Nakamura, Masashi Goto, Aaron Chen, Jian Li, James Wade III. Preliminary safety and efficacy of DSP-7888 plus nivolumab (NIV) or pembrolizumab (PEM) in patients (pts) with advanced solid tumors (ASTs): A phase (Ph) 1b/2 open-label study [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 CT135.

Abstract CT187: Phase 1 Trial of RTX-240, allogeneic red blood cells engineered to express 4-1BBL and trans-presented IL-15, in patients (Pts) with advanced solid tumors

Abstract Background: RTX-240 is an allogeneic cellular therapy genetically engineered to express high copy numbers of trimeric 4-1BBL and IL-15/IL-15Rα fusion proteins on the RBC surface membrane. RTX-240 is designed to activate and expand CD8+ memory T cells and NK cells and is restricted to the normal biodistribution of red blood cells to mitigate toxicity. Safety, pharmacodynamic (PD) effects, pharmacokinetics (PK) and preliminary efficacy of RTX-240 were assessed in a Phase 1 study of pts with solid tumors. Methods: Pts with relapsed/refractory solid tumors not eligible for standard therapy were treated with monotherapy RTX-240 in 10 cohorts utilizing 6 dose levels (1x108-5x1010 cells per dose) and 4 different schedules until disease progression or unacceptable toxicity. Peripheral blood and tumor tissue were collected at baseline and on-treatment. Results: As of Dec 3, 2021, 30 pts with solid tumors (median age 58 yr, range 23-80, 17 males, 20 ECOG 1), were treated with single agent RTX-240. Pts had previously received a median of 3 therapies (range, 1-9); 21 pts had received prior PD-1/PD-L1 inhibitor (i) therapy. Common tumor types included NSCLC (n=7), melanoma (n=7), colorectal/lower GI (n=4) and RCC (n=3). Per RECIST v1.1, a confirmed partial response (PR) was observed in 1 pt with anal carcinoma and an unconfirmed PR in a uveal melanoma, both of whom had been previously treated with a PD-1. Disease control (PR or stable disease > 12 weeks) occurred in 11/30 pts (37%), of which 7 had received a prior PD-1 for a median of 8 months. Peripheral blood PD studies demonstrate activation, expansion, and cytotoxic potential (GzB) of both NK and memory CD8+ T cells. Every pt with evaluable samples (n=29) had an increase in at least one of the activation or expansion parameters, and the majority had an increase in all. There was also a clear dose response effect in NK cell numbers and trends in other PD markers. Immune activation was observed by increases in plasma IFN-γ in a subset of patients. On-treatment biopsies in a subset (3/5) of evaluable pts show infiltration of NK and/or T cells into the tumor microenvironment (TME) after RTX-240 dosing. No DLTs or related grade (Gr)>3 AEs were seen. The most common treatment-related AEs (Gr 1-2) were fatigue (n = 6); chills, nausea, decrease in appetite, arthralgia (n =3); and fever, myalgia, dysgeusia, and hyperhidrosis (n=2). Additional Gr 2 irAEs include pneumonitis, adrenal insufficiency, hypothyroidism, and worsening transaminitis. Conclusions: RTX-240 is well tolerated at all tested doses, schedules and routes. The drug leads to activation, expansion and trafficking of two target cells (memory CD8+ T cells and NK cells) into the TME, exhibits a clear dose response effect with NK cells and demonstrates preliminary evidence of anti-tumor activity. Dose escalation continues and a PD-1 inhibitor combination arm is also enrolling. Citation Format: Omid Hamid, Melissa L. Johnson, Jason Luke, Richard T. Maziarz, Jamie Merchan, Emerson E. Lim, Sandip P. Patel, Geoffrey M. Kuesters, Iga Sienczylo, Gilad Gordon, Karen Campbell, Kristin Horton, Laurence Turka, Alexander I. Spira. Phase 1 Trial of RTX-240, allogeneic red blood cells engineered to express 4-1BBL and trans-presented IL-15, in patients (Pts) with advanced solid tumors [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 CT187.

Selected Articles from This Issue

Highlights| June 01 2022 Selected Articles from This Issue Author & Article Information Online Issn: 1557-3265 Print Issn: 1078-0432 ©2022 American Association for Cancer Research2022American Association for Cancer Research Clin Cancer Res (2022) 28 (11): 2199. https://doi.org/10.1158/1078-0432.CCR-28-11-HI Related Content A commentary has been published: A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors A commentary has been published: Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study A commentary has been published: First Clinical Results of Fluorescence Lifetime-enhanced Tumor Imaging Using Receptor-targeted Fluorescent Probes View more A commentary has been published: Venetoclax Cooperates with Ionizing Radiation to Attenuate Diffuse Midline Glioma Tumor Growth View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record June 1 2022 Citation Selected Articles from This Issue. Clin Cancer Res 1 June 2022; 28 (11): 2199. https://doi.org/10.1158/1078-0432.CCR-28-11-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search The phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in many tumor types, but development of PI3K inhibitors is challenging because of toxicity risks associated with inhibiting multiple PI3K isoforms. AZD8186 is a potent, selective inhibitor of PI3Kβ. In a phase I open-label study Choudhury and colleagues evaluated the safety, tolerability, and recommended phase II dose of AZD8186 monotherapy and in combination with abiraterone acetate or vistusertib. Eligible patients had advanced prostate cancer, triple-negative breast cancer, or squamous non-small-cell lung cancer, and patients with other solid tumor types were eligible if they were PTEN-deficient/mutated or PIK3CB-mutated/amplified. As monotherapy and in combination, AZD8186 was well tolerated, with few dose-limiting toxicities reported. Both monotherapy and combination therapy showed preliminary evidence of antitumor activity, which merits further assessment in subsequent studies. FGFR alterations occur in ∼8% of gliomas, with most detected in FGFR1 and FGFR3. Although FGFR fusions have proven oncogenic potential... You do not currently have access to this content.

Phase 1 dose escalation study of MH048, a novel and non-covalent BTK inhibitor in patients with relapsed or refractory B-cell malignancies.

7547 Background: Despite impressive clinical response of covalent Bruton’s tyrosine kinase (BTK) inhibitors in multiple B cell malignancies, treatment failure often occurs through drug resistance most commonly due to BTK cysteine-481 (C481) mutation or intolerance due to off-target toxicities. We evaluated the safety, pharmacokinetics (PK) and preliminary antitumor efficacy of MH048, an orally bioavailable, potent, and reversible inhibitor of both wild type and C481S-mutant BTK, in selected patients with relapsed or refractory (R/R) B-cell malignancies. Methods: Eligible patients with R/R B-cell malignancies were enrolled in a Phase 1, multicenter, open-label, dose escalation study. The primary objectives were to assess the safety and tolerability of MH048, and to determine the maximal tolerated dose (MTD) and the recommended dose for expansion. The secondary objectives were to assess the PK profile and preliminary evidence of anti-tumor activity. Results: Twelve patients were treated with MH048 across six dose levels (5 mg, 15 mg, 45 mg, 90 mg, 135 mg, 200 mg QD) in fast state. No dose-limiting toxicities were observed and the MTD was not reached. The most common drug-related TEAEs (Any grade) that occurred in > 2 patients were platelet count decrease (n=5), anemia (n=4), neutrophil count decrease (n=4), lipase increase (n=3), and white blood cell count decrease (n=3). Drug-related grade 3 TEAEs included platelet count decrease, neutrophil count decrease, lipase increase, and hypertension (one patient for each). Plasma exposure of MH048 and its active metabolite (M3) increased in a dose-proportional manner from 5 to 200 mg dose levels. Sign of efficacy was observed starting from 15 mg. Among eleven efficacy-evaluable patients (one patient in 200 mg cohort is yet to be evaluated), one complete response (CR) and four partial responses (PRs) were achieved in ≥90 mg cohorts, including patients with MZL (n=1, CR), MCL (n=2), SLL (n=1) and DLBCL (n=1). Of the two MCL patients with PRs, one was heavily pretreated including ibrutinib prior to the enrollment. The recommended doses for expansion were selected as 135 and 200 mg. Conclusions: MH048 was well-tolerated and efficacy in heavily pre-treated patients with B-cell malignancies was observed. Pharmacokinetics studies suggest once-daily dosing. The dose expansion study is ongoing at 135 and 200 mg QD for CLL and MCL patients. Clinical trial information: NCT04689308.