Primary Objective Of Phase Research Articles

A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced solid tumors.

TPS9599 Background: Immune checkpoint inhibitors (ICI) have improved outcomes for pts with solid tumor malignancies; however, most pts relapse and treatment options are limited. Unengineered TIL cell therapy has shown promising efficacy in pts with ICI-resistant melanoma (1,2) and non-small cell lung cancer ([NSCLC] 3,4), but requires co-administration of systemic high-dose IL2, which is associated with safety risks and limits pt eligibility. OBX-115 TIL are engineered to express membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2. A first-in-human single-institution study (NCT05470283) evaluating the safety of OBX-115 in metastatic melanoma is ongoing. The current study (NCT06060613) is enrolling pts with solid tumors at multiple US sites using centralized manufacturing. Methods: This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in pts with histologically confirmed unresectable Stage IIIC, IIID, or Stage IV metastatic melanoma (excluding uveal) with documented radiographic progression after systemic therapy containing an anti–PD‐1/PD-L1 agent (if adjuvant, progression during or within 12 wks after the last dose) and received a BRAF inhibitor ± MEK inhibitor if BRAF V600 mutation-positive OR metastatic NSCLC previously treated with an approved systemic therapy for metastatic disease (including an ICI-based regimen and/or targeted therapy where applicable) and progressed, no longer deriving benefit, or unable to continue due to treatment intolerance. Pts must have ECOG PS of 0 or 1 and life expectancy >~6 months. Pts must have ≥1 lesion suitable for OBX-115 manufacturing (≥1.5 cm) and ≥1 RECIST v1.1-measurable lesion remaining after tumor tissue procurement. Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of OBX-115 + ACZ; Phase 2 will evaluate efficacy of the regimen (ORR using RECIST v1.1 per investigator). Cryopreserved OBX-115 is generated from the pt’s own tumor tissue procured by surgical excision or core needle biopsy, and is infused after standard- (5 days) or low-dose (4 days) lymphodepletion (cyclophosphamide and fludarabine), based on clinical status. ACZ is administered at cohort-defined doses once daily for up to 10 days starting day of OBX-115 infusion, with optional ACZ redosing at Wk 6–8 for up to 10 days in pts with suboptimal radiographic response. No systemic high-dose IL2 is administered. Two sites are open and recruiting, with additional sites being activated. 1. Rohaan NEJM 2022. 2. Chesney JITC 2022. 3. Creelan Nat Med 2021; Schoenfeld SITC 2021. Clinical trial information: NCT06060613 .

EVEREST-1: A seamless phase 1/2 study of A2B530, a carcinoembryonic antigen (CEA) logic-gated Tmod CAR T-cell therapy, in patients with solid tumors associated with CEA expression also exhibiting human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH).

TPS2698 Background: Chimeric antigen receptor (CAR) T-cell therapies for treating solid tumors are challenging due to a lack of tumor-specific targets that discriminate cancer from normal cells. Previous studies using CEA T-cell receptors and T-cell engagers have resulted in dose-limiting, on-target, off-tumor toxicities (1,2). A2B530 is an autologous logic-gated, CEA-targeted Tmod CAR T-cell therapy that addresses the challenges of on-target, off-tumor toxicity by combining a CAR-activating receptor with a blocking receptor to discriminate tumor from normal cells (3). The activator recognizes CEA on the surface of both tumor and normal cells while specificity for tumor cells is provided by a blocker that binds HLA-A*02. In patients with both germline HLA-A*02 and tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (4). HLA-A*02 LOH can be detected using next-generation sequencing (Tempus AI, Inc.). With this definitive discriminator target, A2B530 can potentially provide a therapeutic window to treat patients with CEA-expressing solid tumors exhibiting HLA LOH. Methods: EVEREST-1 (NCT05736731) is a seamless, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B530 in adult patients. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease. BASECAMP-1–eligible patients undergo leukapheresis and, when clinically appropriate, their banked T cells are manufactured for the EVEREST-1 study. The key inclusion criteria include histologically confirmed recurrent unresectable, locally advanced, or metastatic cancers associated with CEA expression: non-small cell lung, colorectal, or pancreatic cancers. Patients should have received ≥1 line of prior therapy such as checkpoint inhibitor, molecular targeted, or chemotherapy. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B530 and determine the recommended phase 2 dose (RP2D). The dose-escalation portion is based on the Bayesian optimal interval design. The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B530. Phase 2 will assess overall response rate per RECIST v1.1. As of January 29, 2024, 8 patients have been enrolled on EVEREST-1. A2B530 was successfully manufactured for all patients, and all patients have received A2B530 infusion, with the first patient dosed in May 2023. Dose escalation is ongoing. 1. Parkhurst, et al. Mol Ther. 2022. 2. Tabernero, et al. J Clin Oncol. 2017. 3. Hamburger, et al. Mol Immunol. 2020. 4. Sandberg, et al. Sci Transl Med. 2022. Clinical trial information: NCT05736731 .

EVEREST-2: A seamless phase 1/2 study of A2B694, a mesothelin (MSLN) logic-gated Tmod CAR T-cell therapy, in patients with solid tumors that show MSLN expression and human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH).

TPS2699 Background: Despite the success in hematologic cancers, chimeric antigen receptor (CAR) T-cell therapies are challenging to implement in solid tumors owing to a lack of tumor-specific targets that discriminate cancer from normal cells. MSLN expression normally is limited to the mesothelium of major body cavities but can be upregulated in diverse solid tumor types (TCGA 2022), making it a potential target for cancer therapy. MSLN-targeted cell approaches, including CAR T-cell and T-cell receptor fusion therapies, have shown promising clinical activity; however, on-target, off-tumor toxicity including fatal events have occurred (1-3). A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T-cell therapy that addresses the challenges of on-target, off-tumor toxicity by combining 2 CARs: an activating and blocking receptor. The activator recognizes MSLN present on the surface of both tumor and normal cells; the blocker binds HLA-A*02 and prevents CAR T-cell activity. Thus, in patients with both germline HLA-A*02 and tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (4). Through this unique discriminatory mechanism, A2B694 may provide a therapeutic window to treat patients with MSLN-expressing solid tumors exhibiting HLA-A*02 LOH. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 in adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, mesothelioma, or other solid tumors with MSLN expression. Eligible patients should have received ≥1 line of prior therapy such as checkpoint inhibitor, molecular targeted, or chemotherapy. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), which identifies patients with tumor-associated HLA-A*02 LOH via next-generation sequencing (Tempus AI, Inc.). Eligible patients enroll in the BASECAMP-1 study and undergo leukapheresis. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess overall response rate per RECIST v1.1. 1. Beatty, et al. Gastroenterology. 2018. 2. Haas, et al. Mol Ther. 2023. 3. Hong, et al. ESMO 2021. Abstract 9590. 4. Hamburger, et al. Mol Immunol. 2020. Clinical trial information: NCT06051695 .

Abstract CT285: Trial in progress: A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma

Abstract Introduction ICI have improved outcomes for pts with melanoma; however, most pts (~60%) do not achieve long-term survival. Unengineered bulk TIL cell therapy has an objective response rate (ORR) of 31-49% in pts with unresectable or metastatic melanoma (Rohaan NEJM 2022, Chesney JITC 2022), but requires co-administration of systemic high-dose IL2, which is associated with safety risks and limits pt eligibility. OBX-115 TIL are engineered to express regulatable membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2. A first-in-human single-institution study (NCT05470283) evaluating the safety of OBX-115 in metastatic melanoma is currently enrolling. The current study (NCT06060613) is enrolling at multiple US sites using centralized manufacturing. Methods This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in pts with unresectable or metastatic melanoma resistant to ICI (Table). Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of the OBX-115 regimen; Phase 2 will evaluate efficacy (ORR using RECIST v1.1). Cryopreserved OBX-115 is generated from the pt’s own tumor tissue procured by surgical excision or core biopsy, and is infused after standard- or low-dose (based on clinical eligibility) lymphodepletion (cyclophosphamide and fludarabine). ACZ is administered at cohort-defined doses once daily for up to 10 days, with ACZ redosing at Week 6-8 for 10 days if the initial observed tumor response is less than partial response. No systemic high-dose IL2 is administered. Two sites are open and recruiting pts. TABLE 1. NAND Key Eligibility Criteria Key Inclusion Criteria Key Exclusion Criteria Age ≥18 years Uveal melanoma Histologically confirmed diagnosis of unresectable Stage IIIC, IIID, or Stage IV metastatic melanoma Brain metastasis or leptomeningeal disease Documented radiographic disease progression after systemic therapy containing a PD-1- or PD-L1-blocking antibody (if adjuvant setting, progression during or within 12 weeks after the last dose) Active autoimmune disease, including active uveitis or any other medical illness that would pose increased risks for study participation Received a BRAF inhibitor ± MEK inhibitor if BRAF V600 mutation-positive Prior allogeneic organ transplant, allogeneic cell therapy, or genetically engineered cell therapy (not including autologous stem cell or unengineered TIL cell therapy) ≥1 lesion suitable for OBX-115 generation with expected minimum of 1.5-cm diameter; minimally invasive tumor tissue procurement (core biopsy) may be considered on a case-by-case basis after discussion with the Medical Monitor Systemic steroid therapy >10 mg/day of prednisone or equivalent ≥1 RECIST 1.1-measurable lesion remaining after tumor tissue procurement ECOG performance status 0 or 1 Estimated life expectancy >6 months Citation Format: Sajeve S. Thomas, Jason A. Chesney, Omid Hamid, Gino K. In, Alexander N. Shoushtari, Yazan Samhouri, Parameswaran Hari, Giridharan Ramsingh, Prakash Prabhakar, Lauren Mclaughlin, Allison Betof Warner. Trial in progress: A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma [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 CT285.

Abstract CT067: The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed multiple myeloma

Abstract Background: HDP-101 is a new antibody drug conjugatetargeting B-cell maturation antigen (BCMA) that carries a synthetic amanitin payload with a new mode of action. Amanitin inhibits RNA polymerase II, effectively stopping transcription and inducing apoptosis in tumor cells, regardless of their proliferation status. It's shown cytotoxicity in vitro against BCMA-positive myeloma cell lines and non-proliferating primary CD138+ cells from refractory myeloma patients withefficacy even in cells with low BCMA density. Clinical Study: HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial in patients with multiple myeloma whose disease has progressed or is refractory, aiming to determine the Maximum Tolerated Dose and/or the Recommended phase 2 Dose in Phase 1. Dose escalation is guided by an adaptive Bayesian logistic regression model with overdose control. The primary objective in phase 2 is to assess anti-tumor activity. Study Progress: As of November 2023, 18 patients (7 females, 11 males) were enrolled in 5 consecutive dose cohorts of 20, 30, 60, 80, and 100µg/kg. Patients had a median age of 70 years (48-82), were heavily pre-treated and multidrug-resistant, and had a median of 6,5 prior treatments (2-15). Study Results: Preliminary data shows that pharmacokinetics of HDP-101 aligns with expectations, and exposure to HDP-101 is dose proportional. Free payload was not detected in serum at a limit of detection of 30 ng/mL, and no anti-drug antibodiesor immunogenic reactions were noted. 17 of 18 patients were evaluable for dose limiting toxicities (DLT) in the 5 treatment cohorts. Initial cohorts were well tolerated, without any DLTs, including no signs of hepatic and renal toxicities, infusions reactions, or ocular disorders. All patients in Cohort 5 had Grade 1-4 transient thrombocytopeniawith platelet reductions starting on Cycle 1/Day 2 (C1/D2), a nadir on C1D5, and full recovery by C1D15 at the latest without any clinical sequelae or interventions. Notably, subsequent dosing with HDP-101 did not produce similarly deep episodes of thrombocytopenia, supporting the possibility that this event is not due to a direct cytotoxic effect against megakaryocytes. After Cohort 5, mitigation strategies are being considered and further dose and schedule optimization is planned with fractionated dosing and/or with premedication. Efficacy: Cohort3 has a patient with stable disease (SD) after 15 cycles. Cohort 5 has 4 ongoing patients with promising results after 3-4 cycles: 2 patients achieved PR, and 2 have SD. Updated data will be presented at the AACR2024 meeting. Citation Format: Jonathan Kaufman, Marc Raab, Shambavi Richard, Sebastian Grosicki, István Takács, András Strassz, Andreas Pahl, Michael Kulke, Thorsten Michael, Anette Last, Hajnalka Szabóki, Garrit Jentsch, Oliver Schönborn-Kellenberger, Robert Orlowski. The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed multiple myeloma [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 CT067.

A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors

IntroductionTargeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies. MethodsThis single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate. ResultsA total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%–60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%–17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%–27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%–33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%–27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%–100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors. ConclusionsVorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.

Abstract B042: Efficacy and safety outcomes of ABN401 in NSCLC patients with MET Exon 14 Skipping: A clinically relevant subgroup analysis

Abstract Background: In non-small-cell lung cancer (NSCLC), approximately 3-4% of patients exhibit MET exon 14 skipping (METex14) mutations. ABN401, a selective type I MET kinase inhibitor, has demonstrated promising antitumor activity and safety in advanced solid tumor patients. Here, we report updated outcomes of ABN401, focusing on METex14 NSCLC patients. Methods: Patients enrolled in the ABN401 Phase I (NCT04052971) and Phase II (NCT05541822) trials were analyzed. The safety population consists of all patients who have been dosed at ABN401 800 mg QD, while the efficacy population comprises METex14 NSCLC patients dosed at 800 mg QD. The primary objective for phase I study was safety, and for phase II study was the objective response rate (ORR) in patients. Secondary objectives include recommended dose and regimen of ABN401, PK and preliminary efficacy of ABN401 for phase I and duration of response (DOR), objective disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, safety, and tolerability of ABN401 for phase II. Results: Between June 23, 2022, and July 6, 2023, a total of 24 patients received ABN401 800 mg QD, including 17 METex14 NSCLC patients. Of 24 patients evaluable for safety, 2 (8.3%) experienced grades ≥3 treatment-related adverse events (TRAE). The most common treatment-related adverse events were nausea (70.8%), vomiting (29.2%), and diarrhea (33.3%). Grade ≥3 treatment-emergent adverse events occurred in 5/24 (20.8%) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 0% (0/24) of patients. Peripheral edema was observed in 29.2% (grade 1-2) and there was no grade 3 or greater event in all safety evaluable populations, and 17.6% (grade 1-2) and 0% (grade 3) in METex14 NSCLC population. For the 17 METex14 NSCLC patients, one was not evaluable because the patient did not had the first tumor assessment at the time of DCO. The median age is 69 (41-81) and 70.6% were male, with 1 (0-3) as the median prior lines of treatment. 41.2% of 17 patients were ex-smoker and 58.8% were non-smoker. All patients were MET inhibitor naïve. The objective response rate was 56.2% (9/16) in the evaluable population. Overall (n = 9), 66.7% is treatment-naïve patients (n = 6). The median duration of treatment was 5.4 months for all who dosed 800 mg QD as of the data cut-off on July 6, 2023. At the time of DCO, data is not mature enough for PFS and DoR. Conclusions: ABN401 has shown promise in antitumor efficacy and favorable toxicity in patients with locally advanced or metastatic METex14 NSCLC. The phase 2 multicenter, open-label trial (NCT05541822) is actively enrolling in the US, South Korea, and Taiwan. Citation Format: Se-Hoon Lee, Ji-Youn Han, Ki Hyeong Lee, Gyeong-Won Lee, Charlotte Lemech, Michael Millward, Aflah Roohullah, Xiuning Le, Keunchil Park, Jun Young Choi, Na Young Kim, Sunyhe Im, Nirmal Rajasekaran, Kyung Eui Park, Sangsuk Lee, Hanlim Moon, Sunjin Hwang, YoungKee Shin, Dae Ho Lee. Efficacy and safety outcomes of ABN401 in NSCLC patients with MET Exon 14 Skipping: A clinically relevant subgroup analysis [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 B042.

A Phase I/II Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BTK Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory Central Nervous System Lymphoma

Background: HZ-A-018 is a highly selective and potent covalent BTK inhibitor with CNS-penetrating profile, which was previously reported (Abstract 5501, ASH 2022). Phase I/II study is ongoing in China, and here we present preliminary results of HZ-A-018 monotherapy of the phase I part in central nervous system lymphoma. Methods: HZ-A-018-102 is an ongoing phase I/II study (CTR20210181) to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of HZ-A-018 in central nervous system lymphoma. The primary objective for phase I monotherapy was to determine the safety and tolerability and the recommended phase 2 dose (RP2D), and secondary objectives included preliminary antitumor activity and pharmacokinetics in patients with relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) and primary vitreoretinal lymphoma (PVRL) who had received ≥1 prior therapy. HZ-A-018 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. Results: At the data cutoff date of 30 May 2023, 21 pts from the phase I monotherapy were analyzed, including 18 R/R PCNSL and 3 R/R SCNSL. 3 pts received 300mg/d, 12 pts received 450mg/d and 6 pts received 600mg/d. 600mg was the highest dose pre-defined in the study and MTD was not reached. Pts were with a median age of 62 years (range: 36-80), median KPS 80 (range: 60-90) and a median of 2 prior systemic therapies (range: 1-5). 20 pts (95.2%) presented with brain parenchyma, and 1 pt (4.8%) presented with intraocular (IO) involvement. All patients had received HD-MTX based chemotherapy, 19 pts (90.5%) had received rituximab and 1 pt had received whole brain radiation therapy (WBRT). 16 of 21 pts (76.2%) experienced a treatment related adverse event (TRAE). The most common TRAEs (≥10%) were thrombocytopenia (42.9%), neutropenia (23.8%), leukopenia (23.8%), and hypokalemia (14.3%), majority of which were grade 1 to 2. DLTs occurred in 1 pt at 450 mg/d and 1 pt at 600 mg/d. 4 pts (19.0%) had dose interruption, no pts had dose reductions, and no pts discontinued from the study due to TRAEs. The plasma and cerebrospinal fluid (CSF) pharmacokinetics showed HZ-A-018 was rapidly absorbed and could cross the blood-brain barrier with CSF HZ-A-018 concentration ranged from 5.94 to 17.5 ng/mL two hours post-dose. Of 19 pts available for tumor assessment (16 PCNSL with brain parenchyma, 1 PCNSL with IO and 2 SCNSL with brain parenchyma) and 2 pts not evaluable (1 PCNSL with brain parenchyma, and 1 SCNSL with brain parenchyma), the overall response rate (ORR) was 52.4% (95%CI: 29.8, 74.3), including 23.8% (5 pts) complete response(CR)/unconfirmed complete response(CRu), 28.6% (6 pts) partial response (PR), and 19.0% (4 pts) stable disease (SD), contributing to an 71.4% (95%CI: 47.8, 88.7) disease control rate (DCR). At 600mg/d, all 6 pts had achieved high and deep responses, contributing to 100% ORR and 50% CRR, with the 3-month duration of response (DOR) rate not reached. Dose expansion was ongoing at 600mg QD. Conclusions: These results demonstrated that HZ-A-018 was efficacious and well-tolerated in CNS lymphoma patients with high CNS penetrating profile. The monotherapy RP2D for R/R PCNSL was determined as 600 mg QD and a phase 2 R/R PCNSL registration study in China is currently planned.

Preconditioning Single High-Dose Palifermin Alters the Posttransplant Inflammatory Cytokine Profile

Palifermin is a truncated form of human recombinant keratinocyte growth factor (KGF) that binds to the FGF receptor 2b expressed in epithelia including that of the epidermis, oral and GI mucosa, and thymus. In animal models, the cytoprotective and regenerative effects of KGF showed efficacy in controlling acute and chronic graft-versus-host disease (A/C GVHD), but these were not demonstrated in subsequent clinical studies using the FDA-approved dosing schedule for oral mucositis prevention (60 µg/kg/day for 3 consecutive days). The current study aims to investigate alterations in immune cell reconstitution and cytokine expression among patients (n=31) participating in the ongoing prospective open-label phase 1/2 trial NCT02356159. This trial evaluates the incidence of severe CGVHD (primary objective of phase 2) following the addition of a single high dose of palifermin to GVHD prophylaxis with TMS (tacrolimus, methotrexate, sirolimus). Four different dose levels of palifermin (DL1: 180 µg/kg; DL2: 360 µg/kg; DL3: 540 µg/kg; DL4: 720 µg/kg) were tested on day −7 in the phase 1 part of the trial, with the recommended phase 2 dose being 720 µg/kg. All patients received cyclophosphamide (total 4.8 g/m 2) and fludarabine (total 120 mg/m 2) as conditioning on days −6 to −3 followed by infusion of an 8/8 HLA-matched unrelated donor peripheral blood cell graft on day 0. Results of correlative studies were compared with patients of the identical TMS treatment arm of the NCT00520130 study without palifermin (n=31). In the DL4 group, a previous interim analysis revealed no cases of classic (day +100) AGVHD II-IV in 16 patients (P=0.014), whereas the TMS group showed a 22.6% (95% CI: 9.8% to 38.6%) incidence (Schulz et al. Cell Ther Transplant. 2023;29(2):S258). T, B and NK cells were routinely measured by flow cytometry at days +14, +28, +60, +100, +180, +365, +730. The V-PLEX human cytokine 36-plex kit and U-PLEX assays of human BAFF, CXCL9 and IL1RL1/ST2 (all MSD, Rockville, MD) were used to measure cytokine levels in plasma at days −8, 0, +14, +28, +60, +100. The measures at various time points were compared between two treatment groups using multiple Mann-Whitney tests, and the false discovery rate approach was applied with Q=0.05. Comparison between the four DL groups and the TMS group was performed using the Kruskal-Wallis H-test and Dunn's post-hoc test, with a significance threshold set at P<0.05. The statistical analyses were conducted using GraphPad Prism 9. In comparison to patients receiving TMS only, those treated with KGF exhibited reduced NK cell counts at day +28 (Q=0.0155) and increased B cell counts from day +60 (Q<0.01) onwards. However, there were no differences in the absolute numbers of CD3+, CD4+, and CD8+ T cells between patients from both trials. Additionally, no apparent dose-response relationship was observed. KGF-treated patients showed significantly reduced plasma levels of proinflammatory cytokines, including TNF-α at day 0, TNF-β at days 0, +14, +28, IL-12/IL23p40 at days 0 and +14, and CXCL9 at days 0 and +14, compared to patients receiving TMS only. Notably, levels of homeostatic IL-7, previously linked to AGVHD, were significantly lower in KGF-treated patients from day +28 (TMS vs. DL4, P=0.002) to +100. There was a trend towards lower levels of IL-22 at days 0 and +14 (both unadjusted P<0.05, Q>0.05) in KGF-treated patients. Other proinflammatory biomarkers showed increased levels in KGF-treated patients: IL-15 at day 0 (Q=0.0121), BAFF at days +14 and +28 (both Q<0.01), and ST2 at day 0 and day +14 (both Q<0.01). As reported previously by others, patients who developed classic or late onset AGVHD II-IV without prior relapse up to day +180 had higher ST2 levels at day +14 compared to patients without AGVHD II-IV (P=0.03). Here, this association was mainly observed in patients from the TMS and DL1 groups (6/8 tested patients with any AGVHD II-IV). The administration of a single high dose of palifermin (KGF) prior to conditioning treatment resulted in a notably distinct cytokine profile, characterized by a reduction in several GVHD associated pro-inflammatory cytokines, consistent with KGF's proposed cytoprotective effect. Further investigations focusing on GI microbiome and immune cell subsets are needed to elucidate the consequences of cytokine alterations induced by KGF on immune cell reconstitution. This research was supported by the Intramural Research Program of the NIH, NCI, CCR.

A CD19/CD20-Directed Bispecific CAR-T Cell Therapy in Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (NHL)

Three CD19-directed chimeric antigen receptor (CAR) T cell products are approved in the US for patients with relapsed or refractory (R/R) aggressive B cell lymphoma. Most patients treated in the third or later line will experience disease progression. Resistance to CD19-directed CAR T cell therapy may be due to tumor, T cell, or microenvironmental factors. Tumor-intrinsic causes of relapse include CD19 antigen loss, which is observed in approximately one third of relapsed cases(Spiegel, Dahiya, et al., 2021). Lower pretreatment CD19 antigen density has also been associated with treatment failure(Spiegel, Patel, et al., 2021). Conversely, enrichment of memory CD8+ T cells within the infusion product has been associated with achievement of complete remission (CR)(Deng et al., 2020). IMPT-314 is an autologous, naïve/memory enriched T cell product transduced by a lentivirus to express a tandem, OR-gate CD19/CD20-directed CAR with a 4-1BB co-stimulatory domain(Zah et al., 2016). IMPT-314 incorporates the same CAR and a highly similar manufacturing process as CART19/20, which was evaluated in a single-institution, Phase 1 study (NCT04007029)(Larson et al., 2023; Puliafito et al., 2023). Eleven patients with R/R B cell NHL have been treated at two dose levels (50 x 10 6 ± 30%, n=8; 200 x 10 6 ± 30%, n=3). Ten patients were evaluable for safety, and eleven patients were evaluable for response. Cytokine release syndrome (CRS) occurred in 60% of patients, however there were no CRS events above Grade 1. No patients experienced immune effector cell associated neurotoxicity syndrome (ICANS) of any grade. The overall response rate (ORR) and CR rate were 91% and 73%, respectively. As of March 6, 2023, with a median follow-up of 20.7 months, median progression-free survival (PFS) was 18.2 months (2.6-not estimable), and the median overall survival (OS) has not been reached (5.7-not estimable). This study of CART19/20 demonstrates the potential of simultaneous targeting of CD19 and CD20 with a bispecific CAR. Study Design The MPCT-012L study (NCT05826535) is a Phase 1/2 multicenter, open label study to evaluate the safety and efficacy of IMPT-314 in participants with relapsed/refractory aggressive B-cell NHL, defined as diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal large B cell lymphoma (PMBCL), and high-grade B-cell lymphoma (HGBL), after 2 or more lines of systemic therapy. Participants who have progressed after prior CD19 CAR-T cell therapy are eligible and are included in a separate cohort. All participants must have received prior anti-CD20 monoclonal antibody and an anthracycline. Patients with tFL must have received at least one line of therapy after transformation to DLBCL. Subjects with active (symptomatic or untreated) CNS involvement are excluded. There is no requirement for demonstration of CD19 or CD20 tumor expression at baseline. Phase 1 will be conducted using a modified 3+3 design with a starting dose of 100 x 10 6 CAR-T cells. Dose limiting toxicities (DLTs) will be evaluated for 28 days post-dosing. If a dose level is determined to be safe based on the DLT incidence, a total of up to 15 total subjects may be backfilled at that dose, per cohort. The primary objectives for Phase 1 are to evaluate the safety of IMPT-314 and to determine the recommended Phase 2 dose. The primary objective of Phase 2 is to estimate the efficacy of IMPT-314 as measured by CR rate. Secondary endpoints include evaluation of pharmacokinetics and time to event outcomes.

A Phase 1/2, open label dose-escalation and expansion trial of NKT2152, an orally administered HIF2α inhibitor, to investigate safety, PK, PD and clinical activity in patients with advanced ccRCC

Abstract Background: Inactivation of the VHL gene leading to aberrant HIF2α activity is nearly universal in clear cell renal cell carcinoma (ccRCC). NKT2152 is a novel, potent, selective orally available HIF2α inhibitor optimized for enhanced PK exposure and sustained target inhibition which has demonstrated robust activity in both ccRCC cell line-derived and patient-derived xenograft RCC and other solid tumor models. This is a Phase 1/2 open label, multicenter, first in human study of NKT2152 in adults with advanced clear cell renal cell carcinoma (ccRCC) (NCT05119335). In Phase 1, up to ~60 patients will be enrolled according to a 3 + 3 design with backfill as permitted by the Safety Review Committee. The primary objective of phase 1 is to determine the recommended dose for expansion (RDE) based on the totality of clinical data. Phase 2 will enroll ~50 additional patients with the primary objective of determining investigator-assessed by RECIST v1.1. Key secondary objectives include safety, tolerability, PD effects, progression free survival, duration of response, and disease control rate. Exploratory objectives include evaluation of biomarkers predictive of tumor response. Adults who have advanced ccRCC without available standard therapy), ECOG PS 0-2, with measurable disease per RECIST 1.1 are eligible. Patients who have had prior HIF2a inhibitors, require supplemental oxygen, and with significant cardiac disease are excluded. Tumor assessments by CT or MRI are conducted every 8 weeks until 48 weeks, then every 12 weeks thereafter. Adverse events will be monitored and graded in severity using CTCAE v5.0. The Phase 1 study is currently actively accruing in the United States with Phase 2 dose expansion anticipated to start in Q3, 2023.

Abstract CT174: First-in-class anti-CD200R1 antibody 23ME-00610 in patients with advanced solid malignancies: Phase 1 results

Abstract Background: CD200R1 was identified as a promising immuno-oncology (IO) target from the 23andMe database. Pleiotropic causal variants with opposing effect on risks for cancer and immune diseases, referred to as an IO signature, were observed in 3 components of the CD200R1 pathway. 23ME-00610 is a first-in-class monoclonal antibody that potently inhibits the CD200R1 immune checkpoint (KD less than 0.1 nM). The dose escalation portion of the first-in-human, Phase 1/2a study of 23ME-00610 (NCT05199272) has been completed and we are reporting data for the first time. Methods: Eligible patients were alteast 18 years with histologically diagnosed locally advanced (unresectable), or metastatic carcinoma or sarcoma who have progressed on standard therapies with ECOG 0 or 1. Key exclusion criteria included active autoimmune disease requiring immunosuppressive therapy and Grade 3 or above immune-mediated toxicity related to prior immunotherapy that led to discontinuation. Dose escalation consisted of accelerated titration (2 and 6 mg) followed by a 3+3 design (20, 60, 200, 600 and 1400 mg). Up to 12 participants were included in a PKPD backfill cohort at the recommended phase 2 dose (RP2D) or a previously evaluated dose level. Participants received 23ME-00610 intravenously every 3 weeks (Q3W) infused over 30 minutes. The primary objectives of Phase 1 were determination of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and tolerability. Key secondary and exploratory objectives included pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of 23ME-00610. Results: Between January 5th, 2022 and November 28, 2022, 21 participants (11/10 male/female; age range: 21-80 years) were enrolled and received ≥ 1 dose of 23ME-00610 across the 2 to 1400 mg cohorts (median duration of exposure: 50 days; range:1-231 days). No dose limiting toxicities, treatment related serious adverse events (TRSAEs) or AEs leading to discontinuation were observed. 14/21 (67%) participants experienced atleast 1 TRAE; the majority were Grade 1 or 2. The most commonly reported TRAEs occurring in atleast 2 participants across all dose levels were headache, fatigue, nausea and pruritis. There was 1 Grade 3 TRAE of increased blood creatinine phosphokinase. Investigator-assessed immune-related AEs including hypothyroidism, pruritis, fatigue and chills were observed at doses 60 mg and above. The PK of 23ME-00610 were dose-proportional at doses 60 mg and above, with a median terminal half-life of ~12 days at 1400 mg. Peripheral saturation of CD200R1 was observed at doses 60 mg and above, as measured by receptor occupancy on T cells and neutrophils, and levels of free soluble CD200R1. Analysis of additional PD data, including cytokines, is ongoing. Conclusion: 23ME-00610 demonstrated an acceptable safety and tolerability profile, with favorable PK and peripheral CD200R1 saturation. Increased immune-related AEs were observed at higher, pharmacologically relevant dose levels. Based on Phase 1 data, 1400 mg 23ME-00610 Q3W will be evaluated in Phase 2a. Citation Format: Shivaani Kummar, Albiruni ABDUL RAZAK, Scott Laurie, Sariah Kell, Dylan Glatt, Sophia R. Majeed, Drew Rasco. First-in-class anti-CD200R1 antibody 23ME-00610 in patients with advanced solid malignancies: Phase 1 results [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 CT174.

Early results from a phase 1, multicenter trial of PSCA-specific GoCAR T cells (BPX-601) in patients with metastatic castration-resistant prostate cancer (mCRPC).

140 Background: Prostate stem cell antigen (PSCA) is expressed in >80% of metastatic prostate cancers. BPX-601 is an autologous PSCA-directed chimeric antigen receptor (CAR)-T cell immunotherapy engineered to express a rimiducid-inducible MyD88/CD40 costimulation switch to enhance T cell potency and persistence. Safety and activity of BPX-601 with rimiducid in mCRPC and pancreatic cancer is being assessed in an ongoing, phase 1/2 clinical trial (NCT02744287). Results from the first two prostate cancer cohorts are reported. Methods: Eligible mCRPC patients (pts) had progressed on ≥ 2 prior therapies including an androgen receptor antagonist and taxane. Using a 3+3 design, pts received lymphodepleting chemotherapy followed by a single-dose of 5 x 106 BPX-601 cells/kg and single or weekly doses of 0.4 mg/kg rimiducid infused over 2 hours beginning 7 days following cell infusion. Primary objective of phase 1 is to determine safety, tolerability and MTD or RP2D. Secondary objectives include characterization of clinical efficacy, PK of rimiducid and long-term safety. Biomarkers indicative of GoCAR-T cell expansion in blood, immune cell activity, and infiltration to tumor are being monitored. Results: As of Sept 2022, 8 pts received BPX-601 5x106 cells/kg; 3 and 5 pts received a single or weekly (range: 1-30) doses of rimiducid. Most common ≥ grade 3 adverse events were myelosuppression, attributed to lymphodepletion. All patients developed cytokine release syndrome (6 G1, 2 G3). Immune-effector cell associated neurotoxicity syndrome occurred and resolved in 2 pts (1 G1, 1 G4). One pt experienced a DLT of neutropenic sepsis (G5) with possible hemophagocytic lymphohistiocytosis (eg, IL-18, ferritin, M-CSF, fractalkine, MIP-1β and IL-1RA levels were elevated). Of 7 evaluable pts, PSA50 response was observed in 3 pts at Day 28. Preliminary RECIST-based results demonstrated partial response in 1, stable disease in 3, 1 progressive disease; at data cut off 2 had not reached imaging timepoint. One patient continues on study with SD after >9 months, with persistent evidence of rimiducid responsiveness. Peripheral blood BPX-601 cells expanded to an average of 3466 vector copies / μg DNA +/- 3109 during the first week with continued re-expansion to an average of 30234 copies/ug DNA +/- 67031) following rimiducid treatment. Serum IFN-γ, GM-CSF and IL-6 rapidly increased over 24 hours following rimiducid treatment (mean IFN-γ increase 26.9-fold ± 14.2) and subsequently diminished over 2 days. Conclusions: BPX-601, a PSCA-directed GoCAR-T cell product, has preliminary evidence of biologic activity with toxicity characteristic of previously reported CAR-T studies. Markers of rimiducid-induced GoCAR-T cell activation and proliferation were observed. Exploration of escalating weekly rimiducid doses > 0.4 mg/kg and BPX-601 cell doses is planned. Clinical trial information: NCT02744287 .

Sotorasib in KRAS p.G12C–Mutated Advanced Pancreatic Cancer

BackgroundKRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C–mutated pancreatic cancer are unknown.MethodsWe conducted a single-group, phase 1–2 trial to assess the safety and efficacy of sotorasib treatment in patients with KRAS p.G12C–mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed.ResultsThe pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation.ConclusionsSotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C–mutated advanced pancreatic cancer who had received previous treatment. (Funded by Amgen and others; CodeBreaK 100 ClinicalTrials.gov number, NCT03600883.)

Adct-602, a CD22 Targeting Antibody Drug Conjugate Bound to PBD Toxin in Adult Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: A Phase 1 Trial

Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal. CD22 is expressed on lymphoblasts in >90% of pts with B-ALL and is an established therapeutic target. Inotuzumab ozogamicin is an approved CD22 targeting antibody for pts with R/R B-ALL; however, the toxin calicheamicin can lead to veno-occlusive disease (VOD) of the liver, especially after allogeneic SCT (allo-SCT). ADCT-602 is an antibody drug conjugate composed of a humanized monoclonal antibody directed against CD22 and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, ADCT-602 demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present here results from an ongoing phase 1/2 trial evaluating ADCT-602 in pts with R/R B-ALL (NCT03698552). Methods: This is an investigator-initiated phase 1/2 trial of ADCT-602 monotherapy in pts with R/R B-ALL. The primary objective of the phase 1 part is to assess the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ADCT-602. The primary objective of phase 2 is to evaluate efficacy (CR/CRi rate). Eligible pts must be ≥18 years of age with R/R B-ALL with bone marrow blasts ≥5%. CD22 must be expressed in ≥20% blasts. Pts must have adequate organ function (creatinine ≤1.5 mg/dL; ALT and AST ≤2 times upper limit of normal (ULN), ≤5 times ULN if there is liver or bone involvement; total bilirubin ≤1.5 times ULN; LVEF ≥45%). A 3+3 dose-escalation design was used for phase 1. ADCT-602 was initially given IV once every 3 weeks; based on the PK data, the administration schedule was later amended to weekly infusions. Results: From November 2018 to July 2022, 21 pts (11 women, 10 men) with R/R B-ALL were enrolled and received treatment with ADCT-602. The median age was 39 years (range, 21-82) and pts had received a median of 5 (range, 2-9) prior therapies [inotuzumab ozogamicin 12/21 (57%); blinatumomab 18/21 (86%); venetoclax 12/21 (57%)]. A total of 8/21 (38%) had a prior CD19 CAR-T, including 1 pt who had both CD19 and CD22 CAR-T. Ten (10/21, 48%) pts had a prior allo-SCT, including 3 pts with 2 prior allo-SCT. The median pretreatment bone marrow blasts were 70% (range, 16-96). The median CD22 expression on blasts was 97% (range, 33.6-100). A total of 11 pts were treated in the Q3week schedule [30µg/kg, n=3; 60µg/kg, n=4; 90µg/kg, n=4]. As the PK data indicated rapid clearance of the antibody, the trial was amended to allow for weekly dosing. A total of 10 pts were treated at the weekly dose level [30µg/kg, n=3; 40µg/kg, n=4; 50µg/kg, n=3]. One pt (30µg/kg weekly dose level) had grade 4 thrombocytopenia possibly related to ADCT-602. One pt (50µg/kg weekly dose level) had a DLT of prolonged myelosuppression (marrow blast clearance without blood count recovery). No pt had VOD. Notably, all 3 pts treated at the 50µg/kg weekly dose level (a dose level expected to be close to RP2D) had evidence of anti-tumor activity (2 pts achieved MRD negative CR; one pt had bone marrow blast clearance). First pt at this dose level was a 26-yr-old with R/R B-ALL with PAX5-JAK2 fusion with 5 prior therapies including 2 CD19 CAR-T and an allo-SCT who achieved MRD negative CR and is receiving ongoing therapy in Cycle 5. Second pt at this dose level was a 66-yr-old with TP53- and KRAS-mutated B-ALL with 2 prior therapies including modified BFM regimen and blinatumomab who achieved MRD negative CR and is receiving ongoing therapy in Cycle 4. Third pt at this dose level was a 21-yr-old with TP53- and KRAS-mutated B-ALL with 4 prior therapies including inotuzumab and a CD19 CAR-T who had morphologic blast clearance without blood count recovery. Two additional pts treated at lower doses levels (1 each at 30µg/kg Q3week and 30µg/kg weekly schedule) achieved MRD negative CR. All responding pts had CD22 expression noted in >97% of the blasts by flow cytometry. Conclusions: In this phase 1 study in pts with very heavily pretreated R/R B-ALL with a median of 5 prior lines of therapy and high baseline bone marrow tumor burden, single-agent ADCT-602 was well tolerated with one pt with DLT noted at the 50µg/kg weekly dose level. Notably, all 3 pts treated at this dose level had evidence of clinical activity with 2/3 pts achieving MRD negative CR. Due to 1 pt with DLT at this dose level, this cohort is being expanded to treat 3 additional pts. This trial continues to accrue pts and updated data will be presented at the ASH meeting.

CLL-120 Pirtobrutinib, A Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Previously Treated CLL/SLL: Updated Results from the Phase 1/2 BRUIN Study

Covalent BTK inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but many patients (pts) will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type and C481-mutated BTK with equal low nM potency. To evaluate the safety and efficacy of pirtobrutinib in previously treated CLL/SLL. BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy. Global; community hospitals, academic medical centers. Pts with advanced B-cell malignancies. Oral pirtobrutinib, phase 1 dose escalated in a standard 3+3 design, phase 2 continuous monotherapy, 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D). The primary objective of phase 2 was ORR. Secondary objectives included duration of response, progression-free survival, overall survival, safety and tolerability, and pharmacokinetics. As of 27 September 2020, 323 previously treated pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other) were treated on 7 dose levels (25-300mg QD). No dose limiting toxicities were reported and MTD was not reached (n=323). 200mg QD was selected as RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent TEAEs regardless of attribution or grade seen in >10% pts. Most common AE of grade ≥3 was neutropenia (10%). 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (0.16-17.8+). ORR was 63% (95%CI 55-71) with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%) and 1 PD (1%), and 5 (4%) discontinued prior to first response assessment. Among 121 BTKi pretreated pts, ORR was 62% (95%CI 53-71). Responses deepened over time with an ORR of 86% among pts with >10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other (52%). Of 88 responding pts, all except 5 remained on therapy. Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data from 252 efficacy evaluable BTK pre-treated CLL/SLL patients with a data cutoff date of 16 July 2021 will be presented.

PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN PREVIOUSLY TREATED CLL/SLL: UPDATED RESULTS FROM THE PHASE 1/2 BRUIN STUDY

To evaluate the safety and efficacy of pirtobrutinib in previously treated CLL/SLL. BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received ≥ 2 prior therapies. Primary objective for phase 1: determine the RP2D. Primary objective of phase 2: ORR. Secondary objectives included DoR, PFS, OS, safety and tolerability and pharmacokinetics. As of 27 Sept 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT and 6 other) were treated on 7 dose levels (25-300mg QD). Median number of prior lines of therapies=3 (1-11). No DLTs were reported and MTD was not reached (n = 323). 200mg QD was selected as RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent TEAEs regardless of attribution or grade seen in ≥ 10% pts. Most common AE of grade ≥3 was neutropenia (10%). 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (0.16-17.8+). ORR was 63% (95%CI 55-71) with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%) and 1 PD (1%), and 5 (4%) discontinued prior to first response assessment. Among 121 BTKi pretreated pts, ORR was 62% (95%CI 53-71). Responses deepened over time with an ORR of 86% among pts with ≥ 10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other reasons (52%). Of 88 responding pts, all except 5 remained on therapy. Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 100 new pts with CLL and an additional 10 months since the prior data cut will be presented. Previously presented at the American Society of Hematology - 63rd Annual Meeting.

PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN PREVIOUSLY TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS FROM THE PHASE 1/2 BRUIN STUDY

To evaluate the safety and efficacy of pirtobrutinib in previously treated patients (pts) with MCL. BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received ≥ 2 prior therapies. The primary objective for phase 1 was to determine the RP2D. The primary objective of phase 2 was ORR. Secondary objectives included DoR, PFS, OS, safety and tolerability, and pharmacokinetics. As of 27 Sept 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT and 6 other NHL) were treated on 7 dose levels (25-300mg QD). Among the 61 MCL pt, median number of prior lines of therapy was 3 (1-8). No DLTs were reported and MTD was not reached (n = 323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent TEAEs regardless of attribution or grade seen in ≥ 10% pts. The most common AE of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage/hypertension occurred in 5 (2%)/4 (1%) pts. 5 (1%) pts discontinued due to TEAEs. 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95%CI 38-66; 13 CR (25%), 14 PR (27%), 9 SD (17%), 11 PD (21%) and 5 (10%) discontinued prior to first response assessment). Median follow up was 6 months (0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy. Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented. Previously presented at American Society of Hematology - 63rd Annual Meeting.

P1101: PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN PREVIOUSLY TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS FROM THE PHASE 1/2 BRUIN STUDY

Background: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients (pts) will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent (reversible) BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. Aims: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received ≥2 prior therapies. Methods: Pirtobrutinib was dose escalated in a standard 3 + 3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification. Safety was assessed in all pts (CLL/SLL and NHL). Results: As of 27 September 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts. Among the 61 MCL pts, median number of prior lines of therapy was 3 (range, 1-8) and a majority of them had received a prior BTKi (93%), an anti-CD20 antibody (98%) or chemotherapy (92%). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in ≥10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. Five (1%) pts discontinued due to treatment-related adverse events. At the efficacy cutoff date, 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95% confidence interval 38-66; 13 complete response (CR) [25%], 14 partial response (PR) [27%], 9 stable disease (SD) [17%]), 11 progressive disease (PD) [21%] and 5 [10%] discontinued prior to first response assessment). Median follow up was 6 months (range 0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy. Summary/Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented.

Abstract CT251: LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors

Abstract Background: Fibroblast activation protein (FAP) is a membrane-bound protease that is highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers. With limited expression observed in normal tissues, FAP is a promising therapeutic and imaging target for delivery of radionuclides to cancer tissues. FAP-2286, a low-molecular-weight cyclic peptide that potently and selectively binds to FAP, is attached to a linker and tetraazacyclododecane tetraacetic acid (DOTA) cage that can be used to conjugate radionuclides such as lutetium-177 (177Lu) or gallium-68 (68Ga) for therapeutic or imaging applications, respectively. 177Lu-FAP-2286 has demonstrated antitumor activity in preclinical studies. The LuMIERE study (NCT04939610) is the first phase 1/2 clinical trial of an FAP-targeted radionuclide therapy evaluating 177Lu-FAP-2286 in patients with FAP-expressing solid tumors that are identified with the imaging agent 68Ga-FAP-2286. Methods: Eligible adult patients with advanced or metastatic solid tumors and measurable disease (per RECIST v1.1) will be selected for treatment with 177Lu-FAP-2286 on the basis of FAP expression using 68Ga-FAP-2286. In phase 1, tumors must be refractory to or have progressed following prior treatment, with no satisfactory alternative treatment options. Phase 1 includes dose escalation of 177Lu-FAP-2286, starting at 3.7 GBq to a maximum of 9.25 GBq. Patients may receive up to 6 cycles of 177Lu-FAP-2286 administered on day 1 of each 6-week cycle. Three to 12 patients will be treated at each dose level in the dose-escalation portion. Tolerability will be assessed across multiple doses for determination of a recommended phase 2 dose (RP2D), which may be further evaluated in a phase 1 dose-expansion portion. FDG-PET/CT scans will be collected prior to treatment, and patients will be imaged by planar and SPECT/CT scans at multiple time points to calculate organ and tumor dosimetry to determine absorbed radiation dose. Disease status will be assessed per RECIST v1.1 every 6 weeks. The primary objective of phase 1 is to evaluate the safety of 177Lu-FAP-2286 and determine the RP2D. Secondary objectives include the assessment of radiation dosimetry, pharmacokinetics, and preliminary efficacy of 177Lu-FAP-2286 and the evaluation of safety and tumor uptake of 68Ga-FAP-2286. Phase 2 will evaluate the efficacy, safety, and dosimetry of 177Lu-FAP-2286 in patients with select FAP-expressing solid tumors. Citation Format: Jonathan McConathy, Mallika Dhawan, Ajit H. Goenka, Emerson A. Lim, Yusuf Menda, Beth Chasen, Moh'd Khushman, Akiva Mintz, Yousef Zakharia, John J. Sunderland, Owen Bowles, Jim Xiao, Andrew D. Simmons, Kenton Wride, Aaron Enke, Thomas A. Hope. LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic 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 CT251.