Q2W Cohorts Research Articles

Abstract PO5-05-03: Phase 1/2 Dose Expansion Study Evaluating First-In-Class eIF4A Inhibitor Zotatifin in Patients with ER+ Metastatic Breast Cancer

Abstract Background Zotatifin (eFT226) is a first-in-class, potent and sequence selective inhibitor of RNA helicase eIF4A that promotes a stable mRNA:eIF4A:drug ternary complex at specific polypurine motifs present within the 5’-UTR of select transcripts, thereby blocking production of the encoded proteins. In preclinical models zotatifin treatment simultaneously down-regulated translation of numerous oncogenes including CDK4, ERα, ERBB2, KRAS, and CCND1. Previous clinical research has demonstrated the activity of zotatifin in combination with other agents in ER+ metastatic breast cancer (MBC). Methods Part 1 is a 3+3 dose escalation portion of the protocol followed by Part 2 as a Simon’s two-stage design in patients with ER+ MBC enrolled at the recommended phase 2 dose (RP2D) of zotatifin (0.07 mg/kg IV two weeks on/one week off) in combination with fulvestrant (ful) and abemaciclib (abema) (Z+F+A). Part 1a and Part 1b are 3+3 dose escalation portions evaluating zotatifin in combination with ful (Z+F) at QW IV and Q2W IV dosing schedules, respectively. Key eligibility criteria included at least one line of therapy for advanced/metastatic disease, progression on hormone therapy, and in addition, the Z+F cohorts required prior CDK 4/6 inhibitor (CDKi). Primary endpoint of Part 1a/1b was determination of RP2D and primary endpoint of part 2 was objective response rate (ORR) per RECIST v1.1. Additional endpoints included safety, progression-free survival (PFS) and other efficacy analyses, and characterization of pharmacodynamic (PD) markers and pharmacokinetics. Results As of a data cut-off of July 6, 2023, 20 pts were enrolled in the Z+F+A cohort and had a median of four prior metastatic lines of therapy. In 19 evaluable pts in Z+F+A cohort, there were four confirmed partial responses (PR), one unconfirmed PR, and 10 pts with best overall response (OR) of stable disease (SD). All pts with PR/unconfirmed PR received prior CDKI, ful, and chemotherapy for MBC. Confirmed PRs were observed in patients with and without mutations in ESR1 and PIK3CA. mPFS, while not yet mature, exceeds 20 weeks. In Z+F+A the most common adverse events (AEs) were diarrhea (80%, all grades (Gr)) and nausea (75%, all Gr 1/2) and the most common Gr 3/4 AE was diarrhea (15%). In Z+F cohorts of 0.07 mg/kg QW (n=3), 0.1 mg/kg Q2W (n=3), and 0.14 Q2W (n= 2) there were no dose-limiting toxicities or Gr 5 adverse events (AEs). There was one confirmed PR and one SD in 0.1 and 0.14 mg/kg Q2W cohorts, respectively, and no PR or SD in the 0.07 mg/kg QW cohort. In Z+F+A, 9 pts had paired pre- and on-treatment ctDNA analyzed by Guardant assay. Of the remaining 11 pts, 4 came off study prior to scheduled collection of the on-treatment sample and 5 had unavailable samples. Of the 9 patients with paired samples, 8 had ctDNA decreases of >50%, all of whom had SD or PR. In the Z+F Q2W cohort, 2 of 3 patients had ctDNA decreases >50%, one of whom had a PR. Reduction below the limit of detection was seen for mutant alleles in ESR1, PIK3CA and other genes with potential to confer resistance to endocrine therapy. Conclusion Z+F+A showed encouraging efficacy in heavily pretreated ER+ MBC patients, with results that compare favorably to other treatment options available after progression on CDKi plus endocrine treatment. Efficacy was seen independent of ESR1 or PIK3CA mutations, suggesting the potential to treat a broad, unrestricted patient population. Initial results with Z+F Q2W dosing are encouraging and support continued dose escalation of this regimen. Citation Format: Ezra Y. Rosen, Manish Sharma, David Berz, Jennifer Caswell-Jin, Georgina Fulgar, Mark Densel, Gary Chiang, Samuel Sperry, Douglas Warner, Funda Meric-Bernstam. Phase 1/2 Dose Expansion Study Evaluating First-In-Class eIF4A Inhibitor Zotatifin in Patients with ER+ Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-05-03.

Symptoms, Functioning, and Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma Treated with Talquetamab: Updated Patient-Reported Outcomes from the Phase 1/2 MonumenTAL-1 Study

Introduction: Patients (pts) with advanced and heavily pretreated relapsed/refractory multiple myeloma (RRMM) have worse health-related quality of life (HRQoL) than those at earlier stages of the disease and have limited treatment options available to enable improvement in HRQoL, particularly those who are triple-class exposed. Talquetamab (tal), a novel GPRC5D×CD3 bispecific antibody, has shown deep and durable responses in the MonumenTAL-1 study (NCT03399799/NCT04634552) in pts with RRMM. Here, we report patient-reported outcomes (PROs) from the MonumenTAL-1 study, focusing on data through cycle 21 from the tal 0.4 mg/kg weekly (QW) dosing cohort (initial results presented at ASH 2022) and new data through cycle 15 from the tal 0.8 mg/kg every other week (Q2W) dosing cohort. Methods: MonumenTAL-1 is a first-in-human, phase 1/2, single-arm study of tal monotherapy. Pts with triple-class exposed RRMM received the recommended phase 2 doses of tal (0.4 mg/kg QW or 0.8 mg/kg Q2W). PRO assessments included the following instruments: the European Organisation for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ-C30), a cancer-specific PRO instrument, with scores ranging from 0 to 100 (higher scores indicate better global health status [GHS] and functioning, whereas higher scores for symptoms represent worse severity, and a 10-point change from baseline indicates meaningful change); the EuroQol 5-Dimension 5-Level (EQ-5D-5L) visual analogue scale (VAS), which rates pt health from 0 (worst) to 100 (best); and the Patient Global Impression of Severity (PGIS) instrument, a single item that assesses severity of disease. PRO instruments were administered at screening, day 1 of cycle 1, then day 1 of every other cycle. Results for each instrument are presented for specific cycles that have a larger sample size (n≥30); later cycles presented for the QW cohort are due to longer follow-up duration (median,18.7 months) compared with the Q2W cohort (median, 12.3 months), for which earlier cycles are presented. Results: As of January 17, 2023, phase 2 data were available for 122 and 109 pts who received ≥1 administration of tal QW or Q2W, respectively; compliance for completion of the EORTC QLQ-C30 was >97% at baseline and >80% at most post-treatment visits (in each cohort). Least squares (LS) mean change from baseline demonstrated clinically significant improvements in GHS (16.4 points QW, 8.8 points Q2W) and physical functioning (9.6 points QW, 3.1 points Q2W) at cycle 15 in QW and cycle 11 in Q2W cohorts, respectively, along with reductions in fatigue (-10.1 points QW, -5.9 points Q2W) and pain (-16.8 points QW, -1.9 points Q2W) symptoms at cycle 15 in QW and cycle 11 in Q2W cohorts, respectively (Figure). An increasing ability to engage in social roles and activities (role functioning) was also reported by pts in the QW cohort, with an 8.5-point improvement from baseline at cycle 15. Pts in the QW cohort reported meaningful improvement from baseline at later cycles; these improvements were particularly evident in GHS (57%) and social function (47%) at cycle 15. In the Q2W cohort, meaningful improvements from baseline in fatigue (45%) and emotional function (42%) were larger at cycle 7. Pts' global impression of their MM disease severity (PGIS) also improved from baseline, consistent with the meaningful improvement data: for example, in the QW cohort, ratings were 10.8% (very severe) and 40.8% (severe) at baseline compared with 0% and 6.7%, respectively, at cycle 15; in the Q2W cohort, ratings were 11.1% (very severe) and 34.3% (severe) at baseline compared with 2.8% and 19.4%, respectively, at cycle 11. Pts reported improvements from baseline in their health status (EQ-5D-5L VAS score), with LS mean change of 8.1 (95% CI, 2.6, 13.7) and 2.7 (95% CI -2.3, 7.7) at cycle 9 in the QW and Q2W cohorts, respectively. Median time to improvement from baseline in most EORTC QLQ-C30 subscales and EQ-5D-5L VAS scores was ~2 months in both cohorts; estimates of median time to first worsening ranged from 2 to ~9 months. Conclusions: Meaningful improvements from baseline in MM symptoms, physical function, and overall HRQoL were observed in tal QW and Q2W cohorts, with durable and short-term improvements, respectively. These favorable results in PROs add to the efficacy and safety profile of tal, highlighting tal as a compelling treatment option for pts with triple-class exposed RRMM.

Talquetamab + Pomalidomide in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Preliminary Efficacy Results from the Phase 1b MonumenTAL-2 Study

Introduction: Talquetamab (tal) is a T-cell redirecting bispecific antibody (BsAb) targeting GPRC5D and CD3. GPRC5D is a novel antigen that is highly expressed on malignant plasma cells but has low expression on B cells and normal plasma cells. Tal has demonstrated deep and durable responses, including in high-risk populations, and a clinically manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in the MonumenTAL-1 study (NCT03399799/NCT04634552). Pomalidomide (pom) is an established immunomodulatory drug (IMiD) that has direct on-tumor apoptotic activity and enhances immune activity. Combining pom with T-cell redirection therapy may lead to synergistic antimyeloma effects. We report initial efficacy and safety results of tal + pom from the MonumenTAL-2 study. Methods: MonumenTAL-2 (NCT05050097) is a multi-arm, phase 1b study of tal in combination with antimyeloma agents in pts with MM. Pts received the recommended phase 2 doses of subcutaneous tal 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), with step-up dosing, + oral pom 2 mg daily (dose escalation to 4 mg daily permitted) starting in cycle 2. Pts received ≥2 prior lines of therapy (LOT) including a proteasome inhibitor and an IMiD; prior T-cell redirection therapies including BsAbs and chimeric antigen receptor (CAR)-T along with prior pom exposure were permitted. CRS and ICANS were graded by ASTCT criteria; all other adverse events (AEs) were graded by CTCAE v5.0. Response was assessed by IMWG criteria. Efficacy endpoints are presented as individual cohorts (QW and Q2W); safety is presented across both cohorts. Results: As of June 5, 2023, 35 patients were enrolled with a median follow-up of 11.4 months (range, 1.2-14.9) in the QW cohort (N=16) and 7.7 months (range, 1.6-10.8) in the Q2W cohort (N=19). Median ages were 69.5 years (range, 49-78) and 63.0 years (range, 43-76), respectively; 41.7% and 33.3% of pts had high-risk cytogenetics (del[17p], t[4;14], or t[14;16]) and 12.5% and 10.5% of pts had extramedullary disease, respectively. Median prior LOT were 3 in both cohorts; 25.0% and 21.1% were triple-class refractory, respectively, and 6.3% were penta-drug refractory (all in QW cohort). Prior treatments included CAR-T (18.8% and 0%), BsAb (6.3% and 0% [0% refractory]), and anti-CD38 Ab (75.0% and 73.7% [56.3% and 36.8% refractory]) in the QW and Q2W cohorts, respectively; 31.3% and 15.8% had prior pom exposure (18.8% and 5.3% refractory). All pts had ≥1 AE; most common were dysgeusia (77.1%), CRS (74.3%; most grade 1/2, 2.9% grade ≥3), and neutropenia (60.0%). Grade 3/4 AEs occurred in 88.6% of pts; most common were neutropenia (48.6%), anemia (25.7%), and thrombocytopenia (20.0%). Nail, skin, and rash toxicities occurred in 65.7%, 40.0%, and 20.0% of pts (majority grade 1/2 with no discontinuations), respectively. ICANS occurred in 2 pts (both grade 1). Infections occurred in 71.4% of pts (22.9% grade 3/4); most common were pneumonia (20.0%) and COVID-19 (14.3%). AEs led to dose reduction or schedule change of tal in 34.3% of pts and dose reduction of pom in 31.4% of pts. Two pts (5.7%) in the Q2W cohort had AEs, myocardial infarction and pulmonary embolism (PE), that led to treatment discontinuation (not drug related). One death due to PE occurred (same pt who discontinued treatment). ORR was 86.7% and 83.3% in the QW and Q2W cohorts, respectively, with ≥CR in 60.0% and 44.4% and ≥VGPR in 86.7% and 77.8%, respectively. ORRs were consistent across pt subgroups (>80% independent of prior pom or CAR-T exposure). Median time to first response was 1.0 month (range, 0.9-2.1) in the QW cohort and 1.3 months (range, 0-4.8) in the Q2W cohort. At 6 months, 100% of responders were still responding in both cohorts. Median DOR and PFS were not reached, with 6-month PFS rates of 93.3% (QW) and 88.9% (Q2W). Conclusions: In this first reported combination of a GPRC5D-targeted therapy and an IMiD, tal + pom showed rapid, deep responses in pts with RRMM and ≥2 prior LOT. The safety profile of the combination, including grade 3/4 hematologic toxicity, was consistent with the individual agents, with no evidence of additive hematologic toxicities; additionally, there were low rates of treatment discontinuation due to AEs. The promising efficacy and manageable safety profile of this combination further supports tal as a versatile combination partner and warrants further evaluation of this regimen.

Clinical Outcomes of Subsequent Therapies in Patients with Relapsed/Refractory Multiple Myeloma Following Talquetamab Treatment: Analyses from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal) is an off-the-shelf, T-cell redirecting bispecific antibody (BsAb) targeting G protein-coupled receptor family C group 5 member D. Results from the phase 1/2 MonumenTAL-1 (NCT03399799/NCT04634552) trial showed overall response rates (ORRs) of >71%, which were durable, and a manageable safety profile with the recommended phase 2 doses (RP2Ds) of subcutaneous (SC) tal, 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), in patients (pts) with relapsed/refractory multiple myeloma. Data with tal also demonstrated preservation of B cells throughout treatment, contributing to relatively few severe infections. To date, there is a paucity of data describing pt outcomes after T-cell redirection therapies. Here, we report outcomes for pts who received subsequent antimyeloma therapies (SATs) after discontinuing tal in MonumenTAL-1, including pts who went on to receive subsequent T-cell redirection therapies. Methods: Pts eligible for MonumenTAL-1 were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor (PI), ≥1 immunomodulatory drug (IMiD), and ≥1 anti-CD38 monoclonal antibody (mAb) (phase 2). Pts received step-up doses and the QW or Q2W RP2Ds of SC tal until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. Following tal discontinuation, SAT, start/end date of SAT, best response to SAT, and date of PD on SAT were recorded, if available. Data are pooled for the QW and Q2W RP2D cohorts. Response to SAT is based on investigator-reported assessment. Efficacy is presented for first SAT received post tal discontinuation. Results: As of 17 Jan, 2023, 288 pts with no prior exposure to T-cell redirection therapies received tal at the RP2Ds (0.4 mg/kg QW [n=143] or 0.8 mg/kg Q2W [n=145]). Median prior LOT was 5. In the QW and Q2W cohorts, respectively, 74.1% and 69.0% were triple-class refractory, 29.4% and 23.4% were penta-drug refractory, and 15.4% and 11.0% had prior belantamab mafodotin exposure. Overall, 135 pts received ≥1 SAT post tal discontinuation: chemotherapy-based regimens (n=60 [44.4%]), a PI-, IMiD-, or other anti-neoplastic-containing regimen (n=40 [29.6%]), anti-CD38 mAb-containing regimens (n=36 [26.7%]), BsAbs (mostly monotherapy, n=23 [17.1%]: n=18 [13.3%] anti-B-cell maturation antigen [BCMA]; n=5 [3.7%] anti-Fc receptor-like protein 5 [FcRH5]), chimeric antigen receptor T-cell (CAR-T) therapy (n=20 [14.8%]; of whom n=18 [13.3%] were reported as receiving anti-BCMA-targeting CAR-T therapy), or anti-BCMA antibody-drug conjugates (n=13 [9.6%]). Time from tal discontinuation to the start of first SAT was generally similar across all drug classes (median, 1.1 months [range, 0.1-7.4]), including T-cell redirection therapies and bridging therapy in pts receiving CAR-T therapy: 1.5 months (range, 0.1-7.4) with CAR-T, 1.7 months (range, 1.0-3.5) with anti-BCMA BsAbs, and 1.0 month (range, 1.0-2.3) with anti-FcRH5 BsAbs. Best responses for each treatment class are shown in the Table. Pts had deep responses to CAR-T therapy as the first SAT post tal discontinuation with an ORR of 66.7% (8/12) (Table). ORR was 33.3% (2/6) in pts treated with anti-BCMA BsAbs as the first SAT post tal and 66.6% (2/3) with subsequent anti-FcRH5 BsAb therapy. Conclusions: Pts from MonumenTAL-1 who discontinued tal were effectively treated with several classes of therapy. Subsequent treatment with T-cell redirection therapies appears feasible, with 25.0% of pts achieving a complete response or better with CAR-T therapy post tal. Further investigation in larger pt populations is warranted to better understand the sequencing of T-cell redirecting therapies after tal to optimize outcomes.

A phase 1/2 study of a first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients with advanced HER2-expressing solid tumors.

2538 Background: BDC-1001 is a HER2-targeted immune-stimulating antibody conjugate (ISAC), designed to trigger local activation of the innate immune system and generate a durable tumor-targeted adaptive immune response. BDC-1001 incorporates a trastuzumab biosimilar (EG12014) conjugated to a proprietary TLR7/8 agonist using a non-cleavable linker and a cell membrane-impermeable payload. An international phase 1/2 study was initiated to evaluate the safety of BDC-1001 ± nivolumab (nivo) and to identify the recommended phase 2 dose (RP2D) considering PK/PD analyses and preliminary efficacy. Methods: Dose-escalation (3+3, +backfills) enrolled patients (pts) with HER2-positive (amplified, or IHC 3+) or HER2 low (IHC 2+ and not amplified) solid tumors who had progressed after standard therapies. BDC-1001 was given IV q3w, q2w, or q1w as monotherapy (mono; n=91) and q2w or q1w with nivo 240 mg q2w (combo; n=27). Results: As of Nov 23, 2022, 118 pts with 16 different tumor types, were enrolled with BDC-1001 doses ranging from 0.15 to 20 mg/kg. Mean age was 61 yrs with a median of 4 and 5 prior lines of therapy (range, 1-11; 1-14; prior anti-HER2 therapy (HER2Tx) [66%/70%], immunotherapy (IO) [23%/22%]) for mono and combo, respectively. Median follow-up time was 5.0-6.1 months. Treatment was well tolerated with only 1 DLT (Gr3 supraventricular tachycardia) at 8 mg/kg q1w combo cohort. Low-grade IRRs were the most common related TEAEs (mono, 26.5%; combo, 25.9%). A related SAE (Gr4, bronchopulmonary hemorrhage) was seen in 1 pt (mono, 1.1%). Antitumor activity was observed at a range of doses and malignancies. There were 4 confirmed (RECIST 1.1) durable PRs (all in MSS tumors with low/intermediate TMB, prior Tx: 1 HER2Tx, 1 IO) including 1 pt with colon cancer (CRC) in the 5 mg/kg q3w mono cohort, and 3 in the 20 mg/kg q2w cohorts (mono 1/7; combo 2/7; ovarian, biliary, and rectal cancers). After the data cut, an additional PR (unconfirmed) was reported at week 6 in a pt with CRC receiving 12m/kg 1qw combo. Ten additional pts had SD lasting ≥6 months (8 mono; 2 combo; prior Tx: 6 HER2Tx; 1 IO; e.g., ovarian, endometrial, colorectal, gastric). Durable SDs were most frequent in the q2w cohorts. BDC-1001 exposure (e.g., Cmin) correlated with activity among pts in q2w cohorts. Increases in myeloid and T cell infiltration markers in post-Tx tumor biopsies align with mechanism of action (MoA). No anti-drug antibodies were detected. Conclusions: BDC-1001 mono and combo were well-tolerated. Targeted serum exposure levels were achieved, and encouraging clinical activity was noted in heavily pretreated pts with various HER2 positive tumors, especially in the 20 mg/kg q2w cohorts. Immune biomarker changes from plasma and tumor were consistent with MoA of this ISAC. These data support further development of BDC-1001 with phase 2 expansion in HER2-expressing solid tumors at the RP2D. Clinical trial information: NCT04278144 .

Phase 1 trial of a novel C’Dot drug conjugate (CDC), ELU001, in patients with solid tumors known to overexpress folate receptor alpha (FRα).

TPS3159 Background: ELU001 is a novel first-in-class nanoparticle drug conjugate that consists of ~13 folic acid targeting moieties and a payload of ~22 molecules of the topoisomerase-1 inhibitor, exatecan. Folic acid and exatecan are covalently bound by non-cleavable and cathepsin-B cleavable linkers, respectively, to short polyethylene glycol chains which surround the C’Dot’s silica core. CDCs are very small (~6 nm), allowing for more efficient penetration into solid tumors compared to ADCs and a rapid elimination by the kidneys, which is expected to lead to less toxicity than ADCs that have a longer half-life in circulation. ELU001’s high avidity is designed to promote binding to FRα on the surface of cancer cells that express any level of antigen (low to high). ELU001 then internalizes into the tumor cell and traffics to the lysosome where enzymatic cleavage releases the exatecan payload. ELU001 has demonstrated efficacy in preclinical models with low, moderate and high levels of FRα. The first-in-human trial, ELU-FRα-1, is currently recruiting patients with ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma cancers, and, in the opinion of the Investigator, have no meaningful life-prolonging therapy option available. Methods: This is a Phase 1 / 2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). In Part 1, patients with cancer types with a high likelihood of having FRα overexpressing tumors, (ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma) will be enrolled. FRα expression is determined retrospectively. ELU001 is administered either weekly (QW) (once a week for 3 weeks, 1 week rest), every other week (Q2W, with no rest between cycles), or every three weeks (Q3W). Initial Part 2 expansion cohorts are planned in ovarian cancer with high FRα expression, ovarian cancer with moderate or low FRα expression, and endometrial cancer with any positive FRα expression. Here, FRα will be prospectively determined. Other cancer types may be assessed in the future. The primary objective for Part 1 is to identify the MTD/RP2D. The primary objective for Part 2 is to determine the ORR. Secondary objectives include DOR, PFS, TFST, PFS2, OS, frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. Part 1 Dose Escalation will recruit about 2-5 patients at each dose for each regimen (QW; Q2W; Q3W). Part 2 Stage 1 will recruit about 15 patients per tumor group expansion cohort and is expected to begin recruitment in the second half of 2023. The study is enrolling in Part 1 Q2W Cohort 301 and Q3W Cohort A in the US. Clinical trial information: NCT05001282 .

Abstract CT255: ELU-FRα-1: a study to evaluate ELU001 in patients with solid tumors that overexpress folate receptor alpha (FRα)

Abstract Background: ELU001 is a novel, first-in-class, new molecular entity described as a C’Dot Drug Conjugate (CDC). ELU001 consists of ~13 folic acid targeting moieties and a payload of ~22 molecules of the topoisomerase-1 inhibitor, exatecan. Folic acid and exatecan are covalently bound by non-cleavable and cathepsin-B cleavable linkers, respectively, to short polyethylene glycol chains which surround the C’Dot’s silica core. CDCs are very small (~6 nm), allowing greater ability to penetrate more efficiently into solid tumors compared to ADCs. CDCs are rapidly eliminated by the kidneys, which is expected to lead to less toxicity than ADCs that have a longer half-life in circulation. ELU001’s high avidity is designed to promote binding to FRα on the surface on FRα overexpressing cancer cells with a wide range of antigen expression including high, moderate and low expressing tumor cells. Following antigen binding, ELU001 internalizes into the tumor cell, and traffics to the lysosome where enzymatic cleavage releases the exatecan payload. The first-in-human trial, ELU-FRα-1, is currently recruiting patients that have advanced, recurrent or refractory tumors associated with indications that are known to potentially overexpress FRα and have been shown to be topoisomerase 1 inhibitor-sensitive, and, in the opinion of the Investigator, have no satisfactory therapeutic options available. Methods: This is a Phase 1/2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). Part 1 is a basket trial enrolling patients with cancer types with a high likelihood of having FRα overexpressing tumors, (specifically, ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma). Patients are receiving ELU001 weekly (QW) (once a week for 3 weeks, 1 week rest), every other week (Q2W, with no rest between cycles), or every three weeks (Q3W). Analysis of FRα expression will be retrospectively determined. Part 2 will use Simon’s Two-Stage design to evaluate 4-6 Expansion Cohorts, comprised of tumor histologies anticipated to have greatest activity to ELU001 treatment. FRα will be prospectively determined. The primary objective for Part 1 is to identify the MTD/RP2D. The primary objective for Part 2 is to determine the ORR. Secondary objectives include DOR, PFS, TFST, PFS2, OS, frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. Part 1 Dose Escalation will recruit about 25 patients per dose regimen (QW; Q2W; Q3W). The first stage of Part 2 (Dose Expansion) will recruit about 15 patients per tumor group expansion cohort. The study is actively enrolling in the US and currently recruiting in Q2W Cohort 201 and Q3W Cohort A. QW Cohorts 1-3 and Q2W Cohort 101 are complete. Clinical trial information: NCT05001282. Citation Format: Wen Wee Ma, Anthony Tolcher, Cesar A. Perez, Douglass Orr, Erika Hamilton, Yujie Zhao, Yonina Murciano-Goroff, Carey Anders, Gregory P. Adams, Catherine W. Reddick, Eliel Bayever. ELU-FRα-1: a study to evaluate ELU001 in patients with solid tumors that overexpress folate receptor alpha (FRα) [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 CT255.

Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma Treated with Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody: Patient-Reported Outcomes from MonumenTAL-1

Introduction: Studies of multiple myeloma (MM) populations indicate that patients with more advanced and heavily pretreated disease have worse health-related quality of life (HRQoL) than those at earlier stages. In addition, treatment options are limited for triple-class exposed relapsed/refractory MM (RRMM), with little hope of improving HRQoL. Talquetamab is a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody targeting both GPRC5D and CD3 receptors. MonumenTAL-1 is a phase 1/2 trial (NCT03399799/NCT04634552) of talquetamab in patients with RRMM. Patient-reported outcomes (PROs) data on HRQoL, symptoms, and functioning were collected in the phase 2 cohorts of MonumenTAL-1. Here, we report PROs, focusing on global health status (GHS), physical functioning, pain, and fatigue, for the 0.4 mg/kg subcutaneous (SC) weekly (QW) cohort. Data for the 0.8 mg/kg SC every 2 weeks (Q2W) cohort are immature currently. Methods. Patients enrolled in phase 2 must have previously received ≥3 prior lines of therapy, including ≥1 proteosome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody (ie, triple-class exposed). After screening, patients received talquetamab step-up doses, requiring hospitalization, before cycle 1. The European Organization for Research and Treatment of Cancer Quality of Life Core 30-item (EORTC QLQ-C30) questionnaire is a cancer-specific PRO instrument administered at screening, cycle 1, and then every other cycle. It includes a subscale to measure HRQoL, 5 functional scales, 3 symptom subscales, and 6 additional single items. Scores range from 0 to 100; higher scores indicate better GHS and functioning, whereas a higher score represents more symptom severity. Compliance with PROs was calculated as the number of completed assessments divided by the number of patients on study treatment at each assessment time point. Treatment effect was assessed with a mixed-effects model with repeated measures. For the analysis of the proportion of patients with meaningful improvement, the threshold for meaningful improvement from baseline was defined as a change of ≥10 points. Time to worsening was determined using the Kaplan-Meier estimate. Results: For patients treated with 0.4 mg/kg SC QW (n=122), compliance with completing the EORTC QLQ-C30 was 96% at screening and over 80% at most post-treatment visits. After an immediate decline in overall HRQoL between screening and cycle 1, patients reported meaningful improvements in EORTC QLQ-C30 GHS and a meaningful reduction in pain symptoms compared with baseline (Figure). Least squares [LS] mean change for fatigue symptoms was -8 (95% CI, -13.83, -2.26) at cycle 9 and reached a mean decrease (ie, improvement) of 11.2 points (95% CI, -18.9, -3.53) at cycle 13. Similar results were observed in the physical (LS mean change at cycle 9: 6.5 [95% CI, 2.05, 10.93]) and role (LS mean change at cycle 9: 11.4 [95% CI, 4.55, 18.25]) functioning subscales. With treatment, the proportion of patients with meaningful improvement was high; for example, at cycle 9 for the 0.4 mg/kg cohort, 42% improved in GHS, 34% in physical functioning, 40% in role functioning, 86% in pain symptoms, and 78% in fatigue symptoms. Median time to worsening ranged from 2 (role and social functioning) to 9 months (nausea/vomiting). Overall, changes in PROs were similar in the 0.8 mg/kg SC Q2W cohort in early cycles, but conclusions are limited due to short follow-up and small sample size. The 0.8 mg/kg SC Q2W cohort will be updated with additional follow-up. Conclusions: With talquetamab treatment, patients in the 0.4 mg/kg SC QW cohort reported improvement in overall HRQoL and physical and role functioning and a decrease in pain and fatigue. These findings are consistent with the clinical benefits of talquetamab as demonstrated by the efficacy results from the MonumenTAL-1 study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population Pharmacokinetic Modeling and Exposure-Response Analysis Providing a Basis for Selecting Penpulimab Dose in a Population with Relapsed/Refractory Classic Hodgkin's Lymphoma

BackgroundPenpulimab is an IgG1 anti-PD-1 antibody with Fc-engineering to eliminate effector functions. Treatment with penpulimab as a single agent at 1.0, 3.0 and 10.0 mg/kg Q2W cohort were safe during the phase Ia dose-escalation phase with no dose-limiting toxicity observed and 80-100% receptor occupancy being observed in all of the above dose cohorts. It was administered in a fixed dosing regimen [200 mg every 2 weeks (Q2W)] in a phase II study (AK105-201) demonstrating efficacy and safety in Relapsed/Refractory classic Hodgkin's lymphoma (R/R cHL). Longer dosing intervals may offer greater flexibility and convenience to both patients and healthcare professionals. To provide alternative extended dosing schedules for patients receiving penpulimab, we explored the feasibility of a longer dosing regimen [200 mg every 3weeks (Q3W) and 400 mg Q6W] using exposure-response (ER) analysis approach.MethodsA penpulimab population PK(PopPK) model was established based on PK data from a total of 332 subjects from six clinical studies. The following PK parameters were determined and used for penpulimab E-R analysis: the trough concentrations at steady-state (C min,ss); the peak concentration at steady-state (C max,ss); area under the concentration-time curve at steady-state (AUC ss). ER evaluation using modeling and simulation was used to demonstrate the similarity of efficacy and safety for 200 mg Q3W and 400 mg Q6W regimens compared with 200 mg Q2W regimen. The efficacy endpoints used in the analysis were complete response (CR), overall response rate (ORR) and disease control rate (DCR) in AK105-201 study and the safety endpoints included ≥ grade 3 treatment-related adverse event (TRAE), ≥ grade 3 immune-related adverse events (irAE), or AE leading to suspension in all the six clinical studies.ResultThe final PopPK structural model for penpulimab was a two-compartment model with first-order elimination by intravenous infusion. The simulation showed that after multiple doses, the concentration-time curves for 200 mg Q2W or 3 mg/kg Q2w administration were generally consistent. Compared to the 200 mg Q2W regimen, the mean C min,ss of 200 mg Q3W and 400 mg Q6W regimen were approximately 36.5% and 55.5% lower, respectively. However, the fixed-dose simulation (200 mg Q3W, 400 mg Q6W) showed that the C min,ss of 97.5% of the population were higher than 3 μg/mL, 6 times higher than the 90% receptor occupancy concentration in vitro. The C max,ss and AUC ss under the 400 mg Q6W regimen were lower than the observed maximum administered dose (10 mg/kg). Results of the univariate logistic regression analyses evaluating relationships between efficacy (CR, ORR and DCR) and PK exposure (simulated C max,ss, C min,ss, AUC ss) demonstrated a relatively flat ER relationship without dose dependency in R/R cHL patients. The relationship between PK exposure (the same as above) and safety response (≥ grade 3 TRAE, ≥ grade 3 irAE or AE leading to suspension) were also analyzed in patients with different types of cancer, and the result showed no apparent correlation between safety and drug exposure.Conclusions:PopPK simulations and ER analyses indicate that both weight-based dose and fixed-dose (200 mg Q3W or 400 mg Q6W) are appropriate for penpulimab. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract CT203: First-in-human phase 1b study of ATRC-101, a patient-derived antibody with a tumor-specific target, as monotherapy or in combination with pembrolizumab, in patients with solid tumors

Abstract Background: ATRC-101 is a fully human, engineered IgG1 version of an antibody discovered through a target-agnostic process designed to identify patient-derived, tumor-targeting antibodies. The parental antibody of ATRC-101 was discovered from a patient with metastatic non-small cell lung cancer (NSCLC) undergoing an active immune response while receiving a checkpoint inhibitor. ATRC-101 binds selectively to human tumor specimens, including a majority of NSCLC, acral melanoma, breast, colorectal, and ovarian cancer samples. The target of ATRC-101 appears to be a tumor-associated ribonucleoprotein complex containing a form of polyadenylate-binding protein 1 (PABP-1) that can be found on the surface of tumor cells. Studies to further elucidate the tumor selectivity of ATRC-101 and the extracellular presentation of the target are ongoing. Preclinical data suggest that ATRC-101 stimulates an adaptive immune response against tumors via the innate immune system. ATRC-101 displays dose-dependent, single-agent activity in syngeneic mouse tumor models, including the EMT6 breast cancer model, which displays a T cell-excluded microenvironment and in which PD-1/PD-L1 inhibitors exhibit limited activity. ATRC-101 plus an anti-PD-1 antibody demonstrated significantly greater antitumor activity and longer survival in the EMT6 model compared with either agent alone, consistent with the mechanism of action proposed for ATRC-101. Methods: ATRC-101-A01 is an open-label, 3+3, dose-escalation phase 1b safety study of ATRC-101 as monotherapy (mono) or in combination (combo) with pembrolizumab (pembro) to treat patients with certain solid tumor types. Expansion cohorts of ≤12 patients may be enrolled at doses and frequencies at which biological activity is observed. The primary objective is to determine the safety of ATRC-101. Secondary objectives include evaluation of the following: recommended dose and schedule of ATRC-101 for expansion, pharmacokinetic profile of ATRC-101, immunogenicity, antitumor activity by RECIST v1.1, and lymphocytic infiltration in the tumor microenvironment. ATRC-101 is administered every 2 (q2w) or 3 (q3w) weeks up to 24 months or until disease progression. ATRC-101 dosing is increasing from the initial 0.3 mg/kg according to the following schedule, pending dose-limiting toxicity data: 1, 3, 10, and 30 mg/kg. In the combo cohort, ATRC-101 will be given q3w, and pembro will be administered at 200 mg q3w or 400 mg q6w to patients with disease progression while receiving prior pembro treatment or those with stable disease who were deemed by their physician to potentially benefit from the addition of ATRC-101. The q3w mono cohort is currently accruing patients at the 10-mg/kg dose, and the combo and q2w cohorts will begin at an ATRC-101 dose one level below the most recent cleared q3w mono dose. Trial registration NCT04244552. The study was approved by the institutional review board of each participating site. Citation Format: Jonathan E. Benjamin, Nicholas Higgins, Carl Millward, Jeff DeFalco, Amy Manning-Bog, Iraz T. Aydin, Danhui Zhang, Shaun M. Lippow, Alexander Scholz, Yvonne Leung, Yanhong Zhu, Anna Sedello, Zane Rogers, Ish K. Dhawan, Daniel Emerling, William H. Robinson, Tito A. Serafini, Norman M. Greenberg. First-in-human phase 1b study of ATRC-101, a patient-derived antibody with a tumor-specific target, as monotherapy or in combination with pembrolizumab, in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT203.

Real-world data on overall survival associated with biweekly versus weekly cetuximab among metastatic colorectal cancer (mCRC) patients in the United States.

33 Background: Cetuximab 250mg/m2 weekly (Q1W) after an initial dose of 400mg/m2 is approved for treatment of K-Ras wild-type mCRC. In real world 29% of patients received cetuximab 500mg/m2 biweekly (Q2W). In this study overall survival (OS) associated with Q2W vs Q1W dosing of cetuximab for mCRC in real world was compared. Methods: This study utilized Flatiron Health electronic health record-derived database to identify adult patients with stage IV or recurrent K-Ras wild-type mCRC who received cetuximab+FOLFIRI/FOLFOX/irinotecan, or cetuximab monotherapy in first, second or third-line therapy from 01/01/2013 to 12/31/2019. Patients were assigned to Q1W or Q2W cohort if they had 70% or more cetuximab infusions with a gap of 4-10 days or 11-18 days from previous infusion. Patients who did not fall into either cohort were excluded from analysis. Propensity score (PS) matching was used to balance cohorts on their baseline demographic, clinical and treatment characteristics. Kaplan-Meier methods and Cox proportional hazards regressions were used to compare OS. Results: Baseline characteristics for Q2W (N = 422) vs Q1W (N = 653) cohorts before PS matching- median age 62 vs 65 years, male 58.5% vs 59.3%, white 68.3% vs 66.5%, stage IV 56.6% vs 58.5%, ECOG PS 0/1 61.6% vs 52.1%, ECOG PS 2+ 9.2% vs 9.5%. After PS matching, baseline characteristics were balanced. Hazard ratios (HRs) comparing OS in PS-matched Q2W vs Q1W cohorts were not significant for overall or line of therapy populations (Table). Conclusions: Weekly and biweekly cetuximab had comparable effectiveness in this real-world study. [Table: see text]

Phase Ia, first-in-human study of AbGn-107, a novel antibody-drug conjugate (ADC), in patients with gastric, colorectal, pancreatic, or biliary cancers.

713 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in pts with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility criteria: locally adv or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). DLTs were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Pts were treated until dz progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 pts experienced Grade 3 or 4 neutropenia, all at higher dose levels, with 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs include grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. MTD was not reached at either 1.2 mg/kg Q4W or 0.8 mg/kg Q2W; the 1.0 mg/kg Q2W cohort will complete enrollment in Oct 2019. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days); best response observed to date is stable dz lasting > 6 months at 0.8 mg/kg Q4W and Q2W cohorts (n = 1 each). Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy (prolonged dz control) in non-biomarker selected pts with advanced GI cancers. Pre-screening for high AG-7 expression is underway for subjects with G, CRC, PDA, and BIL cancers for the cohort expansion phase of this study, which will be open across multiple sites in U.S. and Taiwan. Clinical trial information: NCT02908451.

Abstract 4100: Receptor occupancy and neo-epitope specific T-cell repertoires in patients with solid tissue tumors following anti-PD-1 therapy

Abstract Background: In patients undergoing chemotherapy and/or immune therapy, endogenous T cells within the tumor micro-environment (TME) and in the periphery are subject to dynamic changes. Particularly, exhausted T cells in the TME and peripheral blood mononuclear cells (PBMCs) isolated from whole blood express the inhibitory receptor, Programmed Cell Death Receptor 1 (PD-1). A small but significant number of these T cells can recognize neo-epitopes (neoE) arising from patient specific mutations. We determined receptor occupancy (RO) in patients treated with monoclonal anti-PD-1 antibody AB122, which is currently in clinical development. Methods: Multi-color flow cytometry was used to determine RO post-AB122 administration using a directly-conjugated competitive antibody to AB122. In addition, we determined RO values using the established method for nivolumab using a biotinylated anti-human IgG4 to detect bound anti-PD-1. The assays were also optimized to determine RO in whole blood from patients with solid tumors treated with AB122. Receptor occupancy using both methods were compared. Further, whole exome sequencing from archival formalin-fixed, paraffin-embedded (FFPE) tissue was performed and T cells that recognized patient-specific neoE resulting from tumor-specific mutations were identified in patient blood. Results: In the dose-escalation study for AB122 monotherapy arm, a variety of dosing regimens have been evaluated, including Q2W, Q3W and Q4W. The number of doses received ranged from 1 to 20. Data from patients in the 80 and 240 mg Q2W cohorts showed that AB122 serum concentrations ≥1.5 μg/mL (equivalent to 10 nM) are associated with full receptor occupancy. The RO associated with AB122 dosing is maintained when dosed in combination with the potent A2aR/A2bR dual adenosine receptor antagonist AB928 in an ongoing clinical trial. Conclusions: Full RO is observed with both cohorts of AB122 monotherapy (80 and 240 mg Q2W) and in the 240 mg Q2W combination with AB928. Study of peripheral target engagement and expansion of neoE-specific T cell populations in a longitudinal study of solid tumor patients treated with AB122 could provide insight towards designing successful combination immune therapy regimens in future clinical trials with AB122. Citation Format: Devika Ashok, Songming Peng, Benjamin Yuen, Matt Walters, Stephen W. Young, Lisa Seitz. Receptor occupancy and neo-epitope specific T-cell repertoires in patients with solid tissue tumors following anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4100.

Every 2 Weeks or Every 4 Weeks Subcutaneous Injection of Emicizumab in Pediatric Patients with Severe Hemophilia A without Inhibitors: A Multi-Center, Open-Label Study in Japan (HOHOEMI Study)

Introduction: Emicizumab is a novel, subcutaneously injectable, recombinant humanized bispecific monoclonal antibody which mimics the function of activated coagulation factor VIII. Due to its mechanism of action and lack of sequence homology, emicizumab is not expected to induce or be affected by anti-factor VIII (FVIII) antibodies (inhibitors). Emicizumab once-weekly dosing has been approved for hemophilia A patients with inhibitors of all ages in several countries. A clinically meaningful prophylactic effect and favorable safety of emicizumab given every 2 weeks (Q2W) and every 4 weeks (Q4W) in adult/adolescent patients has been demonstrate in HAVEN3 study (NCT02847637) and HAVEN4 study (NCT03020160). This is the first report to assess emicizumab prophylaxis in pediatric patients without inhibitors including a patient previously untreated with FVIII.Methods: The present study (JapicCTI-173710) enrolled Japanese patients aged <12 years with hemophilia A without inhibitors. Patients received a loading dose of 3 mg/kg weekly for the first 4 doses, followed by a maintenance dose of 3 mg/kg Q2W or 6 mg/kg Q4W. This interim analysis was performed after at least 6 patients in each dosing cohort had completed at least 12 weeks of treatment with emicizumab prophylaxis.Results: A total of 13 male patients were enrolled in 2 cohorts. The numbers of patients aged 0 - < 2, 2 - < 6, and 6 - < 12 years were 1, 2, and 3 in the Q2W cohort and 2, 2, and 3 in the Q4W cohort. All patients had been previously treated with FVIII prophylaxis except for 1 patient aged 4 months in the Q4W cohort who was previously untreated. As of the data cutoff date of March 14, 2018, the medians (range) of treatment duration were 21 (18.3 - 22.1) and 16 (4.3 - 16.6) weeks in the Q2W and Q4W cohorts, respectively.The interim analysis results showed a clinically meaningful effect of emicizumab prophylaxis with the Q2W and Q4W regimens. As of the data cutoff date, 3/6 patients in the Q2W cohort and 5/7 patients including 1 patient previously untreated with FVIII in the Q4W cohort experienced no treated bleeds. There were no treated spontaneous bleeds and a total of 6 treated bleeds were traumatic. Two out of them were treated joint bleeds. Model-based annualized bleeding rates for treated bleeds with FVIII products under emicizumab prophylaxis were 1.6 (95% CI, 0.60 to 4.25) and 1.0 (95% CI, 0.25 to 4.06) in the Q2W and Q4W cohorts, respectively.All 13 patients experienced at least 1 adverse event (AE) and a total of 78 AEs were reported. There were no AEs that were grade 3 or higher, serious, led to withdrawal from treatment, or resulted in dose modification or interruption. None of the AEs were considered related to emicizumab. Neither thromboembolic events, thrombotic microangiopathy, systemic hypersensitivity reactions, nor local injection site reactions were reported. The most frequent AEs were contusion in 10 (76.9%) patients, excoriation and nasopharyngitis in 4 (30.8%) patients each, and ligament sprain and influenza in 3 (23.1%) patients each.The emicizumab exposures observed in this study were within the observed variability in preceding studies. No effects of age or body weight on emicizumab exposure were evident.Conclusions: This interim analysis results suggested clinically meaningful efficacy and favorable safety of the emicizumab Q2W and Q4W regimens in patients aged <12 years with severe hemophilia A without inhibitors. This suggests that it should be appropriate to apply the same dosing regimens of emicizumab for pediatric patients without inhibitors and other patient populations of hemophilia A. The updated results of primary analysis after completing at least 24 weeks on emicizumab treatment will be presented at the meeting. DisclosuresShima:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Nagami:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership. Yoshida:Chugai Pharmaceutical Co., Ltd: Employment. Yoneyama:Chugai Pharmaceutical Co., Ltd: Employment, Patents & Royalties: Anti-FIXa/X bispecific antibodies . Ishiguro:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Taki:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Maturing Clinical Profile of IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Maturing Clinical Profile of IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Abstract CT011: First in human study of activin-A inhibitor, STM434, in patients with granulosa cell ovarian cancer and other advanced solid tumors

Abstract Background: STM434 is a soluble receptor ligand trap targeting activin A, a protein in the TGF-beta family that plays important roles in growth, differentiation, and cancer cachexia. Activin A overexpression is a common feature in many gynecologic cancers. Granulosa cell tumors also harbor pathognomonic mutations in FOXL2, which specifically promotes dysregulated activin signaling. The role of inhibiting activin A signaling in human cancers has not been previously explored. Methods: Primary endpoint was to establish to maximum tolerated dose of STM434. Dose was initially escalated by accelerated titration and then 3+3 design. Secondary endpoints included safety per CTCAE v4, pharmacokinetics, and response by RECIST v1.1. As Activin A is also implicated in metabolism and muscle function, changes in key metabolic parameters including lean body and fat mass established by DXA scan and 6 minute walk test (6MWT), were serially measured. Results: 32 patients were treated at doses ranging from 0.25 - 8 mg/kg IV every 2-4 weeks. Tumor types included ovarian granulosa cell (n=13), epithelial ovarian (n=7), colon (n=3), pancreatic (n=2), and other solid tumors (n=7). A total of 5 DLTs were observed in 3 pts (all grade 3): hemorrhagic ascites (0.5 mg/kg Q4W) and stomatitis, gastritis, epistaxis, and alkaline phosphatase increase (all 8 mg/kg Q2W). The most common treatment-related AEs were fatigue (n=12), epistaxis (n=11), and gingival bleeding (n=6). Other observed hematologic related-AEs included telangiectasia (n=3), hemorrhagic ascites (n=2), and petechiae (n=2). No treatment-related grade 4 or 5 AEs occurred. STM434 resulted in the expected FSH level decreases in most patients. STM434 also resulted in metabolic parameter changes, including an increase in total lean body mass (1%-20%, 0.5 mg/kg Q2W to 4 mg/kg Q2W cohorts) and 6-minute walk test (25-150 meters in the 0.5 mg/kg Q2W-2 mg/kg Q2W cohort) and decrease in total fat mass (-3% to -18% in the 0.5 mg/kg Q4W- 4 mg/kg Q2W cohorts). One patient with fatty liver on baseline imaging had complete resolution of this finding after 2 cycles of therapy. No responses were observed in the 28 evaluable patients. In granulosa cell patients, the stable disease rate was 9/12 (75%) although the significance of this finding is uncertain. Conclusions: The MTD of STM434 was 4 mg/kg Q2W. STM434 use resulted in mucocutaneous bleeding complications likely related to off-target inhibition of bone morphogenic protein 9 (BMP9). BMP9 bears substantial homology to activin A and inherited inactivation of BMP9 can result in hereditary hemorrhagic telangiectasia which shares a phenotype similar to the AE profile observed here. While no direct antitumor efficacy was documented, potentially clinically meaningful dose-related metabolic effects were observed that support further exploration of Activin A inhibitors that avoid BMP9 blockade in cancer. Citation Format: Jessica J. Tao, Joyce F. Liu, Drew W. Rasco, Willis Navarro, Christopher M. Haqq, David M. Hyman. First in human study of activin-A inhibitor, STM434, in patients with granulosa cell ovarian cancer and other advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT011.

FPA144-001: A first in human study of FPA 144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal antibody in patients with advanced solid tumors.

140 Background: FPA144 is a humanized monoclonal IgG1 antibody directed against the 2b Isoform of thefibroblast growth factor receptor (FGFR2b) that has been glycoengineered to enhance ADCC. Amplification of FGFR2 is found in a number of tumors, including 3 – 9% of gastric cancer, and is associated with poor prognosis. FPA144-001 is a phase 1 study in two parts: Part 1 will evaluate the safety and pharmacokinetics (PK) of FPA144 in patients with solid tumors; Part 2 will evaluate efficacy in gastric cancer patients whose tumors overexpress FGFR2b, as determined by a proprietary test. Here we present early safety and PK results from solid tumor patients treated with FPA144. Methods: A standard 3+3 design was used to assess safety, tolerability and PK of escalating doses of FPA144 in patients with advanced solid tumors (Part 1A) or recurrent/metastatic gastric cancer (Part 1B). Tumor testing for FGFR2gene amplification or FGFR2b overexpression was conducted centrally by a proprietary assay consisting of both FISH and IHC. Results: At the time of data analysis, enrollment of FPA144-001 through the 6mg/kg q2w cohort had been completed. In Part 1A, 13 patients with 8 different tumor types have been enrolled. Patients have been treated for an average of 4 cycles (range 1 – 10, median 2) or 101 days (range 28 – 287, median 43). Nine patients have discontinued the study for progressive disease or lack of clinical benefit; all others continue on study treatment. No dose-limiting toxicities have been observed, and no patients have withdrawn due to an adverse drug reaction. Upper respiratory infection, alopecia and fatigue are the AEs reported in more than one patient; one SAE of dyspnea and pyrexia not related to drug has been reported. PK analysis demonstrates non-linear clearance in doses up to 3mg/kg, likely due to receptor-mediated clearance. Conclusions: FPA144 is a glycoengineered monoclonal antibody directed against FGFR2b that is being developed for the treatment of patients with tumors that overexpress FGFR2b. FPA144 has been safely administered at doses up to 6mg/kg q2w; dose escalation continues. Updated safety, PK and anti-tumor activity will be presented. Clinical trial information: NCT02318329.

KRN330, a fully human antibody against A33, in combination with irinotecan for patients with metastatic colorectal cancer (mCRC).

534 Background: KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen on normal colonic epithelium, which is uniformly expressed in 95% of colorectal cancers. A KRN330 monotherapy phase I study showed over 1 year of stable disease in 2 pts with refractory mCRC. We report results of the phase I part of a phase I/II trial of KRN330 in combination with irinotecan in pts with mCRC. Methods: Pts with mCRC who progressed on one or more prior therapies received weekly (QW) or biweekly (Q2W) intravenous doses of KRN330 at 0.5 or 1.0 mg/kg with Q2W irinotecan at 180 mg/m2 in a standard 3+3 dose escalation design. Results: Nineteen pts were treated. Four pts received 1.0 mg/kg of KRN330 Q2W and irinotecan treatment. Three pts developed DLTs, which included G4 febrile neutropenia and G3 colitis, prolonged G3 diarrhea, and, G4 neutropenia with prolonged G3 diarrhea. KRN330 was then deescalated to 0.5 mg/kg Q2W and 0.5 mg/kg QW. There were no DLTs in 7 of 8 pts in the Q2W cohort. The 1 DLT in this cohort was G3 colitis. None of the 7 pts in the QW cohort experienced DLT. The most common G3/4 toxicities included diarrhea (26.3%) and febrile neutropenia (15.9%), leucopenia (10.5%), neutropenia (10.5%), abdominal pain (10.5%), and colitis (10.5%). Of the 16 pts evaluable for efficacy, 2 pts had PR, 8 SD and 6 PD as best response. The 2 pts with PR had previously received an irinotecan-containing regimen, one with PD on an irinotecan-containing regimen. The responses are being confirmed by independent adjudicator. Conclusions: QW and Q2W intravenous doses of KRN330 at 0.5 mg/kg KRN330 with irinotecan were tolerable and demonstrated antitumor effect in pts who had received previous irinotecan-containing regimens. The phase II part of the phase I/II study of QW KRN330 plus irinotecan in pts with second line mCRC is ongoing. No significant financial relationships to disclose.

A phase II, open-label trial of skin toxicity (ST) evaluation (STEPP) in metastatic colorectal cancer (mCRC) patients (pts) receiving panitumumab (pmab) + FOLFIRI or irinotecan-only chemotherapy (CT) as 2nd-line treatment (tx): Interim analysis

15007 Background: Pmab, a fully human monoclonal antibody against the epidermal growth factor receptor, is approved in the US for the tx of pts with refractory mCRC. This randomized study examined differences between pre-emptive and reactive skin tx for ST associated with pmab therapy. Methods: Pts with unresectable mCRC and disease progression whose 1st-line tx with CT± bevacizumab failed were enrolled. Pts received Q2W FOLFIRI+pmab (6.0mg/kg) or Q3W irinotecan+pmab (9.0mg/kg). Within cohorts, pts were randomized 1:1 to pre-emptive ST tx (24 hrs prior to 1st pmab dose, daily through wk 6) or reactive tx (after ST developed). ST tx included use of skin moisturizers, sunscreen, topical corticosteroids, and oral doxycycline. The primary endpoint was incidence of specific ≥ grade (gr) 2 ST during the 6-wk skin tx period. This early analysis assessed pooled safety (data cutoff 06/07). Results: Of 58 pts with available data, 32 pts and 26 pts received the Q2W and Q3W regimens, respectively. Pts received a median of 7.5 (Q2W cohort) and 4.0 (Q3W cohort) doses of pmab and CT. Tx-related adverse events (AEs) were seen in 95% of pts; 62% had gr 3/4. AEs of interest are shown (table). Pmab dose reductions occurred in 6 pts (10%) due to ST; 19 pts had serious AEs; 2 pts ended the study because of an AE. Ten pts (31%) in the Q2W cohort and 1 pt (4%) in the Q3W cohort had an objective response to pmab. Planned enrollment of 95 pts has been completed; efficacy outcomes (pre-emptive vs reactive ST tx and objective response) by KRAS status for all pts will be presented. Conclusions: No safety issues were identified in this early analysis of pts receiving pmab + irinotecan-based CT. Pooled Analysis of Adverse Events (n = 58) AE Any grade, n (%) ≥ Grade 3, n (%) Skin Toxicity 51 (88) 13 (22) Infections * 42 (72) 13 (22) Diarrhea 40 (69) 8 (14) Nausea 31 (53) 4 (7) Neutropenia 16 (28) 9 (16) Dehydration 13 (22) 7 (12) Hypomagnesemia 10 (17) 3 (5) Deep venous thrombosis 2 (3) 2 (3) Pulmonary embolism 0 (0) 0 (0) Per MedDRA; grading based on CTCAEv3, modified for ST. * Includes rash pustular and paronychia No significant financial relationships to disclose.