Search

Purpose: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both and wild-type and mutant ERα by targeting cysteine 530 and enforcing antagonist conformation. H3B-6545 demonstrated preclinical high activity in breast cancer models with constitutively active ESR1 mutations (Furman C, SABCS 2020) and clinical activity in pretreated women with ER+ breast cancer (Hamilton EP, ASCO 2021). Patients and Methods: The primary objective of the phase II is to estimate the objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and secondary objectives include safety. Results: 94 pts were treated with 450 mg daily, the recommended phase II dose: 11 in the phase I and 83 in the phase II parts of the trial. Patients and tumor characteristics were presented previously (Hamilton EP, ASCO, 2021). As of March 31, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), nausea (17%), fatigue (16%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (39%), hemoglobin decrease (38%), Lymphocytes decrease (37%), ALT increase (14%), AST increase (13%), bilirubin increase (12%), and creatinine increase (12%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 35% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in Table 1. CI: Confidence interval. N: total number of pts in full analysis set, used in PFS analysis. n: number of response-evaluable pts, used in ORR and CBR analysis. Efficacy estimates were consistent across the various subgroups. Responses were demonstrated in heavily pretreated pts, pts with visceral metastases, pts with constitutionally active ESR1 Y537S mutations, and in pts who received chemotherapy in the metastatic setting. Numerically higher response rate and longer PFS were observed in pts with ESR1 Y537s. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was consistent across the various subgroups. Tumors harboring the constitutionally active ESR1 Y537S mutation may present higher ERα activity, and consequently enrich for luminal A traits and demonstrate greater lineage dependence on ERα. Table 1.Consistency of H3B-6545 activity across the key subgroupsEfficacyClinical CharacteristicORR % (95% CI)CBR % (95% CI)Median PFS mo (95% CI)Overall population (N=94, n=72)16.7 (8.9, 27.3)40.3 (28.9, 52.5)5.1 (3.2, 6.2)Liver and/or lung metastases (N=76, n=62)17.7 (9.2, 29.5)41.9 (29.5, 55.2)5.4 (1.8, 7.2)≥3 prior regimens (N=49, n=39)20.5 (9.3, 36.5)48.7 (32.4, 65.2)5.4 (3.5, 7.3)Prior chemotherapy (N=47, n=35)17.1 (6.6, 33.6)51.4 (34.0, 68.6)5.5 (3.6, 7.3)PgR+ (N=38, n=32)15.6 (5.3, 32.8)50.0 (31.9, 68.1)5.4 (2.0, 8.8)ESR1 clonal Y537S (N=10, n=10)30.0 (6.7, 65.2)60.0 (26.2, 87.8)7.3 (0.8, 11.2)ESR1 clonal D538G (N=19, n=17)0.0 (0.0, 19.5)35.3 (14.2, 61.7)5.4 (1.7, 7.2) Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Aki Morikawa, E Claire Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail S Wright, Fadi Kayali, Lisa Cantagallo, Manav Korpal, Jenny Long, Jianjun Xiao, Benoit Destenaves, Lei Gao, Tarek Sahmoud, Antonio Gualberto, Dejan Juric. H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer - A phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-10.

Background: Engineered toxin bodies (ETBs) are composed of a de-immunized Shiga-like Toxin A subunit genetically fused to an antibody-like binding domain. ETBs can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other therapeutics. MT-5111 is a 55 kD ETB targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of MT-5111 monotherapy in adult pts with advanced HER2+ solid tumors. Secondary objectives are pharmacokinetics (PK), efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study enrolls pts with HER2+ tumors into 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg/dose. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and other HER2+ tumors. All pts receive MT-5111 weekly as 30-min IV infusions in each 21-day treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: Per data cut in June 2021, 21 pts (mean age 64 years, range 34-78; 38% male) in cohorts 1-6 with breast (n=7), biliary (n=6), gastric (n=3), pancreatic (n=2), lung (n=2), and colon (n=1) cancer were treated (Table 1). Pts had a median of 4 prior lines of systemic therapies (range, 1-8) and 2 prior lines of HER2-targeting treatments (range, 0-6). No Grade (G)4 or 5 tx-emergent (TE) adverse events (AEs) occurred. Tx-related AEs occurred in 11 (52%) pts; the most common was fatigue (n=7, 33%). One pt (4.5 µg/kg) had a possibly (per PI) related G3 serious AE (SAE) of dyspnea and hypoxia, but also lymphangitic carcinomatosis and H. influenzae infection. The other related SAE occurred in a pt (6.75 µg/kg) who had a G1 transient troponin increase without concomitant cardiac symptoms or ECG/ECHO changes. All other related AEs were ≤G2. There were no clinically significant changes in cardiac biomarkers (troponin, ECG, left ventricular ejection fraction) nor were there cases of capillary leak syndrome. Two pts (3 µg/kg and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies, and Cmax data at 6.75 µg/kg indicated that current in-human exposure was between the IC50 values of high and medium HER2-expressing cell lines (approximately 10-89 ng/mL). Thus, a dose of at least 10 µg/kg may be required to achieve effective exposure. To date, no dose-limiting toxicities have been observed and the 10 µg/kg/dose cohort is now accruing. Conclusions: MT-5111 was well tolerated with no clinically significant immuno- or cardiotoxicity. Dose escalation is ongoing and nearing levels expected to be required for efficacious exposure. Table 1.Metastatic HER2 status and MT-5111 treatment by cohortDose0.5 µg/kg1.0 µg/kg2.0 µg/kg3.0 µg/kg4.5 µg/kg6.75 µg/kgCohort123456Number of patients treated with MT-5111433335Metastatic HER2 2+ by IHC: ALL/BC1/11/11/01/10/04/0Metastatic HER2 3+ by IHC: ALL/BC3/12/02/12/13/01/1BC, breast cancer. Citation Format: Brian A. Van Tine, Monica Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Angela Georgy, Joshua Pelham, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Zev A. Wainberg. Interim results of a phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+tumors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-45.

Background: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both mutant and wild-type ERα by targeting cysteine 530 and enforcing antagonist conformation. It demonstrated a manageable safety profile and single-agent antitumor activity in heavily pretreated ER+, HER2- mBC patients (pts) (Hamilton et al, ASCO, 2021). Methods: The study aims at determining the recommended phase II doses of the combination of H3B-6545 and palbociclib in pts with ER+, HER2- mBC. Other endpoints include safety, pharmacokinetics, and preliminary efficacy. The escalation phase enrolls pts with at least 2 prior therapies in the metastatic setting. Up to one prior chemotherapy and up to one prior CDK4/6 inhibitor are allowed. Each cohort enrolled 6 pts to ensure availability of sufficient PK data. During the first cycle, H3B-6545 was added to palbociclib on day 9. Dose-limiting toxicities (DLTs) were assessed during the first 28 days starting from the 1st day of adding H3B-6545 to palbociclib (cycle 1 day 9 to cycle 2 day 8). Both drugs were started on day 1 of each of the subsequent cycles. Results: As of June 15, 2021, 14 pts were enrolled: 7 in Cohort 1 (H3B-6545 300 mg QD and palbociclib 100 mg QD) and 7 in Cohort 2 (H3B-6545 300 mg QD and palbociclib 125 mg QD). Median age was 61 years (range: 28-75 years), ECOG performance status was 0 in 7 pts (50%) and 1 in 7 pts (50%) and 9 pts (64%) had lung and/or liver metastases. Median number of prior therapies in the metastatic setting was 3 (range: 1-6). Prior therapy in the metastatic setting included fulvestrant (93%), CDK4/6 inhibitors (79%), aromatase inhibitors (64%), and chemotherapy (29%). One pt in each Cohort was not evaluable for dose limiting toxicity (DLT) assessment and no DLTs were observed in the first 2 Cohorts. Seven pts discontinued study treatment because of progression and 1 pt discontinued due to diagnosis of a second primary cancer during the first cycle. Non-hematological grade 2 or higher adverse events (AE), irrespective of causality, reported in ≥2 pts were: nausea, vomiting, abdominal pain, and bone pain, each observed in 2 pts (14%). Gr. 1 and 2 sinus bradycardia were reported in 6 (43%) and 1 pts (7%), respectively. One pt (7%) had grade 1 QT prolongation. No grade 4 AEs or treatment-related deaths were reported. For hematology and chemistry laboratory abnormalities: gr. 3 and 4 neutropenia in 7 pts (50%) and 2 pts (14%), respectively, gr. 3 thrombocytopenia in 1 pt (7%), gr. 3 anemia in 2 pts (14%). Grade 2 decrease in estimated glomerular filtration rate was observed in 7 pts (50%), all reported irrespective of causality. Co-administration of palbociclib had no meaningful impact on H3B-6545 exposure (15% and 21% increase in geometric means of AUC and Cmax, respectively). Co-administration of H3B-6545 modestly increased palbociclib exposure (49% and 36% increase in geometric means of AUC and Cmax, respectively). Among 6 response-evaluable pts in Cohort 1, 2 pts (33%) had confirmed partial responses and 4 pts (67%) had stable disease. Both responding pts received prior therapy with a CDK4/6 inhibitor and fulvestrant. Cohort 2 efficacy data is not yet mature. Recruitment is currently ongoing in Cohort 3 (H3B-6545 450 mg QD and palbociclib 125 mg QD). Conclusions: The combination of H3B-6545 (up to 300 mg dose) and palbociclib (up to 125 mg dose) was well-tolerated and demonstrated preliminary anti-tumor activity in heavily pretreated pts with ER+, HER2- mBC. ClinicalTrials.gov Identifier: NCT04288089. Citation Format: Stephen Johnston, Timothy J Pluard, Judy S Wang, Erika P Hamilton, Dejan Juric, Catherine R Scholz, Elizabeth Hnitecki, Sara Dar, Lei Gao, Lisa Cantagallo, Manav Korpal, Jianjun Alan Xiao, Lihua Yu, Tarek Sahmoud, Antonio Gualberto. H3B-6545 in combination with palbociclib in women with metastatic estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer, phase 1b study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-03.

The Bromodomain and Extra-Terminal (BET) Domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all 4 BET family members (BRD2, BRD3, BRD4, and BRDT). PLX2853 development is continuing at Opna Bio as OPN-2853. Clinical experience with PLX2853 monotherapy in subjects with heavily pretreated solid tumors and lymphoma showed signs of activity. The current study (NCT04493619) was designed as a multicenter, open-label trial with two parallel arms: (1) a phase 2a study of PLX2853 monotherapy in advanced gynecological malignancies with a known ARID1A mutation and (2) a phase Ib/2a combination study of PLX2853 plus carboplatin in platinum resistant OC. The primary objective of the Ib portion of the study was safety and tolerability, with the primary objective of both phase 2a portions being efficacy. In the monotherapy arm, up to 6 patients were treated at 80 mg PLX2853 daily in a safety lead-in, with progression to phase 2a using a Simon 2-stage design if dose limiting toxicities (DLTs) were observed in fewer than 33% subjects. In Stage 1, 6 additional subjects (N=12 total) were planned, with progression to stage 2 if two or more patients responded in stage 1. The combination arm included an escalation phase Ib. Three to six evaluable subjects were planned for each group, with dose escalation pending less than 33% DLT rate. The combination arm defined by the phase 1b portion of the study continued to a planned phase 2a Simon 2 stage design similar to that described for the monotherapy arm. 34 of 37 enrolled patients were evaluable with data from at least 1 post-baseline response (14 monotherapy, 20 combination therapy). Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a partial response (PR) with progression-free survival of 278 days, 5 (35.7%) had stable disease (SD) and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable OC patients on the PLX2843 + carboplatin combination, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD. This study in a larger cohort of gynecologic cancer patients confirmed the safety profile of the agent and demonstrated the feasibility of combination with carboplatin. While these results did not meet the pre-specified response criteria, evidence of clinical activity nevertheless highlights the rationale for further exploration of BRD4 inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway, frequently activated in these cancers. Citation Format: Elizabeth M. Swisher, Linda R. Duska, Erika P. Hamilton, Amit M. Oza, Gini Fleming, Oladapo O. Yeku, Alexander I. Spira, Debra L. Richardson, Robin Guo, Jackie Walling, Kerry Inokuchi, Dmitriy Zamarin. Phase 1b/2a clinical trial of the oral BET inhibitor PLX2853 as monotherapy for ARID1A mutated gynecologic cancers and in combination with carboplatin for platinum resistant ovarian cance [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 CT160.

Background: Addition of CDK 4/6 inhibitors to endocrine therapy has provided significant improvements in outcomes for patients (pts) with metastatic breast cancer (mBC). However, acquired resistance to front-line therapy remains a challenge, and response to late lines of therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα) H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins, including Y537S. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα).Methods: This is a multicenter phase I/II trial. The primary objective of the phase I is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) in pretreated pts with ER+, HER2- mBC. Secondary objectives include safety and antitumor activity. The primary objective of the phase II is to estimate the objective response rate (ORR) and secondary objectives include clinical benefit rate (CBR), progression-free survival (PFS) and safety. The trial was designed to exclude a lower limit of ORR of 5% at one-sided level of significance of 0.05 and a power of 90%. Results: Between August 2017 and February 2020, 130 pts were enrolled; 47 in the Phase I part and 83 in the Phase II part of the trial. A total of 105 pts, including 73 patients on 450 mg, were response-evaluable. The phase I evaluated once daily doses from 100 to 600 mg. No dose-limiting toxicities (DLT) were observed at doses up to 450 mg and 2 DLTs were observed in 2 (grade 3 fatigue and grade 3 drug eruption) of 7 pts on the 600 mg cohort. Consequently, the dose of 450 mg was selected as the RP2D. Median age was 62 years (range: 31 to 87 years), 82% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 10), with 41% of the pts receiving ≥ 4 prior therapies in the metastatic setting. Prior CDK4/6 inhibitors, fulvestrant, and chemotherapy were received by 87%, 71%, and 54% of the pts, respectively. 75 pts (58%) had detectable ESR1 mutations. As of May 31, 2020, grade 2 or higher adverse events reported in ≥10% were anemia (20%), fatigue (16%), nausea (14%), diarrhea (11%) and AST increase (11%). Three cases of grade 4 AE were reported (serum bilirubin, urinary tract obstruction, and hyponatremia), all considered related to disease progression. Grade 1 sinus bradycardia (asymptomatic) was reported in 35% and grade 2 (symptomatic, no intervention needed) was reported in 4%. Grade 2 and 3. QTcF prolongation were reported in 2 and 3 patients, respectively. There were no treatment-related deaths. In the response-evaluable group, 13 confirmed partial responses (PR, 12%. 90% confidence limits: 7.5%-19%), including 11 PRs (15%, 90% confidence limits: 8.7%-23.7) on 450 mg dose, were observed, thus achieving the primary objective of the trial. Stable disease (SD) and clinical benefit rates (≥23 weeks) were 45% and 33% respectively at 450 mg and 46% and 34%, respectively on all doses. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, prior CDK4/6 inhibitor, and/or prior chemotherapy, in the metastatic setting. Three PRs (25%) and 4 SDs were observed in 12 pts in whom clonal ESR1 Y537S was the main ERα driver. Median PFS, in all pts and in pts with clonal ESR1 Y537S was 3.7 months and 7.3 months, respectively. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients including those with a constitutively active clonal ESR1 Y537S mutation. Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Stephen Johnston, Aki Aki Morikawa, Claire E Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail Wright, Fadi Kayali, Manav Korpal, Lihua Yu, Lisa Cantagallo, Benoit Destenaves, Zhaojie Zhang, Lei Gao, Marc J Pipas, Tarek Sahmouud, Antonio Gualberto, Dejan Juric. Phase I/II trial of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-06.