Phase 1/2 first-in-human (FIH) study of CPI-0209, a novel small molecule inhibitor of enhancer of zeste homolog 2 (EZH2) in patients with advanced tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3104-3104
Author(s):  
Nehal J. Lakhani ◽  
Martin Gutierrez ◽  
Linda R. Duska ◽  
Khanh Tu Do ◽  
Manish Sharma ◽  
...  
Keyword(s):  
Small Molecule ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dependent Manner ◽  
Open Label ◽  
Polycomb Repressive Complex 2 ◽  
Enhancer Of Zeste ◽  
Dose Dependent ◽  
Advanced Tumors

3104 Background: Enhancer of Zeste homolog 2 (EZH2) is a histone methyltransferase and the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). EZH2 is frequently overexpressed in cancers and correlates with poor prognosis. CPI-0209 is an oral, small molecule, second-generation, selective inhibitor of EZH2 designed to achieve comprehensive target coverage through extended on-target residence time. The compound demonstrates more potent anti-tumor activity in preclinical cancer models, compared to first-generation EZH2 inhibitors. CPI-0209 is currently being evaluated in a Phase 1/2, open-label, FIH study (NCT04104776). Methods: Patients (pts) with advanced tumors were enrolled in a 3+3 design. Primary objective is to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CPI-0209. Secondary objectives are to evaluate the safety, PK, and PD in pts who received CPI-0209 QD in 28 days cycles (C). Results: As of December 16, 2020, 33 pts were treated: pancreatic cancer (n = 6), mesothelioma, breast, colorectal, and ovarian cancer (n = 5 each), leiomyosarcoma, melanoma, cholangiocarcinoma, prostate, bladder, endometrial clear cell and gastric cancer (n = 1 each). Pts received CPI-0209 at 50 mg (n = 4), 100 mg, 137.5 mg, and 187.5 mg (n = 6 each), 225 mg (n = 7), and 275 mg (n = 4) daily dose. Median treatment duration was 43 days (range 1-239); 4 pts are ongoing. Median age was 64 yrs (range 24-79); 15 (45%) pts were male. Patients were heavily pretreated, with 67% of pts had ≥ 3 prior lines of therapy. No dose limiting toxicities have been observed. The most frequent treatment-emergent adverse events (TEAEs) (≥10%) were fatigue (27%), diarrhea (24%), nausea (21%), abdominal pain, alopecia, anemia, thrombocytopenia, and dysgeusia (15% each), and vomiting, headache, decreased appetite, and alkaline phosphatase increased (12% each); usually grade 1 or 2 in severity. Thrombocytopenia was dose-dependent and not associated with bleeding or clinical sequalae. Three pts (9%) discontinued CPI-0209 due to TEAEs. Comprehensive target engagement (assessed by global reduction in H3K27me3 levels in monocytes) was observed within the first cycle at all dose levels. CPI-0209 also increased the expression of PRC2-controlled gene sets in blood in a dose-dependent manner. Updated safety, PK, PD, and preliminary efficacy results from Phase 1 will be presented. Conclusions: CPI-0209 achieved robust PD effects and a PK-PD relationship has been established. CPI-0209 monotherapy was generally well tolerated, and treatment related AEs were manageable and reversible. The MTD has not been reached. Clinical trial information: NCT04104776.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

Anti-tumor activity of recombinant human Interleukin-21 (rIL-21): Preliminary data from a phase 2a study in patients with stage IV malignant melanoma (MM) without prior treatment

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3055-3055
Author(s):  
I. D. Davis ◽  
B. Brady ◽  
M. Millward ◽  
B. K. Skrumsager ◽  
U. Mouritzen ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Performance Status ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Two Stage ◽  
Two Phase ◽  
Study Results

3055 Background: rIL-21 is a pleiotropic class I cytokine that activates CD8+ T cells and NK cells. The safety and pharmacologic profile of rIL-21 was characterized in two phase 1 dose escalation studies including patients with MM, performed in Australia and the US, respectively. Two dosing schedules were tested: “5+9” (5 days of dosing followed by 9 days of rest) and “3/wk” (dosing 3 times per week for 6 weeks). The maximum tolerated dose (MTD) was determined to be 30 μg/kg for both dosing regimens and two complete remissions (at the 30 μg/kg dose level) were observed in the MM patients. A phase 2a study was initiated to estimate the preliminary efficacy of rIL-21 in patients with advanced MM. Methods: The phase 2a study design is an open-label, two-stage trial. Primary objective: antitumor efficacy as determined by response rate. Secondary objectives: safety, effects on blood biomarkers, and measurement of anti-rIL-21 antibodies. Eligible patients had unresectable MM with measurable disease, no prior systemic therapy (adjuvant interferon was permitted), adequate major organ function, good performance status, no brain metastases, and no evidence of significant autoimmune disease. rIL-21 was administered by i.v. bolus injection using the “5+9” regimen for 6 weeks (= three cycles) at 30 μg/kg dose level. Results: At the time of writing (January 2007), all 14 patients have entered the first stage of the phase 2a study and currently seven patients are evaluable for response after completion of 3 treatment cycles (6 weeks). One patient had a complete remission, five patients had stable disease, and one patient had progressive disease. So far, six patients have gone on to receive further treatment with rIL-21. Similar to the phase 1 experience, treatment with rIL-21demonstrated an acceptable safety profile. Updated interim study results, including response data, will be presented. Conclusions: rIL-21 administered at 30 μg/kg/day using the “5+9” regimen is well tolerated by patients with MM. Preliminary evidence of clinical response has been observed and the second stage of the two-stage phase 2a study has opened for accrual. [Table: see text]

Early safety from a phase 1, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 438-438 ◽  
Author(s):  
J. Randolph Hecht ◽  
Miklos Pless ◽  
Antonio Cubillo ◽  
Aitana Calvo ◽  
Steven Raman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Liver Tumors ◽  
Disease Incidence ◽  
Phase 1 ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

438 Background: T-VEC is a genetically modified HSV-1 oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF, and stimulate anti-tumor immune responses. This study evaluates the safety of intrahepatic injection (inj) of T-VEC in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated dose. Eligible pts were ≥ 18 years (y) old, had progressive HCC or breast cancer (BC), colorectal cancer (CRC), gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer with liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 1) or 108 PFU/mL (cohort 2) every 21 (±3) days (Q21D), or up to 8 mL of the maximum tolerated concentration (MTC) Q21D (cohort 3). Inj volume was based on lesion size. Results: Results from cohorts 1 and 2 of group A are reported. 14 pts were treated; 12 (3 BC, 9 CRC) were DLT-evaluable: Median age was 65.5 y (range: 33, 73); median number of inj was 3; 1 pt received all 12 inj. MTC was 108 PFU/mL. There was 1 DLT, grade 3 aspartate aminotransferase (AST)/grade 2 bilirubin increase (inc), after 1 dose. In all treated pts, 4 (28.6%) had grade 3/4 treatment-related adverse events (TRAEs): anemia and inc gamma-glutamyltransferase, alanine aminotransferase (ALT), and AST. There were 2 deaths attributable to disease. Incidence of serious AEs (SAEs) is shown (Table). Conclusions: The MTC was 108 PFU/mL Q21D after initial inj at 106 PFU/mL. Repeated intrahepatic inj of T-VEC at the FDA-approved concentration for intralesional inj of melanoma was deemed tolerable and feasible in pts with liver mets. Additional investigation in combination with a PD-1 inhibitor is planned. Clinical trial information: NCT02509507. [Table: see text]

Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3003-3003 ◽  
Author(s):  
Marwan Fakih ◽  
Bert O'Neil ◽  
Timothy Jay Price ◽  
Gerald Steven Falchook ◽  
Jayesh Desai ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Small Molecule ◽  
Phase 1 ◽  
Locally Advanced ◽  
Bound State ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Ecog Ps ◽  
Tumor Types

3003 Background: The KRASG12C mutation is found in approximately 13% of lung adenocarcinomas and 1–3% of other solid tumors, but there is no approved therapy that targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state. Methods: This phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult patients (pts) with locally-advanced or metastatic KRASG12C mutant solid tumors. The primary endpoint is safety; key secondary endpoints include PK, ORR (assessed every 6 weeks [wks]), DOR, and PFS. Key inclusion criteria: KRASG12C mutation identified through DNA sequencing, measurable or evaluable disease, ECOG PS ≤2, life expectancy >3 months (mo). Key exclusion criteria: active brain metastases, myocardial infarction within 6 mo. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). A dose expansion will enroll pts with NSCLC, CRC, and other advanced solid tumors carrying the KRASG12C mutation. AMG 510 will be given PO until disease progression, intolerance, or withdrawal of consent. Results: 22 pts (8 men, 14 women; median age 55.5 y) were enrolled in the first 3 dose cohorts. Tumor types: 6 NSCLC, 15 CRC, 1 other. Most pts (n=17) had ≥3 prior lines of treatment (tx). Median tx duration was 28 d (range: 8–134). 5 pts reported 10 treatment-related AEs (grade 1, n=9; grade 2, n=1); there were no DLTs. Tumor response was evaluated in 9 pts (4 with ≥2 assessments); 13 pts have not reached their first assessment.1 pt had a PR (NSCLC at wks 6 and 12, tx ongoing), 6 pts had SD (4 CRC and 2 NSCLC; median tx duration 9.7 wks [range: 6.3–19.1], tx ongoing), 2 pts had PD. 20 pts are continuing to receive AMG 510. A second PR (NSCLC at wk 6, tx ongoing) was reported after data cutoff. Conclusions: AMG 510 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to patients with advanced KRAS G12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883.

An open-label study of rovalpituzumab tesirine in patients with DLL3-expressing advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2597-TPS2597 ◽  
Author(s):  
Edward Kavalerchik ◽  
Satwant Lally ◽  
Tae H. Han ◽  
Laura R. Saunders ◽  
Sheila Bheddah ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Solid Tumor ◽  
Phase 1 ◽  
Large Cell ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Notch Receptor ◽  
Antibody Drug Conjugate ◽  
Open Label

TPS2597 Background: Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family. It is highly expressed in high-grade neuroendocrine carcinoma (NEC), such as small cell lung cancer (SCLC) and large cell NEC (LCNEC), but is not expressed in normal tissue. DLL3 is expressed in melanoma, glioblastoma (GBM), neuroendocrine prostate, medullary thyroid carcinoma (MTC), and other solid cancers. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, composed of a DLL3-specific IgG1 monoclonal antibody joined to a toxic DNA cross-linking agent by a cleavable linker. Rova-T binds to DLL3 on target-expressing cells, is internalized and cleaved, releasing the toxin to induce cell death. A Phase 1 study of Rova-T in SCLC showed encouraging antitumor activity in DLL3-high patients (pts), and was well-tolerated (Rudin et al., Lancet Oncol, 2016). As novel therapies are needed for multiple cancers that express DLL3, Rova-T may be effective in these tumors. Methods: This is a Phase 1/2, open-label, multicenter study (NCT02709889) with 8 cohorts of pts (up to ~318 total, 14 pts enrolled as of 20 January 2017) with melanoma, MTC, GBM, LCNEC, neuroendocrine prostate cancer, gastroenteropancreatic NEC, other NEC, or other solid tumor. In Part A, a 3+3 dose escalation will be used. Rova-T 0.2, 0.3, or 0.4 mg/kg will be given on Day 1 of each 42-day cycle. Dose-limiting toxicities (DLTs) will be assessed over a 21-day period. Dose escalation will proceed within cohort until a maximum tolerated dose is reached. Part B expansion, Stage 1, will explore the recommended dose in 7 pts in disease specific cohorts. Stage 2 will use an adaptive 2-stage design to determine sample size. Pt eligibility: ≥ 18 years; histologically confirmed, measurable, advanced solid tumor; relapsed/refractory to prior standard therapy; ECOG 0-1; no prior exposure to a pyrrolobenzodiazepine-based drug. Primary objective: assess safety and tolerability of Rova-T. Secondary objectives: explore Rova-T antitumor activity, pharmacokinetics, and incidence of anti-therapeutic antibodies. Exploratory objectives: explore the relationship between DLL3 and clinical outcome, and effects on biomarkers and pharmacodynamics. Clinical trial information: NCT02709889.

A phase I open-label study to investigate safety and tolerability, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MT-5111 in patients with HER2-positive tumors.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS258-TPS258
Author(s):  
Zev A. Wainberg ◽  
Monica M. Mita ◽  
Minal A. Barve ◽  
Erika P. Hamilton ◽  
Andrew J. Brenner ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitors ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Maximum Tolerated Dose ◽  
Resistance Mechanisms ◽  
Primary Objective ◽  
Her2 Positive ◽  
Open Label

TPS258 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action & are capable of forcing internalization, self-routing through intracellular compartments to the cytosol & inducing potent cell-kill via the enzymatic & permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2+ solid tumors. Its novel mechanism of action, via enzymatic ribosome inactivation, may not be subject to resistance mechanisms that exist for tyrosine kinase inhibitors, antibody-drug conjugates, or antibody modalities. MT-5111 binds an epitope on HER2, distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2-targeting agents. MT-5111 is a 55 kilodalton protein & may have improved tumor penetration capability. The objective of this trial will be to determine the safety, tolerability, & maximum tolerated dose (MTD) of MT-5111 in patients (pts) with advanced HER2+ solid tumors. Methods: This Phase 1, first-in-human, open-label, dose escalation & expansion study will evaluate MT-5111 monotherapy in pts with HER2-positive solid tumors. The primary objective is to determine the MTD; secondary objectives include pharmacokinetics, tumor response & immunogenicity. Part 1 consists of MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10µg/kg/dose) based on a modified 3+3 design (n≤42 pts); Part 2 (dose expansion) will evaluate MT-5111 at the MTD in ≤98 pts. All pts will be administered MT-5111 over 30 min via IV infusion on Days 1, 8, & 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent, or another reason for withdrawal. Part 1 will include pts with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastric or gastroesophageal junction adenocarcinomas (collectively referred as gastroesophageal adenocarcinomas [GEA]) & other HER2+ solid cancers. Immunohistochemistry (IHC) status must be 2+ or 3+, regardless of in situ hybridization (ISH) results; if no IHC is available for pts with BC or GEA, ISH criteria per the American Society of Clinical Oncology College of American Pathologists guidelines will be used. In metastatic cases, HER2 positivity must be demonstrated on metastatic lesions. Pts with HER2+ BC should have had ≥2 lines of HER2-directed therapy; pts with HER2+ GEA should have received or been intolerant to trastuzumab. Pts with evaluable disease may be included in Part 1; in Part 2, all pts must have ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment, which began in September 2019, is ongoing. Clinical trial information: NCT04029922.

A phase I, first-in-human, dose escalation study of intravenous TK216 in patients with relapsed or refractory Ewing sarcoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS11626-TPS11626 ◽  
Author(s):  
Noah Federman ◽  
Paul A. Meyers ◽  
Najat C. Daw ◽  
Jeffrey Toretsky ◽  
James Bradley Breitmeyer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dose Escalation ◽  
Ewing Sarcoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study ◽  
Human Dose

TPS11626 Background: Ewing sarcoma (ES) is a rare cancer that affects children and young adults. Patients with recurrent/refractory ES have a poor prognosis (5-year survival 10-15%) with no improvement despite advances in cytotoxic and targeted therapies. Genomic rearrangements resulting in fusion proteins and over-expression of ets family transcription factors occur in 95% of ES. In particular, the EWS-FLI1 oncogenic fusion creates a constitutively active transcription factor that drives the malignant ES phenotype. Strategies to target the EWS-FLI1 fusion protein have been limited by lack of specificity. A promising approach is to target the interaction of the ets transcription factor with its critical protein partner, RNA helicase A (RHA). TK216 is a novel small-molecule that directly binds to EWS-FLI1 and inhibits its function by blocking binding to RHA. TK216 demonstrates potent anti-proliferative effects on ES cell lines and xenografts. Methods: We initiated a Phase 1, first-in-human, open-label, multi-center, dose-escalation/dose-expansion trial of TK216 in patients with recurrent/refractory ES who are ≥12 years of age (ClinicalTrials.gov: NCT02657005). TK216 is dosed based on body surface area and administered as a continuous intravenous infusion for 7 days followed by 14 days rest every 21 days. Treatment may continue in the absence of disease progression. One intrapatient dose escalation is allowed. Enrollment of 6 to 8 cohorts using a 3+3 dose-escalation design is anticipated. During dose expansion, a total of 18 patients with ES will be accrued at the recommended Phase 2 dose (RP2D). The primary objective of the study is to determine the maximum tolerated dose and RP2D of TK216. Secondary objectives are to assess the safety profile, pharmacokinetics, pharmacodynamics, and antitumor activity of TK216. Molecular assays will be performed to characterize EWS-FLI or EWS-ets abnormalities in archival tumor tissue. The overall response rate, duration of response, progression-free survival, and overall survival will be determined in the expansion cohort. Nine patients have been enrolled since June 2016. Accrual to cohorts 1, 2, and 3 completed and cohort 4 opened in January 2017. Clinical trial information: NCT02657005.

A phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1024-1024
Author(s):  
Erika Paige Hamilton ◽  
Mafalda Oliveira ◽  
Udai Banerji ◽  
Cristina Hernando ◽  
Javier Garcia-Corbacho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Clinical Benefit ◽  
Sinus Bradycardia ◽  
Phase 1 ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Breast ◽  
Open Label

1024 Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown antitumor efficacy in a range of preclinical models of breast cancer. Methods: SERENA-1 (NCT03616587) is an ongoing Phase 1, open-label study in pre- and post-menopausal women, after ≥1 endocrine therapy and ≤2 prior chemotherapies for ER+ HER2- advanced breast cancer (ABC). The primary objective is to determine the safety and tolerability of AZD9833 once daily (QD), with dose-limiting toxicities (DLTs) in 28d defining the maximum tolerated dose. Secondary objectives include pharmacokinetics and anti-tumor response. Pharmacodynamic (PD) analysis includes ER modulation in paired tumor biopsies and ctDNA dynamic changes. Results: At 20 January 2020: 60 patients were treated (median prior therapies 5 (1–9); prior fulvestrant (Fv) 82%; prior CDK4/6i 68%) across five doses; 25 mg QD n=12, 75 mg QD n=12, 150 mg QD n=13, 300 mg QD n=13, 450 mg QD n=10. AZD9833 exposure was dose proportional after multiple doses, with a median terminal t1/2 of 12h. Treatment-related AEs experienced by ≥10% of patients were visual disturbances (53%; 91% G1, 6% G2, 3% G3), bradycardia/sinus bradycardia (45%; 93% G1, 7% G2), nausea (18%; 46% G1, 55% G2), fatigue (13%; 38% G1, 63% G2), dizziness (10%; 83% G1, 17% G3) vomiting (10%; 50% G1, 33% G2, 17% G3), and asthenia (10%; 67% G1, 33% G2). Three patients experienced DLTs: G3 QTcF prolongation (300 mg); G3 vomiting (450 mg); and a combination of G2 visual disturbance, G2 headache and G2 gait disturbance (450 mg). DLTs resolved with dose reduction. No G4 or 5 AEs were reported. Efficacy data are presented in the table below; objective response rate (ORR) and clinical benefit rate (CBR) at 24 weeks. Clinical trial information: NCT03616587 . ER signalling pathway modulation was observed in all dose cohorts. In patients where clinical responses occurred and paired biopsies obtained, 98% reduction in Ki67 was measured. Updated data will be presented. Conclusions: AZD9833 has an encouraging efficacy and dose-dependent safety profile. Evidence of clinical benefit and target engagement was observed at all dose levels in women with ER+ ABC, including patients pre-treated with CDK4/6i and Fv, and those with ESR1 mutations. A Phase 2 study comparing efficacy and safety of three doses AZD9833 vs Fv is planned (NCT04214288). [Table: see text]

A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2624-2624
Author(s):  
Manish R. Patel ◽  
Aung Naing ◽  
Howard A. Burris III ◽  
Chia-Chi Lin ◽  
Giuseppe Curigliano ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Cancer Therapies ◽  
Open Label ◽  
Efficacy Measures ◽  
Grade 3 ◽  
Dual Mechanism

2624 Background: KY1044, is a fully human IgG1 anti ICOS antibody designed to stimulate Teffs and to deplete ICOS high Tregs in the tumor microenvironment. Methods: Patients with advanced/metastatic malignancies received escalating doses of KY1044 as a single agent and in combination with atezolizumab 1200 mg by IV infusion every 3 weeks until disease progression or unacceptable toxicity. Dose escalation was guided by a modified toxicity probability interval design. The primary objective was to determine safety, tolerability, and maximum tolerated dose. Cohorts that were tolerated were later enriched with more subjects. AEs were classified according to CTCAE v5 and efficacy measures performed according to RECIST v1.1 every 8 weeks for the first 16 weeks and then every 12 weeks. Results: As of 16-Dec-2020, a total of 103 patients have been enrolled in the study (38 patients as monotherapy in 6 cohorts at doses ranging from 0.8 to 240 mg and 65 in combination with atezolizumab in 5 cohorts at doses 0.8 – 80 mg). 63% and 55% of patients received ≥4 prior anti-cancer therapies in the single agent and combination cohorts, respectively. All cohorts were completed without DLTs during the first 21 days of treatment. In the KY1044 single agent cohorts, 47.4% of patients experienced treatment-related AEs (TRAEs), all were grades 1 or 2. In the combination cohorts, TRAEs were observed in 58% of patients. Most of the TRAEs were grade 1 or 2 apart from 8 TRAEs that were ≥grade 3 occurring in <8% of patients. Infusion-related reactions, pyrexia and lymphopenia were the most commonly occurring TRAEs in ≥10% of patients. TRAE leading to dose interruptions occurred in 1 patient in the single agent cohort and in 4 patients in the combination cohort. Only 1 patient discontinued treatment due to myositis that was considered related to the combination. Preliminary KY1044 PK data from 69 patients agree with the PK model predictions. Median treatment duration for all enrolled patients was 9 weeks. Treatment duration ≥16 weeks was observed in 24% (9/38) and 27% (17/64) patients in the single agent and combination cohorts, respectively. Five objective responses, including 1 CR in triple negative breast cancer (TNBC) and 4 PRs in TNBC, head and neck squamous cell carcinoma, penile and pancreatic cancer were observed. Four of the 5 responding patients were still on treatment at the data cut, with 3 patients on treatment for >43 weeks (range 45 to 66 weeks). Conclusions: KY1044 is well tolerated as single agent and in combination with atezolizumab. Objective responses have been observed in this phase 1 part of the study. The phase 1 expansion and phase 2 part of the study is ongoing. Clinical trial information: NCT03829501.

MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Yusuke Suzuki ◽  
Mohit Mathur ◽  
Jonathan Barratt ◽  
Frank Engler ◽  
Jill Yarbrough ◽  
...  
Keyword(s):  
Phase 1 ◽  
Study Drug ◽  
Dependent Manner ◽  
Double Blind ◽  
Serum Iga ◽  
Dose Study ◽  
Dose Response Effect ◽  
Japanese Descent ◽  
Dose Dependent ◽  
Single Ascending Dose Study

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

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