Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7508-7508 ◽  
Author(s):  
Farhad Ravandi ◽  
Roland B. Walter ◽  
Marion Subklewe ◽  
Veit Buecklein ◽  
Mojca Jongen-Lavrencic ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Residual Disease ◽  
Phase 1 ◽  
Dose Range ◽  
Dose Schedule ◽  
Cell Transplant ◽  
Dependent Manner ◽  
Dose Escalation Study ◽  
Hematopoietic Stem ◽  
Prior Therapy

7508 Background: In this open label phase 1 dose escalation study, safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of AMG 330 were evaluated in patients (pts) with R/R AML (NCT#02520427). Methods: AMG 330 was evaluated as a continuous IV (cIV) infusion using a 3+3 design. Response was assessed per revised IWG criteria. Each cycle (2–4 weeks duration) was followed by an infusion-free interval. Eligible pts were ≥18 y/o with > 5% blasts in bone marrow and ≥1 line/s of prior therapy. Results: As of December 10, 2019, 55 pts (median age, 58.0 [18.0–80.0] years) were enrolled in 16 cohorts. AMG 330 was administered on 4 schedules (0–3 dose steps) prior to the target dose (TD, 0.5–720 µg/day). Dose steps were implemented in the dose schedule design based on the adverse event (AE) profile. Across all schedules, 55 (100%) pts reported treatment-emergent AEs (any grade). AMG 330–related AEs reported in 49/55 (89%) pts included cytokine release syndrome (CRS; 67%; ≥ grade 3 in 13%), (60%) and nausea (20%) as the most frequent AEs. CRS was reversible and occurred in a dose/schedule-dependent manner mostly within the first 24 hours of administration of triggering AMG 330 dose. The frequency and severity of CRS correlated with the dose level and leukemic burden at baseline. AMG 330 exhibited dose-dependent increase in steady state exposures over the studied dose range with clinical PK profile consistent with cIV administration. Eight of 42 evaluable pts responded: 3 complete remissions (CR; including 1 CR with negative measurable residual disease reported after data snapshot), 4 CR with incomplete hematologic recovery, and 1 morphologic leukemia free state. Seven responders who achieved CR/CRi received a TD equal or above the minimal efficacious dose of 120 μg/day. Among analyzed CR/CRi responders, 4/6 (67%) had adverse cytogenetic risk profile, 3/6 (50%) had ≥4 lines of prior therapy and all had relapsed disease. Responders had higher AMG 330 exposures and 3 responders treated with ≥600 μg/day TD remain in CR/CRi: 1 patient for > 5 months after cycle 1, 1 patient bridged to hematopoietic stem cell transplant after cycle 4 and 1 patient is in cycle 3. Preliminary response assessment showed a correlation with lower tumor burden at baseline with a trend towards higher CD8+ lymphocyte count and E:T ratio. Conclusions: AMG 330 dosed up to 720 μg/day provided early evidence of acceptable safety profile, drug tolerability and anti-leukemic activity, and supports further dose escalation. Clinical trial information: NCT02520427 .

PF-06939999, a potent and selective PRMT5 inhibitor, in patients with advanced or metastatic solid tumors: A phase 1 dose escalation study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3019-3019
Author(s):  
Jordi Rodon Ahnert ◽  
Cesar Augusto Perez ◽  
Kit Man Wong ◽  
Michael L. Maitland ◽  
Frank Tsai ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Urothelial Cancer ◽  
Phase 1 ◽  
Dose Range ◽  
Median Number ◽  
Splicing Factor ◽  
Dose Escalation Study ◽  
Study Objective ◽  
Dose Dependent

3019 Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates known to be dysregulated in cancer, including components of the spliceosome machinery. PF-06939999 is a selective small-molecule inhibitor of PRMT5. Here we report the safety, PK, PD, and preliminary activity of PF-06939999 in patients (pts) with selected advanced/metastatic solid tumors. Methods: This phase 1 dose escalation trial (NCT03854227) enrolled pts with solid tumor types marked by potential frequent splicing factor mutations, including advanced/metastatic endometrial cancer, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), urothelial cancer, cervical cancer, or esophageal cancer. PF-06939999 monotherapy was continuously administered orally QD or BID in 28-day cycles. A Bayesian Logistic Regression Model was used to inform dose level decisions. Primary objectives were to assess dose limiting toxicities (DLTs), AEs and laboratory abnormalities. Tumor response was assessed using RECIST v1.1. PK and PD were assessed by determining PF-06939999 plasma concentration after dosing and changes in plasma levels of symmetric di-methyl arginine (SDMA), the product of PRMT5 enzymatic activity. Results: 28 pts received PF-06939999 at doses from 0.5-12 mg daily (QD or BID) during dose escalation. Median number of cycles was 2 (range, 1-13). Most were female (54%) with a median age of 61.5 (range, 32-84) y. Median number of prior therapies was 4. Overall, 4/24 (17%) pts reported DLTs: thrombocytopenia (n=2, 6 mg BID); anemia (n=1, 8 mg QD); and neutropenia (n=1, 6 mg QD). Treatment-related AEs occurred in 24 (86%) pts. Most common (≥20%) treatment-related AEs across all cycles were anemia (43%), thrombocytopenia (32%), dysgeusia, fatigue and nausea (29% each). Grade ≥3 treatment-related AEs included anemia (25%), thrombocytopenia (21%), fatigue, neutropenia and lymphocyte count decreased (4% each). One pt (6mg BID) had Grade 4 treatment-related thrombocytopenia. All cytopenias were dose-dependent and reversible with dose modification. No pts discontinued treatment for treatment-related toxicity. There were no treatment-related deaths. Exposure to PF-06939999 increased with doses in the dose range tested. Plasma SDMA was reduced at steady state (58.4-87.5%), indicating robust PD target inhibition. Two pts had confirmed partial response (HNSCC and NSCLC). 6 mg QD was identified as the recommended monotherapy dose for expansion. Conclusions: PF-06939999 showed dose-dependent and manageable toxicities in this phase 1 dose escalation study. Objective tumor responses were observed in pts with HNSCC and NSCLC. Analysis of archival tissue for the presence of splicing factor mutations and other potential predictive biomarkers is ongoing. Enrollment to part 2 dose expansion is ongoing in pts with NSCLC, HNSCC and urothelial cancer. Clinical trial information: NCT03854227.

A Phase 1 Dose-Escalation Study of the Novel Cell Cycle Active Agent SNS-595 in Advanced Leukemias.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1962-1962
Author(s):  
Jeffrey E. Lancet ◽  
Judith E. Karp ◽  
Nancy Havrilla ◽  
Ute Hoch ◽  
Jeffrey Silverman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Dose Escalation ◽  
Phase 1 ◽  
Active Agent ◽  
Complete Response ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Acute Leukemias ◽  
Prior Therapy

Abstract SNS-595 is a novel, cell cycle active cytotoxic naphthyridine analog that induces G2 arrest in a variety of preclinical tumor models. We initiated an escalating-dose phase 1 trial of SNS-595, administered as a weekly x 3 (arm A) or twice weekly x 2 bolus (arm B), in patients with advanced or refractory acute leukemias. Objectives: The primary objectives were to:establish safety, tolerability, and MTD of SNS-595 given on each schedule,characterize pharmacokinetics (PK) of SNS-595 when given on these schedules. Secondary objectives were:assessment of clinical activity,exploration of potential biomarkers. Methods: SNS-595 was administered as a slow IV push on days 1, 8, 15 (arm A) or days 1, 4, 8, 11 (arm B). Minimum cycle length was 42 days (arm A) and 39 days (arm B). Additional cycles were permitted if patients achieved stable disease or better. The starting dose was 18 mg/m2/d on arm A, and 9 mg/m2/d on arm B and escalated by cohort using a modified Fibonacci schema. PK analyses for SNS-595 were performed on plasma samples collected during cycle 1. Pretreatment peripheral blood and bone marrow aspirate samples were collected for exploratory analyses of the level and functional activity of the DNA damage repair proteins DNA-PK and MSH2. Results: To date, 21 patients have been enrolled and are evaluable in the live database, including 13 patients assigned to arm A and 8 assigned to arm B, 12 males and 9 females with a median age of 64 years. Diagnoses included AML (19 patients) and ALL (2 patients). All patients had disease refractory to or relapsed from prior therapy (median 3 prior regimens (range 1–6)). Dose escalation has proceeded to 50 mg/m2/d (arm A) and 19 mg/m2/d (arm B). No dose-limiting toxicities have been observed to date. Non-dose limiting toxicities included nausea/vomiting, diarrhea, and mucositis . Grade 4 neutropenic fever was observed in only one patient. Plasma exposures at the first two dose levels in each arm increased linearly, resulting in AUCs of 5.5 – 17.8 ughr/mL for 9–27 mg/m2 doses. CL, Vss, and terminal half-lives were similar to those reported previously in solid tumor patients, and averaged ~2 L/hr/m2, 58 L/m2, and 23 hr, respectively. No patients have achieved complete response to date, although 6 patients (distributed across all dosing groups) experienced >50% reductions in peripheral blasts following cycle 1. Conclusion: SNS-595 appears to be well-tolerated in patients with advanced leukemias, with preliminary and promising signs of clinical activity as measured by decreases in leukemic blasts. Bone marrow ablation has not yet been achieved; patient accrual and dose-escalation are ongoing.

Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2507-2507 ◽  
Author(s):  
Funda Meric-Bernstam ◽  
Shahneen Kaur Sandhu ◽  
Omid Hamid ◽  
Anna Spreafico ◽  
Stefan Kasper ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Dose Schedule ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Grade 3 ◽  
Sting Pathway

2507 Background: MIW815 (ADU-S100) is a novel synthetic cyclic dinucleotide that activates the STimulator of INterferon Genes (STING) pathway impacting tumor cells, tumor microenvironment, vasculature, tumor-associated fibroblasts, and priming APC and CD8+ T cells. Spartalizumab is a humanized IgG4 mAb that blocks the binding of PD-1 to PD-L1/2. Preclinical data support synergistic antitumor effects when MIW815 (ADU-S100) is combined with checkpoint inhibitors. Methods: In this Phase Ib dose escalation study, pts with advanced/metastatic solid tumors or lymphoma received MIW815 (ADU-S100) (intratumoral injections [50–800 µg] either weekly [3 weeks on/1 week off] or Q4W) and spartalizumab (400 mg IV Q4W). Injected and non-injected tumor biopsies were obtained at baseline and on treatment. Primary objectives are to determine safety and identify a dose/schedule for future studies. Preliminary activity, pharmacokinetics (PK), and pharmacodynamics (PD) are also being explored. Results: As of Jan 11, 2019, 66 pts (median age: 61 y) with various solid tumors or lymphomas have been treated. Treatment was discontinued in 49 pts (74%) due to disease progression (n = 28), pt/physician decision (n = 18), AE (n = 2), or death (n = 1). No DLTs were reported during the first cycle at any dose level. Most common (≥5 pts) treatment-related AEs (TRAEs) were injection site pain (12%), pyrexia (11%), and diarrhea (9%). Grade 3/4 TRAEs (in ≥2 pts) were increased AST and ALT (3% each). Serious TRAEs were pyrexia (3%), increased amylase, increased lipase, diarrhea, fatigue, hyperthyroidism, partial seizures, dyspnea, and pneumonitis (all 2%). Partial responses in pts with PD-1–naive TNBC and PD-1–relapsed/refractory melanoma have been observed. MIW815 (ADU-S100) plasma exposure generally increased in a dose-dependent manner with a rapid terminal half-life. Response data, PK and PD analyses will be presented. Conclusions: Thus far, MIW815 (ADU-S100) + spartalizumab has demonstrated antitumor activity in PD-1–naive TNBC and PD-1–relapsed/refractory melanoma. The combination is well tolerated, with no DLTs reported to date. The MTD has not been reached and dose escalation is ongoing. Clinical trial information: NCT03172936.

Dasatinib In Children and Adolescents with Relapsed or Refractory Leukemia: Results of the CA180018 Phase 1 Dose-Escalation Study of the Innovative Therapies for Children with Cancer (ITCC) Consortium

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2265-2265 ◽  
Author(s):  
C. Michel Zwaan ◽  
Carmelo Rizzari ◽  
Francoise Mechinaud ◽  
Donna L Lancaster ◽  
Pamela R. Kearns ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Maximum Concentration ◽  
Phase 1 ◽  
Molecular Response ◽  
Cell Transplant ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Grade 3

Abstract Abstract 2265 Background: Pediatric relapsed/refractory leukemia portends a poor prognosis and more effective therapies are urgently needed. Dasatinib is a potent oral BCR-ABL inhibitor approved for treating adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to imatinib. Dasatinib also has activity against SRC-family kinases and KIT. A phase 3 trial of dasatinib vs imatinib in adults with newly diagnosed with CML in chronic phase (CP) showed superior efficacy of dasatinib with good tolerability (Kantarjian et al. NEJM 2010:362:2260). Methods: The CA180018 trial is a component of a European Medicines Agency-approved comprehensive Pediatric Investigation Plan for dasatinib aimed at improving outcomes in pediatric leukemias. This trial is being conducted via the ITCC consortium in 7 countries (15 centers) as a stratified phase 1 dose-escalation study. The primary aim is to establish a safe and effective phase 2 dose of dasatinib in children/adolescents with subtypes of relapsed/refractory leukemia. Secondary objectives include safety, pharmacokinetics (PK), and rates of hematologic, cytogenetic, and molecular response (cytogenetic/molecular responses in Ph+ only). Patients (pts) were stratified into 3 disease strata: Stratum 1, imatinib-resistant/intolerant Ph+ CML-CP; Stratum 2/3, advanced CML resistant to imatinib or Ph+ ALL relapsed/refractory after imatinib or Ph+ AML in ≥2nd relapse (original strata merged by protocol amendment due to slow enrolment); and Stratum 4, ≥2nd relapse of Ph– ALL or AML. Starting doses were 60, 80, 100, and 120 mg/m2 once daily, with dose escalations based on safety and efficacy. Intrapatient dose escalation was allowed for lack of response. Results: The study opened in March 2006 and closed to accrual in October 2009. 58 pts have been treated, of which 50 (86%) completed therapy by data cut-off of May 2010. No pts with Ph+ AML were enrolled. All pts had prior therapy, including imatinib in 59% (all Ph+ pts), anagrelide or hydroxyurea in 22%, interferon in 3%, other chemotherapy in 69%, radiotherapy in 43%, and stem cell transplant in 50%. Median age (yrs) was 11, including 2 pts (3%) aged <2, 32 (55%) aged 2–11, 23 (40%) aged 12–18, and 1 (2%) aged >18. 39 pts (67%) were male. No pt with Ph– AML had a KIT mutation. Median durations of therapy (range) were: Stratum 1, 11.3 mos (2.3–47.9); Stratum 2/3, 3.0 mos (0.5–24.6); and Stratum 4, 1.1 mos (<0.1–3.4). Dasatinib up to 120 mg/m2, including long-term therapy, was well tolerated. Common drug-related toxicities (≥10%) were: nausea (grade 1/2 in 16 pts [28%], grade 3 in 1 [2%]); headache (grade 1/2 in 11 [19%], grade 3 in 2 [3%]); diarrhea (grade 1/2 in 12 [21%]); vomiting (grade 1/2 in 9 [16%], grade 3 in 1 [2%]); rash (grade 1/2 in 9 [16%]); and pain in extremity (grade 1/2 in 6 [10%]). Pleural effusion occurred in 2 pts (3%) at grade 1 and 1 pt (2%) at grade 3. Two dose-limiting toxicities were seen in Stratum 4: grade 4 anaphylaxis 5 h after first dose (60 mg/m2) and grade 3 upper GI bleed on Day 6 (120 mg/m2) in a pt with platelet count of 16×109/L. Maximum tolerated dose has not been established. PK parameters, analyzed in 52 pts to date, showed high interpatient and intrapatient variability. Dasatinib was rapidly absorbed with median time to maximum concentration of 1.0 h irrespective of dose. Mean half-life ranged from 2.1–3.6 h. With dasatinib 60, 80, 100, or 120 mg/m2, area under the curve was 374, 530, 424, and 606 ng.h/mL and maximum concentration was 113, 138, 114, and 183 ng/mL, respectively. Treatment responses were seen in Ph+ pts who received dasatinib 60 or 80 mg/m2. In Stratum 1 (CML-CP; n=17), rates were complete hematologic response (HR) in 16 (94%), complete cytogenetic response (CCyR) in 14 (82%), major molecular response (MMR) in 6 (35%), and complete molecular response in 4 (24%). In Stratum 2/3 (advanced CML/Ph+ ALL; n=17), rates were major HR in 10 (59%), CCyR in 12 (71%), and MMR in 0/2 pts with advanced CML assessed to date. No pt in Stratum 4 responded (Ph– ALL/AML; n=24). Final data will be presented. Conclusions: This trial shows the safety and efficacy of dasatinib in pediatric pts with Ph+ leukemias and supports the feasibility of evaluating new agents in children with rare malignancies through cooperative group efforts. A phase 2 study is underway to further evaluate dasatinib in children/adolescents with Ph+ leukemias, including newly diagnosed CML. Disclosures: Zwaan: Bristol-Myers Squibb: Consultancy. Off Label Use: Dasatinib treatment of pediatric leukemias. Rosenberg: Bristol-Myers Squibb: Employment, Equity Ownership. Herdlicka: Bristol-Myers Squibb: Employment. Derreumaux: Bristol-Myers Squibb: Employment. Agrawal: Bristol-Myers Squibb: Employment.

scholarly journals 1953. VE303, a Rationally Designed Bacterial Consortium for Prevention of Recurrent Clostridioides difficile (C. Difficile) infection (rCDI), Stably Restores the Gut Microbiota After Vancomycin (vanco)-Induced Dysbiosis in Adult Healthy Volunteers (HV)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S60-S60 ◽  
Author(s):  
Dmitri Bobilev ◽  
Shakti Bhattarai ◽  
Rajita Menon ◽  
Brian Klein ◽  
Shilpa Reddy ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Phase 1 ◽  
Dose Range ◽  
Bacterial Consortium ◽  
Dependent Manner ◽  
Metagenomic Sequencing ◽  
Early Recovery ◽  
Dose Escalation Study ◽  
Dose Dependent

Abstract Background Gut microbiota alterations and resulting changes in metabolites involved in colonization resistance and host responses, including bile acids (BA) and short-chain fatty acids (SCFA), are hallmarks of C. difficile infection. Reduction in rCDI was shown with fecal microbiota transplants (FMT), but FMT has limitations for routine use and carries unforeseen risks. VE303 is a first-in-class drug being developed for prevention of rCDI consisting of a rationally defined bacterial consortium manufactured under GMP conditions. VE303 comprises 8 distinct species belonging to Clostridium clusters IV, XIVa, and XVII, the commensal bacteria associated with clinical response in FMT, suppress C. difficile growth in vitro and improve survival in vivo. Methods A first-in-human Phase 1 dose-escalation study assessed safety and tolerability of VE303 in HV after vanco-induced dysbiosis. PK (strain colonization and durability) and PD (restoration of the resident microbiota, SCFA pool, and BA pool) were evaluated by metagenomic sequencing and metabolomics analysis of fecal material. Results HV (N = 23) received oral vanco 125 mg QID for 5 days followed by VE303 capsules at escalating single then multiple doses (total dose range 1.6 × 109 to 1.1 × 1011 CFU). VE303-related AEs, mostly gastrointestinal, all Grade 1 and transient, were observed in 35% of HV. Colonization with VE303 strains was abundant, durable (detected at 24 weeks), and dose-dependent. VE303 rapidly expanded 10- to 100-fold and each strain was detectable within 2 days after dosing. VE303 enhanced subjects’ microbiota and metabolic recovery after vanco treatment. When compared with the vanco-only cohort (N = 5), VE303 led to earlier and more complete recovery of beneficial taxa (eg, Bacteroidetes, Firmicutes), reduction in inflammatory taxa (e.g., Proteobacteria) (Figure 1.), and recovery of the secondary BA and SCFA pools. Conclusion VE303, a rationally designed microbial consortium, was safe, well tolerated, and efficiently restored microbiome composition after antibiotic-induced dysbiosis in a dose-dependent manner. VE303 was associated with early recovery of key PD markers of response, including microbiota composition, bile acid, and SCFA pools. A Phase 2 study of VE303 for prevention of rCDI is underway (NCT03788434). Disclosures All Authors: No reported Disclosures.

Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1054-1054
Author(s):  
Aditya Bardia ◽  
Hannah M. Linden ◽  
Gary A. Ulaner ◽  
Sarat Chandarlapaty ◽  
Alice Gosselin ◽  
...  
Keyword(s):  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Dose Escalation ◽  
Phase 1 ◽  
Performance Status ◽  
Dose Range ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Dose Escalation Study

1054 Background: SERDs result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, +/- palbociclib in ER+/HER2- mBC. Here are preliminary results, as of 28 Nov 2018, for single-agent SAR439859 dose escalation. Methods: Part A of this Phase 1/2 study (NCT03284957; TED14856) assessed SAR439859 dose escalation (dose range: 20–600 mg once daily [QD]; 3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Endpoints: dose-limiting toxicities (DLTs); maximum tolerated dose (MTD); safety; pharmacokinetics (PK); tumor response (RECIST 1.1); pharmacodynamic (PD) inhibition of ER occupancy (18FES-PET scan). Results: Patients (pts; n = 16) had a median age of 59.5 years (range 40–79), ECOG performance status of 0 (62.5%) or 1 (37.5%) and a median of three prior anticancer therapies (range 1–8) in the advanced setting (endocrine therapy n = 16; chemo/targeted therapy n = 13). All pts had ≥ 1 treatment emergent adverse event (mostly grade 1–2); most frequent were asthenia/fatigue (43.8%), hot flushes (37.5%), nausea (37.5%), diarrhea (31.3%), constipation (31.3%), and decreased appetite (31.3%). There were no DLTs at any of the five dose levels (maximum administered dose: 600 mg QD); MTD was not reached. In 18FES-PET scans, signal inhibition > 87% occurred with plasma concentrations > 100 ng/mL. There was a dose proportional increase of exposure up to 400 mg after repeated QD doses. Average Ctrough was reached after repeated 400 mg QD allowing 90% of 18FES-PET signal inhibition. One pt (6.3%) had confirmed partial response (150 mg QD); eight (50%) had stable disease (SD) including three (18.8%) long-term SD (≥ 24 weeks); seven (43.8%) had progressive disease. Conclusions: SAR439859 had a favorable safety profile, high ER occupancy and encouraging antitumor activity (to be confirmed in dose expansion) in pretreated pts with ER+/HER2- mBC. With no DLTs and MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK data. Funding: Sanofi. Clinical trial information: NCT03284957.

First-in-human study of AZD5153, a small molecule inhibitor of bromodomain protein 4 (BRD4), in patients (pts) with relapsed/refractory (RR) malignant solid tumor and lymphoma: Preliminary data.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3085-3085 ◽  
Author(s):  
Judy Sing-Zan Wang ◽  
Serena De Vita ◽  
Janet L. Karlix ◽  
Carl Cook ◽  
Gillian M. Littlewood ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Solid Tumor ◽  
Target Genes ◽  
Phase 1 ◽  
Dose Range ◽  
Human Study ◽  
Linear Increase ◽  
Dose Escalation Study ◽  
Malignant Solid Tumor ◽  
Experienced Treatment

3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription and additional mechanisms. AZD5153 is a novel, reversible BRD4 inhibitor with bivalent mechanism of action and enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), and pharmacodynamics (PD). We report here preliminary, unvalidated data from AZD5153 monotherapy in pts with RR solid tumor, including lymphoma. Methods: Adult pts received oral AZD5153 QD/BID to determine the MTD. During dose escalation, a continual reassessment model was used to estimate toxicity and all final decisions were made by the Safety Review Committee. PK and PD were characterized using standard methods. Results: As of 1 Nov 2018, 28 pts (78.6% female, median age 66.5 y) were treated in 7 cohorts: 2 mg QD (3 pts), 5 mg QD (3 pts), 10 mg QD (3 pts), 10 mg BID (5 pts), 15 mg BID (4 pts), 20 mg BID (7 pts), and 30 mg QD (3 pts). Treatment was ongoing in 8 pts at data cut-off. Safety findings showed 50% of pts experienced treatment-related AEs. 25% of pts experienced treatment-related Grade ≥3 AEs, which were thrombocytopenia and fatigue (7.1% each), and anemia, diarrhea, and platelet count decreased (3.6% each). SAEs were observed in 25% of pts; none of the SAEs was attributable to AZD5153 alone. Dose-limiting toxicities of thrombocytopenia (1 pt) and diarrhea with herpetic rash leading to discontinuation (1 pt) occurred at 20 mg BID. 53.6% of pts discontinued due to disease progression. Total median treatment duration was 1.3 mo (range up to 8.9 mos). Dose proportional increase in Cmax and AUC were observed across the dose range tested. Tmax ranged from 0.5 to 3 h and t1/2 was 6 h. Dose-dependent changes in expression of target genes (eg, HEXIM1, HIST2H2BF, CD274, and CCR2) and platelet counts were observed in the peripheral blood. Conclusions: AZD5153 monotherapy is safe and tolerated at doses up to 30 mg QD and 15 mg BID. Linear increase in PK was observed. Additional safety and efficacy updates will be reported at the annual meeting. Clinical trial information: NCT03205176.

scholarly journals A Phase 1 Single Dose Escalation Study of Palifermin Administered Pre-Transplant Conditioning in Subjects Undergoing Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-21
Author(s):  
Alen Ostojic ◽  
Noa G. Holtzman ◽  
Lauren M. Curtis ◽  
Brian C. Shaffer ◽  
Jeffrey S Rubin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Dose ◽  
Hematopoietic Stem Cell ◽  
Dose Level ◽  
Hematologic Malignancy ◽  
Phase 1 ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Hematopoietic Stem

Background: Early initiation of graft-versus-host disease (GvHD) is driven by donor alloreactive T-lymphocytes directed against recipient's histocompatibility antigens often overexposed during damage to tissues during the conditioning chemotherapy. Palifermin is a truncated form of human recombinant keratinocyte growth factor (KGF, also known as FGF7) that binds to FGF receptor 2b expressed in many epithelia including the epithelium of the epidermis, oral and GI mucosa, urothelium, and thymus, in which it exerts cytoprotective and regenerative effects. Palifermin also has immunomodulatory effects manifested as improvements in thymic function and downregulation of pro-inflammatory cytokines. Palifermin was FDA approved in 2004 at a dose of 60 mcg/kg/day (x3 consecutive days) for prevention of severe oral mucositis in hematologic malignancy patients receiving autologous hematopoietic stem cell transplant (HSCT). A single dose of 180 mcg/kg/day appears to have similar effects. In animal models, palifermin showed efficacy in controlling acute and chronic GvHD. However, subsequent clinical studies did not confirm efficacy for prevention of GvHD or for stimulation of functional thymus recovery using a dose/schedule based on the one that had been approved for autologous HSCT. We conducted a phase 1 study (NCT02356159) to determine the maximal safe single dose level of palifermin administered prior to starting transplant conditioning. Methods: This was an open-label, dose escalation study with standard 3+3 design. Four different dose levels of palifermin (180, 360, 540 and 720 µg/kg) were administered as a single dose on day -7 pretransplant. The reduced-intensity conditioning regimen (cyclophosphamide 1200 mg/m2/day IV and fludarabine 30 mg/m2/day IV), was given on days -6 to -3. Sirolimus, tacrolimus and low-dose post-HSCT methotrexate were used for GvHD prophylaxis. On day 0 all subjects received a peripheral blood stem cell (PBSC) graft from an unrelated donor (MUD) matched at least at HLA-A, -B, -C, -DRB1. Prior to transplant, subjects received one or two cycles of disease-specific lymphodepleting induction chemotherapy (EPOCH-F/R or FLAG). Subjects must have been ≥18 years old with a high-risk hematologic malignancy, Karnofsky performance status ≥60%, and acceptable organ function. The primary objective was to assess safety of palifermin and to recommend the phase 2 study dose. DLT was defined as non-relapse mortality before day 30 post-HSCT regardless of attribution to palifermin and non-hematologic grade ≥4 adverse events (AEs) occurring within 14 days after administration. AEs were recorded according to CTCAEv4. Results: From Oct 2015 to Mar 2019, 18 subjects were enrolled (NHL=7, AML/MDS=5, ALL/LBL=2, CML=2, MPN=1 and MM=1). Kahl's relapse risk was high, standard, and low in 15, 2, and 1 subject, respectively. Median HCT-CI score was 1 (0-4) with median age 47 years (21-66); 14 (78%) were males. Six subjects received dose level 1 (subject #3 was diagnosed with achalasia and grade 4 elevated lipase without radiological signs of pancreatitis, still attributed as DLT possibly related to palifermin). No DLTs occurred afterwards. Three subjects were enrolled onto each of dose levels 2, 3 and 4, with expansion of dose level 4 to 3 more subjects for additional safety exploration. Skin rash and Increased serum amylase or lipase were the most frequent AEs (Table 1A). Grade 3 increased serum amylase and grade 3 possible pancreatitis in subject #3 were the only SAEs attributed to study drug. All subjects engrafted successfully. Day 14 median CD3 and myeloid chimerism was 97% (36-100) and 99% (82-100), respectively, with the median time to 100% CD3 chimerism of 44 days (14-181). Table 1B lists occurrence of GvHD prior to any malignancy relapse. Four subjects had relapsed malignancy, for which 3 received DLI. After a median follow up of 28 months (2-55), 5 subjects have died, 2 malignancy relapses and 3 non-relapse related causes. Conclusion: Palifermin administered at dose four-times higher than previously given in humans is safe to use in patients undergoing MUD peripheral blood HSCT. MTD was not reached. Recommended phase 2 dose for examining efficacy in prevention of GvHD is 720 µg/kg. Disclosures Rubin: NIH/NCI: Ended employment in the past 24 months, Patents & Royalties; KGF/palifermin: Patents & Royalties; Paradigm Shift Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Palifermin was FDA approved at a dose of 60 mcg/kg/day (x3 consecutive days) for prevention of severe oral mucositis in hematologic malignancy patients receiving autologous hematopoietic stem cell transplant (HSCT).

A phase I dose-escalation study to evaluate pharmacokinetics, safety and tolerability of ACT001 in patients with advanced glioma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2044-2044
Author(s):  
Yehui Shi ◽  
Guiying Bai ◽  
Peng Wang ◽  
Dongpo Cai ◽  
Yue Chen ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Drug Exposure ◽  
Clinical Performance ◽  
Phase 1 ◽  
Single Agent ◽  
Study Drug ◽  
Chinese Patients ◽  
Pharmacokinetic Analysis ◽  
Dependent Manner ◽  
Dose Escalation Study

2044 Background: Management of advanced gliomas including glioblastoma multiforme (GBM) remains as an unmet medical need. Here we report our clinical experience with ACT001, or dimethylamino micheliolide, a synthesized derivative from parthenolide (a natural product of sesquiterpene lactone class), in Han Chinese patients with advanced glioma. Methods: Adult patients were enrolled in a 3+3 dose escalation phase 1 study with the following pre-defined ACT001 cohorts: 100mg, 200mg, 400mg, 600mg and 900mg, twice a day (BID). Pharmacokinetics and adverse events were evaluated during the study. Imaging studies were performed using RANO criteria to assess the therapeutic afficacy. Results: 16 patients with advanced glioma were enrolled in this single agent dose escalation study including 8 primary GBM, 4 astrocytoma (grade 2-3) and 4 other advanced glioma. The median age was 49 years (range: 31-70). Safety evaluation was performed in five cohorts and 13 of the 16 subjecst were evaluable for drug tolerability analysis. ACT001 was tolerated very well and no DLT or MTD was identified. Other than grade 1 adverse reactions (AE) in most cases and grade 2 AEs in other clinical findings, no drug-related grade 3 AE was noted. Pharmacokinetic analysis indicates that there was approximately linear correlate between the drug exposure (Cmax, AUC0-t and AUC0-inf) and study drug dosages evaluated. T1/2 is 4 hours with mean Cmax increased from approximate 300ng/ml to 5000ng/ml in a dose dependent manner with no significant dose accumulation during repeated dosing challenge. Post baseline MRI scans were performed in 11 out of 16 subjects. Among these 11 subjects, 1 GBM patient had a partial response (PR) at end of cycle 2 but had disease progressed at end of cycle 4; two non-GBM patients had a stable disease (SD) lasting for 5 or 6 cycles respectively before being taken off study due to disease pregression (PD) and other 8 patients had a PD. Of note, 9 out of these 11 subjects had stable or even improved clinical performance by the time they were taken off study due to PD. Five other subjects withdrew their consents or were taken off study due to clinical disease progression. Of note, subject S12 with diffusive astrocytoma was taken off study due to PD while still with a stable clinilcal performance and stereotactic biopsies targeting the progressed lesion didn’t reveal viable tumor tissues other than presence of macrophage/microglia. This subject was still alive 666 days after being taken off study. The mode of ACT001 actions is proposed to be at least partially related to its effects on tumor immune microenvironment. Conclusions: ACT001 was safe and tolerated well in patients. Clinical response was observed including a pathologic response in a subset of patients dosed at lower dose cohorts. iRANO criteria will be used in future studies based on its impacts on tumor immune microenvitonment. Clinical trial information: ChiCTR-OIC-17013604.

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