Phase I dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3045-3045 ◽  
Author(s):  
Takashi Seto ◽  
Taito Esaki ◽  
Fumihiko Hirai ◽  
Shuji Arita ◽  
Kaname Nosaki ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Troponin T ◽  
Geometric Mean ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Primary Tumor Site ◽  
Grade 3

3045 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients (pts) with advanced solid tumors (NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at doses of 6 (n=3), 9 (3), 21 (6), and 30 mg (8). The most common primary tumor site was lung (n=14). All pts had received ≥1 prior chemotherapy and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated AST and ALT (Cycle 1; combination therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs resolved following treatment discontinuation. The most frequently reported adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia (50%), hypertension (25%) and fatigue (15%). Overall, the most common AEs were bradycardia (55%), neutropenia (45%), and hypertension, fatigue, and rash (30% each). AEs grade ≥3 were reported in 11 pts, the most common being neutropenia (45%) and leukopenia (25%). No pt died due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately linear manner. Gemcitabine did not appear to affect AZD7762 PK. Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in combination with gemcitabine. There were no objective responses; five pts (all lung cancer) had stable disease. Conclusions: The maximum tolerated dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was determined as 21 mg in Japanese pts.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3611-3611
Author(s):  
Ben George ◽  
Donald A. Richards ◽  
William Jeffery Edenfield ◽  
Steven L Warner ◽  
Lars Mouritsen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .

Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2580-2580
Author(s):  
Jermaine Coward ◽  
Afaf Abed ◽  
Adnan Nagrial ◽  
Ben Markman
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Febrile Episodes ◽  
Antigen Presenting

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Igor Puzanov ◽  
Patricia LoRusso ◽  
Kyriakos P. Papadopoulos ◽  
Christopher T. Chen ◽  
Yvan LeBruchec ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

Phase I, first-in-human, open-label, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2519-2519 ◽  
Author(s):  
Kathleen N. Moore ◽  
Johanna C. Bendell ◽  
Anthony J. Olszanski ◽  
Madhuri Desai ◽  
Mendel Jansen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Anti Tumor Activity

2519 Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member and a ligand for EGFR and Her4. U3-1565 is a fully human anti-HB-EGF monoclonal antibody with preclinical anti-tumor and anti-angiogenesis activity. In this study, we evaluated safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of U3-1565 in patients with advanced solid tumors refractory to standard treatment. Methods: The 3+3 method of enrollment and dose-escalation was used to test U3-1565 at 2, 8, 16, and 24 mg/kg once every two weeks (with the second dose given three weeks after the first), and at 24 mg/kg weekly. Results: 15 patients (11 females, 4 males; median age 62 (range 47-77) years; 5 CRC, 5 NSCLC, 3 ovarian and 2 other cancer) were enrolled, 3 in each dose level cohort. No dose-limiting toxicity was observed and a maximum tolerated dose was not reached. The highest administered dose of 24 mg/kg weekly generated Cmin above the predetermined target concentration corresponding to Cave resulting in 90% preclinical tumor growth inhibition. U3-1565 was safe and well tolerated with related AE consisting of infrequent and non-dose-related G2 (fatigue, anemia, and appetite loss, seen in 20, 13, and 7% of cases, respectively) and G1 toxicities. No anti-U3-1565 antibody was detected. U3-1565 showed bi-exponential disposition with Cmax and AUC increasing proportional to the dose across all dosing regimens. 13 patients discontinued the study, 12 due to progressive disease and 1 due to non-drug-related AE. After 6 months on study, 2 patients entered study extension phase: A 77 year-old female with NSCLC given 24 mg/kg every two weeks, showed SD (best SLD change -3%) for 26 weeks before progression; and a 76 year-old female with CRC given 24 mg/kg weekly, showed PR (best SLD change -35%) and remains on treatment after 71 weeks. Conclusions: U3-1565 is safe and well tolerated up to 24 mg/kg weekly. Anti-tumor activity was observed and is being further explored in an open-label, dose-expansion study. Clinical trial information: NCT0129041.

Dose escalation and expansion cohort study for DS-8895a in patients with advanced solid tumors.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Taroh Satoh ◽  
Kohei Shitara ◽  
Satoru Iwasa ◽  
Kensei Yamaguchi ◽  
Kei Muro ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Japanese Patients ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Igg1 Monoclonal Antibody ◽  
Grade 3 ◽  
Expansion Cohort

99 Background: Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface of many tumors and is associated with poor prognosis, suggesting EPHA2 as a target for cancer therapy. DS-8895a is an afucosylated, humanized anti-EPHA2 IgG1 monoclonal antibody with potent cytotoxicity. We report results from a phase I clinical trial to determine safety, tolerability, and pharmacokinetics (PK) of DS-8895a in Japanese patients with advanced solid tumors (NCT02004717). Methods: Step 1 (dose escalation cohort) had patients with advanced solid tumors and comprised of six dose levels (0.1–20 mg/mL, intravenous infusion, every 2 weeks [Q2W]) with a 28-day dose limiting toxicity (DLT) evaluation period. Step 2 (expansion cohort) patients had gastric or esophageal cancer confirmed to be EPHA2 positive by immunohistochemistry. Dose level in Step 2 was determined based on results obtained in Step 1. We evaluated safety, PK, potential biomarkers including circulating NK cells and cytokines, and tumor response. Results: Maximum tolerated dose was not reached in Step 1 (n = 22). DS-8895a was administered at 20 mg/kg Q2W in Step 2 (n = 15). Among 37 patients in the safety analysis set, adverse events (AEs) were reported in 97.3% (64.9% drug-related); 35.1% presented grade ≥ 3 AEs (8.1% drug-related). Dose delay and study discontinuation due to AEs (treatment related: grade 4 platelet decrease, hypoesthesia, hypotension, peripheral coldness, nausea, and vomiting) were observed in one and four patients (20 mg/kg), respectively. Infusion-related reactions occurred in 51.4% of patients resulting in 10 dose interruptions with one discontinuation. Serum inflammatory cytokines were transiently increased 4 h from the end of infusion drug administration. Serum DS-8895a maximum and trough concentrations increased dose-dependently. Biomarkers had no apparent relationship to best overall response. Seven patients in Step 1 achieved stable disease; in Step 2, six patients achieved stable disease and one patient achieved partial response. Conclusions: DS-8895a was safe and well tolerated up to 20 mg/kg. The PK of DS-8895a was dose-dependent as expected. Clinical trial information: NCT02004717.

Preliminary safety and pharmacodynamic (PD) activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in a phase I dose escalation study of patients with selected advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15001-e15001
Author(s):  
Barbara Hickingbottom ◽  
Raphael Clynes ◽  
John Desjarlais ◽  
Caiyan Li ◽  
Ying Ding
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Clinical Symptoms ◽  
Standard Of Care ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Label Dose ◽  
Pretreated Patients

e15001 Background: Interim safety and PD data from an ongoing first-in-human, multi-center, open-label dose escalation study of XmAb20717 (XmAb20717-01; NCT03517488) are reported here. The primary objectives were to determine safety, tolerability, and the MTD and/or recommended doses (RDs). Secondary objectives included preliminary anti-tumor activity and PK/PD. Methods: A 3+3 dose escalation design was used to establish an MTD/RD(s) for infusions on Days 1 and 15 of each 28-day cycle. DLT evaluation was based on Cycle 1 through Day 28. Patients with selected solid tumors (in indications both with and without approved checkpoint therapy) who have exhausted standard of care are eligible. Results: As of 05FEB 2020, 34 patients were treated in cohorts 1-6 at fixed doses of 0.15 to 10 mg/kg. Patients had a median age of 57 years (range 32-81), a median time since initial diagnosis of 42 months (range 3 -313), and a median of 4 prior systemic therapies (range 0-9). 68% of patients had a TNM stage of III/IV, and 68% had been exposed to checkpoint therapy. XmAb20717 treatment was generally well tolerated through the highest dose cohort tested. Overall rates of Gr3/4 immune-related AEs occurred in 8 (24%) patients including elevations of transaminases 3 (9%), rash 2 (6%), lipase and amylase 1 (3%, without clinical symptoms or radiographic evidence of pancreatitis), lipase (alone) 1 (3%), pruritus 1 (3%), hyperglycaemia 1 (3%), arthritis 1 (3%) and colitis 1 (3%), all reversible. Responses were evaluated based on RECIST 1.1 criteria, and there was 1 CR reported (melanoma, progressed on prior pembrolizumab) at 10 mg/kg (highest dose level). Dose-dependent pharmacodynamic activity consistent with dual PD-1/CTLA-4 blockade was noted, namely a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Table). Conclusions: XmAb20717 is generally safe and has demonstrated PD activity in heavily pretreated patients with selected advanced solid tumors. Dose escalation continues. Clinical trial information: NCT03517488 . [Table: see text]

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