Abstract 1686: A Phase 1 dose escalation study to establish the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) parameters of hydroxychloroquine (HCQ) in combination with vorinostat (V) in patients with advanced solid tumors - final results.

2013 ◽  
Author(s):  
Monica M. Mita ◽  
Devalingam Mahalingam ◽  
John Sarantopoulos ◽  
Ravi Amaravadi ◽  
Alain Mita ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

A phase I dose-escalation and immune biomarker study of intravenous FF-10832, liposomal gemcitabine, in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3163-TPS3163
Author(s):  
Erkut Hasan Borazanci ◽  
Gerald Steven Falchook ◽  
Atif Abbas ◽  
Catherine A. Wheeler ◽  
Gary Maier ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Suppressor Cell ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Normal Tissues ◽  
Mri Scans ◽  
Pre Treatment

TPS3163 Background: FF-10832 (832) is a liposomal formulation of gemcitabine (GEM) that demonstrates a prolonged half-life and preferential uptake in tumor vs normal tissues and marrow in pre-clinical models. Macrophage uptake has been shown in the tumor microenvironment (TME), with subsequent GEM release in tumor cells. This relative selectivity and anti-tumor immunological changes observed in the TME may lead to decreased toxicity and increased efficacy compared to GEM. Ferumoxytol (FMX) may be a surrogate for nanoparticle penetration into tissue and is being examined as a potential correlate for activity. Methods: This ongoing Phase 1, 3+3 dose-escalation study of 832 will determine the safety profile, maximum tolerated dose, dose-limiting toxicities (DLT) and recommended Phase 2 dose, and will be followed by expansion. Enrollment of up to 60 patients (pts) with advanced solid tumors is planned. Pre-treatment (tx) FMX MRI scans are performed, followed by 832 administration on Days 1 &15 of each 28-day cycle until disease progression or unacceptable toxicity. In addition to standard biomarker and imaging evaluations, change in macrophage polarity, myeloid-derived suppressor cell (MDSC) and regulatory T cell populations are being investigatedin peripheral blood and tumor tissue. Clinical trial information: NCT03440450.

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 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumors.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 2574-2574
Author(s):  
Jordan Berlin ◽  
Ramesh K. Ramanathan ◽  
John H. Strickler ◽  
Deepa Suresh Subramaniam ◽  
Herbert Hurwitz ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

Phase I trial of chloroquine (CQ)/hydroxychloroquine (HCQ) in combination with carboplatin-gemcitabine (CG) in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3027-3027 ◽  
Author(s):  
Nagla Fawzy Abdel Karim ◽  
Imran Ahmad ◽  
Ola Gaber ◽  
Ihab Eldessouki ◽  
Olugbenga Olanrele Olowokure ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Early Stage ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Late Phase ◽  
Survival Rates ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Grade 3

3027 Background: Autophagy is a catabolic process triggered in cells during periods of stress to enable their survival. Established tumors utilize autophagy to survive periods of metabolic or hypoxic stress. Inhibition of early stage autophagy can rescue cancer cells, while inhibition of late stage autophagy will lead to cell death due to accumulation of damaged organelles. The antimalarial drugs CQ and HCQ inhibit late phase autophagy. The goal of our study is to assess the safety, tolerability and activity of combining CQ/HCQ with CG in advanced solid tumor patients who either progressed on other therapies or in whom CG is a therapeutic option. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ, later substituted with HCQ, in combination with CG in patients with previously treated advanced solid tumors. Secondary objectives were to determine ORR, PFS and OS. A starting dose of 50 mg of CQ/HCQ was used in conjunction with CG, and increased in increments of 50 mg in each dose cohort. Grade 3 or greater toxicity that is treatment-related, and was not self-limited, or controlled in less than 7 days was considered dose limiting toxicity (DLT). Results: Twenty-three patients were enrolled with a median follow up of 6 months. HCQ 100 mg was found to be the MTD in combination with CG with ≥Grade 3 thrombocytopenia and/or neutropenia as dose-limiting. Median OS was 11 months, and the 1- and 3- year overall survival rates were 30% and 7%, respectively. Median progression free survival was 5 months and the 6-, 12-, and 18-months progression-free survivals were 48%, 21% and 14%, respectively (Table). Conclusions: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537. [Table: see text]

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