Glufosfamide (GLU) plus gemcitabine (GEM) in advanced solid tumors: Phase 1 results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14022-14022
Author(s):  
E. G. Chiorean ◽  
T. Dragovich ◽  
J. T. Hamm ◽  
V. K. Langmuir ◽  
S. Kroll ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Karnofsky Performance Status ◽  
Phase 1 ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Heavily Pretreated ◽  
Isophosphoramide Mustard ◽  
Grade 3 ◽  
Tumor Types

14022 Background: Glufosfamide is glucose linked to isophosphoramide mustard, the active metabolite of ifosfamide. Cancer cells use glucose at a higher rate than normal cells, which may lead to preferential metabolic targeting by GLU. GLU has shown activity in patients (pts) with pancreatic cancer in Phase 1/2 studies with the dose-limiting toxicities (DLT) being nephrotoxicity and neutropenia. The MTD was 4500 mg/m2. In preclinical studies, GLU has shown additive activity when combined with GEM. The objectives of this study are to establish the maximum tolerated dose (MTD) and to evaluate the safety, efficacy and PK of GLU + GEM in advanced solid tumors. Methods: Eligible pts had Karnofsky Performance Status ≥70, no prior GEM, at least one lesion by RECIST, creatinine clearance (CrCL) ≥60 mL/min and acceptable hematologic and liver function. Cohorts of 3–6 patients were treated with GLU 1500–4500 mg/m2 IV over 4 hours on Day 1 and GEM 1000 mg/m2 IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle for up to 6 cycles. CT scans were obtained every 8 weeks. Detailed PK sampling was performed. Results: Nineteen pts with pancreatic (8), gall bladder (4) and other (7) cancers were enrolled. Two DLTs have occurred: Grade 3 fatigue at 2500 mg/m2 and Grade 4 thrombocytopenia at 4500 mg/m2. Both cohorts were expanded. No DLTs occurred in the 1500 or 3500 mg/m2 cohorts. Three pts completed all 6 cycles and 3 pts continue on study. Reasons for early discontinuation were progressive disease (10), clinical deterioration (1), AE (1) and death (1). Grade 3/4 neutropenia occurred in 7 pts (5 during Cycle 1) and Grade 3/4 thrombocytopenia in 5 pts (2 during Cycle 1). The CrCL fell below 60 mL/min in one patient. No objective tumor responses have been reported; 10 of 18 (56%) evaluable pts had stable disease (SD) at 8 weeks, including 1 pt with heavily pretreated ovarian cancer with ongoing SD after 8 months on therapy. PK analyses suggest no interaction between GLU and GEM. Conclusions: Phase 1 data indicate that full dose GLU (4500 mg/m2) can be given safely in combination with GEM. Both early and delayed Grade 3/4 thrombocytopenia and neutropenia have been observed. A Phase 2 cohort of 28 pts with pancreatic adenocarcinoma is currently enrolling. Studies with GEM/GLU in other tumor types are planned. [Table: see text]

Safety, pharmacokinetics, and antitumor activity of MEDI3617, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2621-TPS2621
Author(s):  
Ronald B. Natale ◽  
Naiyer A. Rizvi ◽  
Jeffrey R. Infante ◽  
Lindsay J. Joseph ◽  
Jaye Viner ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Neutralizing Antibodies ◽  
Karnofsky Performance Status ◽  
Phase 1 ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Tie2 Receptor ◽  
Angiopoietin 2

TPS2621 Background: MEDI3617 is an investigational monoclonal antibody that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 (Ang2) ligands with the Tie2 receptor. Methods: This is an ongoing phase 1 dose-escalation and dose-expansion study in patients with advanced solid tumors, Karnofsky performance status ≥70, and adequate organ function. Patients were treated with escalating IV doses of MEDI3617 on day 1 of each 21 day cycle in cohorts of 3-6 patients. The objectives are to evaluate the safety profile and determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and clinical activity of MEDI3617. Results: Preliminary data are presented for 21 patients (14M/7F), median age 65 yrs, evaluable for DLT. One DLT occurred: grade 4 neutropenia lasting more than 7 days. The most frequently reported drug-related adverse events (% of patients) were fatigue (24%), diarrhea (19%), nausea (19%), dysgeusia (14%), and headache (14%), all of which were ≤ grade 2. All monotherapy dose levels have completely enrolled patients without exceeding the maximum tolerated dose. The exposure of MEDI3617 after the first dose showed a more than dose-proportional increase. Suppression of free Ang2 was dose-dependent. Maximum accumulation of total Ang2 was observed at the lowest administered dose. No anti-MEDI3617 neutralizing antibodies were detected. Of the 21 patients, 4 continue on treatment (maximum of 6+ months in a patient with carcinoid tumor of the jejunum) as of the data cut-off date. Of the 17 patients for whom response data are available, 5 had stabilization of disease of 12 weeks or greater. Conclusions: Preliminary safety and activity signals warrant continued evaluation of MEDI3617. This study was funded by MedImmune, LLC.

A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2026-2026 ◽  
Author(s):  
E. I. Heath ◽  
A. Alousi ◽  
J. P. Eder ◽  
M. Valdivieso ◽  
L. S. Vasist ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Minor Response ◽  
Level 3 ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

2026 Background: Ispinesib, a novel cytotoxic agent inhibiting the kinesin spindle protein (KSP) has demonstrated significant antitumor activity in multiple murine tumor models. The primary objectives of the study were to assess the safety and tolerability of SB-715992, to determine the dose limiting toxicity (DLT), and the maximum tolerated dose (MTD). Methods: Ispinesib was administered days 1–3 intravenously over 1 hour every 21 days, starting at a dose of 1 mg/m2/day. Traditional 3-patient cohort trial design was utilized with dose levels of 2, 4, 6, 8 mg/m2/day. Results: Twenty-seven patients (24 Caucasians, 3 African-Americans, 16 males, 11 females) with various tumor types were enrolled; colorectal (7), renal (5), bladder (2), lung (2), pharynx (2), pancreas (2), others (7). Grade 3/4 toxicities were noted starting at the 4 mg/m2 dose level with two patients developing grade 4 neutropenia; one for < 5 days, one for > 5 days (with grade 3 leukopenia). At the 6 mg/m2 dose level, grade 3 neutropenia and leukopenia were reported. At the 8 mg/m2 dose level, 3 of 3 patients had grade 4 neutropenia and leukopenia. The 6 mg/m2 dose level was declared the MTD. Toxicities seen in the additional 6 patients included grade 1 fatigue (1/6), grade 1 infusion- related flushing (1/6), grade 3 febrile neutropenia (1/6), and grade 4 neutropenia and leukopenia (1/6). The MTD cohort has been expanded to 10 evaluable patients for confirmation of tolerability and pharmacodynamic endpoints including phosphohistone 3 (PH3), cyclin E, and TUNEL assay on serial tumor biopsies. Preliminary pharmacokinetic data appear linear, but not dose proportional. As predicted, between days 1 and 3, accumulation ranged from 40 to 106%. Exposures appear comparable between cycles 1 and 2. Stable disease in 2 patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. Conclusions: Treatment with ispinesib at the MTD of 6 mg/m2/day x 3 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.

A phase 1/2 study of intermittent, high dose sunitinib in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2591-2591
Author(s):  
Maria Rovithi ◽  
Mariette Labots ◽  
Richard Honeywell ◽  
Albert J. Ten Tije ◽  
Rita Ruijter ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Population Expansion ◽  
Maximum Tolerated Dose ◽  
Blood Levels ◽  
High Dose ◽  
Advanced Solid Tumors ◽  
Treatment Benefit ◽  
Flat Dose ◽  
Heavily Pretreated

2591 Background: Despite widespread clinical integration, refinement of treatment with sunitinib is actively pursued. Sub-therapeutic blood levels rather than true resistance and tumor adaptation through drug accumulation have been accounted as reasons for treatment failure. Based on our preclinical data with high dose sunitinib and prospective analyses supporting the concept of intermittent dosing, we designed a phase 1 trial to investigate the feasibility and tolerability of high dose, once weekly (1w) or once every two weeks (2w) sunitinib (NCT02058901). Methods: Eligible were patients (pts) with advanced solid tumors, refractory to standard treatment, measurable disease, WHO ≤ 1. Sunitinib was administered orally 1w or 2w. Starting dose was 200 mg, with cohorts escalating in 100 mg steps until maximum tolerated dose (MTD). Response was evaluated by RECIST 1.1. Treatment continued until progression or unacceptable toxicity. Dedicated PK sampling was performed. Sunitinib plasma concentration was measured by LC-MS. Results: 34 (w) and 24 (2w) pts were included, predominantly with mCRC [56% (1w) and 55% (2w)]. MTD was set at 300 mg (1w) and 700 mg (2w). Most common adverse events were fatigue (79%, one pt with G3), nausea (71%, all G1-2), anorexia (29%, all G1-2). Median PFS of evaluable pts was 2.7 mo (1w) and 2.6 mo (2w), while 39% pts (1w) and 25% pts (2w) had PFS > 5 mo. CT scans in pts with treatment benefit showed extensive tumor necrosis. Mean sunitinib plasma Cmax was 190 [300 mg (1w), range: 185-295] and 476 ng/mL [(700 mg (2w), range: 323-580]. Accumulation was minimal. Conclusions: Once weekly or once every two weeks, high dose sunitinib is feasible and clinically efficacious in heavily pretreated pts with advanced solid tumors, while toxicity remains well manageable. Importantly, no accumulation was recorded and sunitinib exposure was significantly increased, compared to the universal, flat dose. Since increased sunitinib exposure has been correlated to improved outcome, we consider this alternative scheduling as promising strategy to produce enduring clinical benefit in a wider patient population. Expansion cohorts are ongoing. Clinical trial information: NCT02058901.

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]

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.

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 .

Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4074-4074 ◽  
Author(s):  
Jean-Charles Soria ◽  
John H. Strickler ◽  
Ramaswamy Govindan ◽  
Seungjean Chai ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Grade 3

4074 Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3099-3099
Author(s):  
Jin Li ◽  
Nong Xu ◽  
Tianshu Liu ◽  
Jianjin Huang ◽  
Yongmei Yin ◽  
...  
Keyword(s):  
Disease Control ◽  
Solid Tumors ◽  
Immune Cell ◽  
Target Lesion ◽  
Advanced Solid Tumors ◽  
Cell Functions ◽  
Potential Clinical Benefit ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

3099 Background: Phosphatidylinositol-3 kinase (PI3K) pathways are important elements of tumor survival and progression, and PIK3C genes are often mutated or overexpressed in many cancers. Additionally, PIK3D (PI3Kδ) modulates immune cell functions in tumors, elaborating another PI3Kδ inhibition feature with a potential clinical benefit. Linperlisib, an oral and highly selective PI3Kδ inhibitor, demonstrated potent anti-tumor activity in syngeneic animals from previous research. In this Phase 1b study, the safety, tolerability, and efficacy of linperlisib is under investigation for patients with advanced solid tumors. Methods: Linperlisib was given orally once daily (QD) in 28-day cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was assessed according to RECIST1.1 criteria. Results: As of December 28, 2020, 70 patients were enrolled in the Phase1b study, with advanced cancers, including colorectal (n = 22), breast (n = 8), lung (n = 8), kidney (n = 5), liver (n = 4), ovarian (n = 1), head and neck (n = 5), and esophageal (n = 1) cancers; sarcomas, (n = 4), small intestinal stromal tumor (n = 3), thymic (n = 2), gallbladder (n = 2), gastric (n = 4), and pancreatic (n = 1) carcinomas. The patients were heavily pretreated with an average of 4 previous lines of therapy. Among the 70 patients, the most common nonhematologic TEAEs (all grades/grade≥3) were proteinuria (37.14%/0%), elevated aspartate aminotransferase (20%/0%), nausea (20%/0%), oral mucositis (2.8%/2.8%), diarrhea (2.8%/2.8%). The most common hematological TEAEs were leukopenia (24.28%/0%) and neutropenia (17.14%/4.28%). There were no unexpected toxicities in this study. Of 42 patients evaluable for response, the overall response rate was 2.38%. Notably, the disease control rate (DCR) was 45.24% from monotherapy treatment. One patient with thymic carcinoma obtained a partial response (80.8% reduction of the target lesion), with a duration of response of more than 6 cycles. The treatment of this subject is continuing. A lung adenocarcinoma subject reached radiological stable disease associated with 13.7% reduction in the target lesion and disease control for approximately 6 months. Conclusions: In this study, the PI3K inhibitor, linperlisib exhibited a favorable safety profile as was previously seen in lymphoma patients. Monotherapy treatment with linperlisib was observed to impart a high DCR in advanced solid cancers of many types. Available data from linperlisib and other PI3K inhibitors suggests that linperlisib may limit tumor growth directly, but also by affecting the tumor immune microenvironment. With these promising indications of clinical tolerability and activity, further investigation of linperlisib alone or in key therapeutic combinations is warranted. Clinical trial information: NCT04049929.

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2631-2631
Author(s):  
Sekwon Jang ◽  
John D. Powderly ◽  
Alexander I. Spira ◽  
Ouiam Bakkacha ◽  
Deryk Loo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Multiple Tumor ◽  
Melanoma Patients ◽  
Tumor Types

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.

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