Neratinib + Valproate in Advanced Solid Tumors, w/Expansion Cohort in Ras-Mutated Ca

2019 ◽  
Author(s):  
Keyword(s):  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Expansion Cohort

265 Phase 1b study of avelumab + M9241 (NHS-IL12) in patients with advanced solid tumors: interim analysis results from a urothelial carcinoma (UC) dose-expansion cohort

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A291-A291
Author(s):  
Jean-Laurent Deville ◽  
Alain Ravaud ◽  
Marco Maruzzo ◽  
Theodore Gourdin ◽  
Michele Maio ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Interim Analysis ◽  
Maintenance Treatment ◽  
Advanced Solid Tumors ◽  
First Line ◽  
Platinum Based Chemotherapy ◽  
Phase 1B ◽  
Expansion Cohort

BackgroundAvelumab is an anti–PD-L1 monoclonal antibody approved for the treatment of advanced UC after disease progression during or following platinum-based chemotherapy and as maintenance treatment in patients whose disease has not progressed with first-line platinum-based chemotherapy.1–3 M9241 is an immunocytokine composed of 2 heterodimers of IL-12 fused to the heavy chains of a human antibody targeting DNA released from necrotic tumor cells.4 During dose-escalation, avelumab + M9241 was well tolerated and showed promising antitumor activity in patients with advanced solid tumors, including 2 objective responses in patients with UC.5 We report on an interim analysis of efficacy and safety from the dose-expansion part of JAVELIN IL-12 (NCT02994953).MethodsEligible patients had locally advanced or metastatic UC that had progressed on first-line therapy, were aged =18 years, had an Eastern Cooperative Oncology Group performance status of 0/1, and were immune checkpoint inhibitor naive. Patients received the recommended phase 2 dose5 of avelumab 800 mg intravenously once weekly (QW) in combination with M9241 16.8 µg/kg subcutaneously Q4W for the first 12 weeks, then continued the combination with avelumab Q2W. The primary endpoints were confirmed best overall response (BOR) per investigator assessment (RECIST 1.1) and safety. The expansion cohort followed a 2-stage design. During stage 1 (single-arm part of the study), 16 patients were enrolled and treated. A futility analysis based on BOR was planned to determine if stage 2 (randomized controlled part of the study) would be initiated.ResultsAt data cut-off (Jun 3, 2020), 16 patients had received avelumab + M9241 for a median duration of 8 weeks (range, 4.0–25.0 weeks). No complete or partial responses were observed; the study failed to meet the criterion (>2 responders) to initiate stage 2. Two patients (12.5%) had stable disease, 13 (81.3%) had progressive disease, and 1 (6.3%) was not evaluable. Any-grade treatment-related adverse events (TRAEs) occurred in 15 patients (93.8%); the most common (in =4 patients) were pyrexia (50.0%), nausea (37.5%), asthenia (31.3%), anemia (25.0%), and hyperthermia (25.0%); grade 4 gamma-glutamyltransferase increased occurred in 1 patient (6.3%). No TRAEs led to death. Pharmacodynamic effects on the peripheral immune system and results of pharmacokinetic and biomarker analyses will also be reported.ConclusionsThe predefined efficacy criterion to proceed to stage 2 was not met. The combination was well tolerated; no new safety signals emerged and the profile was consistent with the dose-escalation part of the study.5Trial RegistrationNCT02994953Ethics ApprovalThe study was approved by each site’s independent ethics committee.ConsentN/AReferencesBavencio(avelumab) injection [package insert]. Rockland, MA: EMD Serono, Inc; New York, NY: Pfizer Inc; 2020.Health Canada. https://www.canada.ca/en/health-canada.html. Accessed July 31, 2020.US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed July 31, 2020.Fallon J, Tighe R, Kradjian G, et al. The immunocytokine NHS-IL12 as a potential cancer therapeutic. Oncotarget. 2014;5:1869–1884.Strauss J, Vugmeyster Y, Sznol M, et al. Phase 1b, open-label, dose escalation study of M9241 (NHS-IL12) plus avelumab in patients (pts) with advanced solid tumours. Ann Oncol. 2019;30(5 Suppl):Abstract 4062.

A pharmacokinetic (PK) and safety study of sorafenib plus capecitabine in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14548-e14548
Author(s):  
C. E. McKay ◽  
J. Infante ◽  
S. Jones ◽  
J. Bendell ◽  
F. A. Greco ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Advanced Solid Tumors ◽  
Safety Study ◽  
Adequate Organ Function ◽  
Expansion Cohort ◽  
Dose Modifications ◽  
Tumor Types ◽  
Dose Reductions

e14548 Background: The addition of a multi-targeted kinase inhibitor such as sorafenib (S) to standard chemotherapy holds promise for improving therapeutic efficacy in multiple advanced solid tumors. This study is designed to evaluate the PK and overall safety of S in combination with capecitabine (C). Methods: Eligibility included patients (pts) with refractory solid tumors, 0–1 ECOG, adequate organ function, and no prior anti-VEGF tyrosine kinase inhibitors. This single institution study enrolled two simultaneous cohorts of 6 pts each followed by an expansion: Cohort A received S 400 mg bid for 21 days and C 750 mg/m2 bid for 14 days of a 21-day cycle. Cohort B received S 400 mg bid for 21 days and C 1,000 mg/m2 bid for 14 days of a 21-day cycle. Intensive PK collections (pre, 30 min, 1, 2, 4, 6, 8, and 12 hr) were obtained following a week of exposure to S alone, C alone (both C and 5FU levels measured), and both S and C in combination. Results: 17 pts dosed since 2/1/08: median age 66 years (range 36–87); ECOG 0 14(82%); and white 15(88%). Tumor types include colon (4), pancreas (2), prostate (2), and other (11). No treatment-related deaths occurred. Target toxicities are outlined in table below. Despite early and aggressive clinical management, hand foot skin reaction (HFS) necessitated dose reductions in 1 pt in cohort A and 4 pts in cohort B. In total, only 1(14%) pt in cohort A required a dose reduction, as opposed to 5(63%) pts in cohort B. The median # of cycles was 2 (range 1–10), and 5 pts (29%) remain on study. Of the 13 pts evaluable for response, 8 (47%) had stable disease following first restaging scans. PK samples are being analyzed to compare Cohort A vs. B. Conclusions: The results of this trial will help guide future trials of S plus C. The 1,000 mg/m2 bid dose of C in combination with full dose S required frequent dose modifications in our pt population secondary to overlapping toxicity (primarily HFS). Alternate schedules should be considered. PK analysis will be presented. [Table: see text] [Table: see text]

A phase I dose-escalation study of TKM-080301, a RNAi therapeutic directed against polo-like kinase 1 (PLK1), in patients with advanced solid tumors: Expansion cohort evaluation of biopsy samples for evidence of pharmacodynamic effects of PLK1 inhibition.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS2621-TPS2621 ◽  
Author(s):  
Donald W. Northfelt ◽  
Solomon I. Hamburg ◽  
Mitesh J. Borad ◽  
Mahesh Seetharam ◽  
Kelly Kevelin Curtis ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Primary Study ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Pharmacodynamic Effects ◽  
Expansion Cohort ◽  
Anti Tumor Activity

TPS2621 Background: TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1, a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis. Anti-tumor activity, RNA interference and pharmacodynamic effects of PLK1 inhibition have been conclusively demonstrated in preclinical models. Demonstration of pharmacodynamic effects of PLK1 inhibition in patient biopsy samples is an exploratory objective of this first-in-human study. Methods: TKME080301 is being evaluated in an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKME080301 as a 30-minute intravenous infusion on Days 1, 8 and 15 of a 28-day cycle. Treatment can continue until disease progression, based on overall clinical benefit. Tumor response is determined according to RECIST criteria. Primary study objectives include determination of safety, maximum tolerated dose and dose limiting toxicities. Secondary objectives include characterization of pharmacokinetics and the preliminary assessment of anti-tumor activity. Five cohorts have been enrolled and a tentative Phase 2 dose has been identified. An expansion cohort of 10 patients began enrolling in February, 2013. The focus of the expansion cohort will be to collect additional safety and pharmacokinetic data at the tentative Phase 2 dose, as well as pharmacodynamic data from mandatory biopsy samples. Pre- and post-dose biopsy samples will be evaluated for potential evidence of PLK1 inhibition using 5’ RACE (rapid amplification of cDNA ends) polymerase chain reaction (to identify the predicted PLK1 mRNA cleavage product), histology (to assess for the presence of aberrant mitotic figures) and immunohistochemistry. An update on enrollment and pharmacodynamic evaluations will be presented. Clinical trial information: NCT01262235.

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.

A phase I study of HM781-36B, a novel pan-HER inhibitor, in patients (pts) with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3076-3076 ◽  
Author(s):  
Tae Min Kim ◽  
Keun-Wook Lee ◽  
Do-Youn Oh ◽  
Jong-Seok Lee ◽  
Seock-Ah Im ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Advanced Solid Tumors ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Expansion Cohort ◽  
Positive Breast Cancer

3076 Background: HM781-36B is a pan-HER tyrosine kinase inhibitor, which showed a potent activity against the gefitinib- or erlotinib-resistant, EGFR L858R/T790M double mutant cells. A phase I study was conducted to determine the MTD, pharmacokinetics, and antitumor activity. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation part, and additional 12 pts were enrolled in the expansion cohort of molecular enrichment. Results: In dose-escalation part, 43 pts (median age: 55 yrs (range 25-82), M:F=25:18, ECOG PS 0/1/2/3: 23/17/2/1, median prior chemotherapy: 4) were treated. DLTs were G3 diarrheas in 5 pts, one at 12 mg, 16 mg, 24 mg, and two at 32 mg. The MTD was determined as 24mg. The most common drug-related adverse events were diarrhea, stomatitis, rash, pruritus, and anorexia. Among 41 evaluable pts, 4 pts achieved PR (1 unconfirmed, duration of response: 11.9 mo, 7.07 mo+, 4.5 mo+), and 19 pts had SD. Two of 4 PR pts were Her2-positive breast cancer pts. The median duration of treatment in pts with PR or SD was 3.87 (2.47- 15.17) months. In the dose range of 0.5 to 24 mg, it showed linear pharmacokinetics proportional to dose-escalation, relatively short half-life, and little accumulation. Additional 12 pts in the expansion cohort are under treatment at 24 mg (6 pts: EGFR-mutant NSCLC, 3 pts: Her2-positive gastric cancer, 2 pts: Her2-positive breast cancer, 1 pt: rectal cancer). Conclusions: HM781-36B was safe and well tolerable in advanced solid tumors. Preliminary evidence of anticancer activity has been observed. Updated data will be presented at the meeting.

Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11036-11036
Author(s):  
John H. Strickler ◽  
Shannon McCall ◽  
Andrew B. Nixon ◽  
Herbert Pang ◽  
Christel Rushing ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Exact Test ◽  
Src Activation ◽  
Expansion Cohort

11036 Background: Src inhibition may augment sensitivity to chemotherapy, but in unselected patients (pts) with advanced solid tumors, src inhibitors have shown limited clinical activity. Biomarkers to predict benefit from src inhibitors in advanced solid tumors are not yet known. Methods: 22 pts (dose escalation cohort= 12 pts; colorectal cancer [CRC] expansion cohort= 10 pts) were enrolled in a phase I study to determine the safety and tolerability of the src inhibitor dasatinib with capecitabine, oxaliplatin, and bevacizumab (J Clin Oncol 29: 2011 [suppl; abstr 3586]). Src activation (src-a) was assessed in tumors from 16 evaluable pts. Src-a was measured by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tumor samples using an antibody that selectively recognizes the active conformation of src (clone 28). A GI pathologist who was blinded to pt outcomes graded membranous src-a using a standard semi-quantitative method. The endpoint of this exploratory analysis was objective response rate ([ORR]= PR+CR). 2-sided Fisher’s Exact test was used to evaluate the association between ORR and src-a. Results: Across all tumor types, 8 tumors had no/faint src-a (IHC=0/1); 8 tumors had moderate/strong src-a (IHC≥2). Benign colonic epithelium had no src-a (IHC=0). The ORR was 75% (6/8) for pts with moderate/strong src-a versus (vs) 0% (0/8) for pts with no/faint src-a (p =0.007). In the CRC expansion cohort, the ORR was 83% (5/6) for patients with moderate/strong src-a vs 0% (0/2) for pts with no/faint src-a (p=0.107); progression free survival range was 7.9-24.4 months for pts with moderate/strong src-a. Conclusions: In this small phase I study, src-a is associated with benefit from the combination of dasatinib and oxaliplatin-based chemotherapy. Further evaluation of dasatinib in patients whose tumors demonstrate high levels of src-a may be warranted. Clinical trial information: NCT00920868.

Phase I expansion cohort trial to investigate the safety and clinical activity of avelumab (MSB0010718C) in patients with metastatic or locally advanced solid tumors.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. TPS3101-TPS3101
Author(s):  
Christopher Ryan Heery ◽  
Jeffrey R. Infante ◽  
Nicholas Iannotti ◽  
Karen Kelly ◽  
Petros Nikolinakos ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Expansion Cohort

scholarly journals Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC)

2017 ◽  
Vol 23 (14) ◽  
pp. 3529-3536 ◽  
Author(s):  
Stacy L. Moulder ◽  
Virginia F. Borges ◽  
Tara Baetz ◽  
Tessa Mcspadden ◽  
Gina Fernetich ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Advanced Solid Tumors ◽  
Expansion Cohort

Final results of a dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of two schedules of OSI-930 in patients (pts) with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
S. George ◽  
R. Lal ◽  
D. R. Camidge ◽  
H. Arkenau ◽  
J. Chick ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Tumor Regression ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dce Mri ◽  
Glycolytic Activity ◽  
Heavily Pretreated ◽  
Xenograft Models ◽  
Expansion Cohort

3564 Background: OSI-930 is an oral TKI with potent activity against Kit, VEGFR2, and PDGFR. Preclinical studies demonstrate tumor regression with long-term remissions across multiple xenograft models. Methods: Sequential cohorts of pts with advanced solid tumors received continuous daily OSI-930 to determine the maximum tolerated dose (MTD) and to evaluate safety, PK/PD and efficacy of OSI-930 with both QD and BID dosing. An expansion cohort was enrolled for detailed PD analysis including sVEGFR2 plasma levels, PET imaging in GIST pts or DCE-MRI in selected pts. Results: A total of 58 pts were treated (20M/38F; median 60 years (range 19–83)). OSI-930 was dosed up to 1600 mg QD without reaching MTD. 46 pts received BID dosing [mg(# pts treated)]; 400(7), 500 (31) and 600(8). DLT's were seen in 3/8 pts at 600 mg BID; G3 rash (2 pts) and G4 GGT; and 3/31 at 500 mg BID; G3 myalgia, G3 fatigue and G3 lipase. G3 hypertension was noted in 3/46 pts but not dose-limiting. Common G1/2 toxicities were fatigue (37%), diarrhea (27%), nausea (31%), and rash (24%). Objective (CA125) responses were seen in platinum-resistant ovarian cancer (2 PR/8) while in heavily pretreated GIST (median 4 prior therapies including imatinib/sunitinib), 8/18 pts achieved SD ≥12 w. Median therapy duration in the BID arm was 9 w and 18/46 pts with SD ≥12 w. PK indicated that Css were achieved after ∼7d with BID dosing. PET scans showed reduction in glycolytic activity in 4/9 pts and DCE-MRI response was seen in 4/6 pts. A trend in decreased sVEGFR levels was seen at higher doses. Conclusions: At the MTD level of 500 mg BID OSI-930 is an active, well-tolerated compound with clinically relevant antitumor activity and exposure levels consistent with antitumor activity in preclinical models. PD data indicate mechanistic proof of concept for OSI-930. OSI-930/erlotinib combination phase I study is currently enrolling. [Table: see text]

Phase I safety and tolerability of once daily oral afatinib (A) in combination with docetaxel (D) in patients (pts) with relapsed or refractory advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13010-e13010
Author(s):  
Helene Senellart ◽  
Jaafar Bennouna ◽  
Nicolas Isambert ◽  
Helene De-Montserrat ◽  
Patrick J. Squiban ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Dose Range ◽  
Safety Data ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Once Daily ◽  
Expansion Cohort ◽  
Initial Starting

e13010 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability, and PK of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part B are presented here. Methods: Eligible pts (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once daily, oral dosing of A in combination with D, given iv on Day 1 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3+3 design. Initial starting dose level was A 30 mg/day and D 60 mg /m², escalating up to A 50 mg/day and D 75 mg/m² until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 21 pts have been treated with A (30–50 mg/day) and D (60–75 mg/m2), with baseline characteristics: mean age (55.4 years), women (42.9%) and number of prior chemotherapies (≤2: 57%; >2: 43%). Fourteen pts received 2–4 cycles of treatment and five patients received 4 or more cycles. In Cycle 1, DLT was experienced by one out of six pts receiving 30 mg afatinib + 60 mg/m² docetaxel (Grade 3 diarrhea). No DLT was observed during the subsequent dose levels up to A 50 mg/day and D 75 mg/m². AEs observed in most pts were diarrhea (76.2%) and asthenia (66.7%). Conclusions: In pts with relapsed or refractory advanced solid tumors, the combination of A and D is well tolerated. AEs were manageable and the MTD was not reached in the tested dose range up to A 50 mg/day and D 75 mg/m². Considering the potential for diarrhea and rash during later cycles, the recommended dose for the expansion cohort was A 40 mg/day in combination with D 75 mg/m². Enrollment is ongoing (nine pts to date) and additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation.

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