Phase I study on preliminary safety and efficacy of rovalpituzumab tesirine in Japanese patients (pts) with advanced, recurrent small cell lung cancer (SCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8557-8557
Author(s):  
Hiroaki Akamatsu ◽  
Hibiki Udagawa ◽  
Kentaro Tanaka ◽  
Masayuki Takeda ◽  
Shintaro Kanda ◽  
...  
Keyword(s):  
Phase 1 ◽  
Study Drug ◽  
Standard Of Care ◽  
Japanese Patients ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Dose Escalation Study ◽  
Open Label Phase ◽  
Reported Study ◽  
Third Line

8557 Background: SCLC rapidly recurs after first-line platinum therapy, and while several agents are approved in the relapsed/refractory setting, there is no approved agent or existing standard of care for third-line in Japan. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting Delta-like 3 protein (DLL3), an atypical Notch ligand that is highly expressed in SCLC but not in normal tissue. This was the first study evaluating safety, PK, and preliminary anti-tumor activity of Rova-T in Japanese pts. Methods: This was an open label Phase 1, 3+3 dose-escalation study of Rova-T in Japanese pts with advanced recurrent SCLC (NCT03086239). Eligibility: progressive disease after ≥2 prior systemic regimens incl. ≥1 platinum-based regimen; ECOG 0-1. Pts received 0.2 or 0.3 mg/kg Rova-T IV on Day 1 of a 6-week cycle for 2 cycles. Objective was to evaluate safety, tolerability, PK, and preliminary efficacy and expression of DLL3. Antitumor activity was measured by RECISTv1.1, and DOR, PFS, OS were evaluated. Results: 29 pts were treated with Rova-T (6 at 0.2mg/kg, 23 at 0.3 mg/kg). Median age 68 yrs; 76% male; 64% DLL3 high (≥75% expression); 86% DLL3 positive (≥25%). 20 pts (69%) had received ≥3 prior lines of therapy. Similar PK and AEs were seen compared to previous studies in non-Japanese pts. The most frequently reported study drug-related AEs were platelet count decreased, pleural effusion, oedema peripheral, and aspartate aminotransferase increased, the majority Grade 1/2. No DLTs occurred, and both dose levels were tolerated. Three pts previously treated with ≥3 prior lines of therapy had confirmed partial response by investigator (10% of all pts; 17% of DLL3 high pts). For DLL3 high pts, mDOR was 3.0 mos (95% CI: 2.9, 4.1), mPFS was 2.9 mos (1.2-3.6), and mOS was 7.4 mos (4.1-11.9). Individual responses were analyzed in detail and radiographic data with tumor shrinkage will be shown. Conclusions: Rova-T demonstrated a manageable safety profile with promising preliminary efficacy in Japanese SCLC pts, in particular pts with DLL3 high expression. These data support further exploration of Rova-T treatment in Japanese pts with SCLC in global Phase 3 studies. Clinical trial information: NCT03086239.

Tyme-88-Panc Part 2: A randomized phase II/III of SM-88 with MPS as third-line in metastatic PDAC.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS789-TPS789
Author(s):  
Shubham Pant ◽  
Sant P. Chawla ◽  
Vincent Chung ◽  
Giuseppe Del Priore ◽  
Dae Won Kim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Open Label ◽  
Improved Outcomes ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Third Line ◽  
Improvement In Survival

TPS789 Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC’s) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician’s choice treatment as third line therapy for patients with metastatic PDAC. Methods: This is a multi-center Phase 3 study of patients ≥18 years with metastatic PDAC that progressed after 2 lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG <2. Randomization will be 1:1 with 250 patients being stratified by site, ECOG, and choice of chemotherapy. SM-88 will be administered at a dose of 460mg twice daily (920 mg/day). Primary end point is Overall Survival (OS). Secondary end points include progression free survival, response rate, duration of response, pharmacokinetics, safety and CTCs. Clinical trial information: NCT03512756.

scholarly journals Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: An open-label phase 1 study

2018 ◽  
Vol 109 (10) ◽  
pp. 3235-3244 ◽  
Author(s):  
Kensuke Usuki ◽  
Toru Sakura ◽  
Yukio Kobayashi ◽  
Toshihiro Miyamoto ◽  
Hiroatsu Iida ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Japanese Patients ◽  
Clinical Profile ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors

2012 ◽  
Vol 69 (6) ◽  
pp. 1477-1486 ◽  
Author(s):  
Hajime Asahina ◽  
Yosuke Tamura ◽  
Hiroshi Nokihara ◽  
Noboru Yamamoto ◽  
Yoshitaka Seki ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Japanese Patients ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1049-1049
Author(s):  
Yongheng Liu ◽  
Wei Lian ◽  
Xi Zhao ◽  
Wei Qi ◽  
Jian Xu ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Locally Advanced ◽  
Human Study ◽  
Study Drug ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Open Label ◽  
Best Response ◽  
Dose Levels

1049 Background: HER2 is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker. Methods: This was a single arm, open-label, multicenter, dose escalating Phase 1 first-in-human study of A166 as monotherapy in solid tumor patients. Dose escalation and MTD identification was directed using a Bayesian logistic regression model with overdose control. The following dose levels were evaluated in this study: 0.3, 1.2, 3.6, 4.8 mg/kg. (ClinicalTrials.gov NCT03602079) Results: As of November 1, 2019 35 pts have completed the DLT evaluation period across 4 dose levels. Overall, A166 had an acceptable toxicity profile with no unexpected toxicities related to the study drug. No adverse events recorded met the protocol specified definition of a dose limiting toxicity at any studied dose level. Most frequently (≥10%) occurring TEAEs include were Keratitis, Decreased appetite, Dry eye, Vision blurred etc. Overall incidence of ophthalmic toxicities in the 3.6 mg/kg cohort was 80% and in the 4.8 mg/kg cohort it was 83%. Among the 27 patients evaluable for efficacy, best response was progression of disease in 11 patients (41%), stable disease in 9 patients (33%) and partial response in 7 patients (26%), for the total disease control rate of 59%.Responses were seen only at the dose levels of 3.6 mg/kg and 4.8 mg/kg. Conclusions: A166 demonstrated clinically meaningful efficacy in heavily pretreated patients with relapsed or refractory advanced solid cancers. The achievement of an ORR of 36% at efficacious dose levels and up to 100% in HER2 positive patients regardless of histology (2 CRC, 1 BC and 1 NSCLC) at the highest studied dose level exceed Clinical trial information: NCT03602079 .

Percutaneous hepatic injection of rose bengal disodium (PV-10) in metastatic uveal melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3143-3143 ◽  
Author(s):  
Sapna Pradyuman Patel ◽  
Brett W. Carter ◽  
Ravi Murthy ◽  
Rahul Sheth ◽  
Sanjiv S. Agarwala ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Uveal Melanoma ◽  
Phase 1 ◽  
Unmet Need ◽  
Standard Of Care ◽  
Complete Response ◽  
Immune Checkpoint Blockade ◽  
Open Label ◽  
Open Label Phase ◽  
Hepatic Lesions

3143 Background: PV-10 is a small molecule autolytic immunotherapy in clinical development for treatment of solid tumors. When administered by intralesional (IL) injection, PV-10 can produce immunogenic cell death that may induce a T cell-mediated immune response against treatment refractory and immunologically cold tumors. Given this mechanism of action and clinical data that metastatic uveal melanoma (MUM) generates low response rates to immune checkpoint blockade (CB), we investigated treatment of MUM with percutaneously-delivered PV-10. Methods: This open-label Phase 1 basket study (NCT00986661) is evaluating the safety, tolerability, and preliminary efficacy of intralesional PV-10 in patients (pts) with solid tumors of the liver. PV-10 is injected into one or more designated hepatic tumor(s) with a maximum sum of diameters ≤4.9 cm. Response assessments using 2D EASL criteria are performed at Day 28, then every 3 months. Pts with additional injectable tumors are eligible to receive further PV-10 after Day 28. Pts can receive standard of care CB immunotherapy during treatment with PV-10. Results: As of February 1, 2020, the initial cohort of 15 pts with MUM to the liver was fully enrolled. Pts had received at least 1 IL injection of PV-10, with an average of 2 hepatic lesions injected per pt (range 1-4). Of these, 4 pts were refractory to prior CB. Three pts received PV-10 alone, 3 received PV-10 + anti-PD-1 and 9 received PV-10 + anti-PD-1 + anti-CTLA-4. Adverse events (AEs) were consistent with established patterns for PV-10 and CB: AEs attributed to PV-10 were transient and included 3 cases of Grade 3/4 transaminitis that resolved within 72 hrs, injection site pain, photosensitivity, and pink discoloration of skin, urine or feces; AEs attributed to CB included nausea, decreased WBC, and fatigue. Response assessments on 24 injected tumors were: 2 complete response (8%), 7 partial response (29%) and 11 stable disease (46%), per 2D EASL. Among the 4 CB-refractory pts, median overall survival (OS) was 9.2 months (range 5.3 - 11.4 months, with 2 pts alive at 5.3 months each), while among the 11 CB-naïve pts OS was undefined (range 0.5 - 21.9+ months, with 1 death at 7.9 months). Pts receiving PV-10 alone (1 CB-refractory, 2 naïve) achieved a median OS of 7.9 months with one CB-naïve pt alive with partial overall response at 21.9 months. Conclusions: Response indicative of regression or stabilization in a majority (83%) of injected lesions is encouraging in a disease of major unmet need. Enrollment and follow-up for safety, duration of response and survival are ongoing. Clinical trial information: NCT00986661 .

scholarly journals A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors

2020 ◽  
Author(s):  
Toshihiko Doi ◽  
Masaomi Tajimi ◽  
Joji Mori ◽  
Hiroya Asou ◽  
Koichi Inoue ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Japanese Patients ◽  
Primary Objective ◽  
Pharmacokinetic Parameters ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Summary Background This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW. Trial registration: NCT02836600 (ClinicalTrials.gov) registered on July 19, 2016.

scholarly journals Mass Balance and Pharmacokinetics of [14C]Telavancin following Intravenous Administration to Healthy Male Volunteers

2010 ◽  
Vol 54 (8) ◽  
pp. 3365-3371 ◽  
Author(s):  
Jeng-Pyng Shaw ◽  
Jonathan Cheong ◽  
Michael R. Goldberg ◽  
Michael M. Kitt
Keyword(s):  
Mass Balance ◽  
Whole Blood ◽  
Phase 1 ◽  
Parent Drug ◽  
Study Drug ◽  
Total Radioactivity ◽  
Healthy Male ◽  
Open Label ◽  
Study Drug Administration ◽  
Open Label Phase

ABSTRACT The mass balance and pharmacokinetics of telavancin, a semisynthetic lipoglycopeptide antimicrobial agent, were characterized in an open-label, phase 1 study of six healthy male subjects. After a single 1-h intravenous infusion of 10 mg/kg [14C]telavancin (0.68 μCi/kg), blood, urine, and feces were collected at regular intervals up to 216 h postdose. Whole blood, plasma, urine, and fecal samples were assayed for total radioactivity using scintillation counting; plasma and urine were also assayed for parent drug and metabolites using liquid chromatography with tandem mass spectrometry. The concentration-time profiles for telavancin and total radioactivity in plasma were comparable from 0 to 24 h after the study drug administration. Telavancin accounted for >95% and 83% of total radioactivity in plasma at 12 h and 24 h, respectively. By 216 h, approximately 76% of the total administered dose was recovered in urine while only 1% was collected in feces. Unchanged telavancin accounted for most (83%) of the eliminated dose. Telavancin metabolite THRX-651540 along with two other hydroxylated metabolites (designated M1 and M2) accounted for the remaining radioactivity recovered from urine. The mean concentrations of total radioactivity in whole blood were lower than the concentration observed in plasma, and mean concentrations of THRX-651540 in plasma were minimal relative to mean plasma telavancin concentrations. These observations demonstrate that most of an administered telavancin dose is eliminated unchanged via the kidneys. Intravenous telavancin at 10 mg/kg was well tolerated by all subjects.

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