scholarly journals 1093TiP An open-label, multicenter, phase I/II clinical trial of RP1 as a single agent and in combination with nivolumab in patients with solid tumors [IGNYTE]

2021 ◽  
Vol 32 ◽  
pp. S903-S904
Author(s):  
F. Aroldi ◽  
M.R. Middleton ◽  
J.J. Sacco ◽  
M.M. Milhem ◽  
B.D. Curti ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Single Agent ◽  
Open Label ◽  
Multicenter Phase

scholarly journals DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3 K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii297-iii297
Author(s):  
Sharon Gardner ◽  
Rohinton Tarapore ◽  
Jeffrey Allen ◽  
Wafik Zaky ◽  
Yazmin Odia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Phase I ◽  
Single Agent ◽  
High Grade Glioma ◽  
Newly Diagnosed ◽  
Liquid Formulation ◽  
Open Label ◽  
Dismal Prognosis ◽  
Expansion Cohort

Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.

An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

First-in-human phase I study of anti-HER2 ADC MRG002 in patients with relapsed/refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1101-TPS1101 ◽  
Author(s):  
Jin Li ◽  
Ye Guo ◽  
Junli Xue ◽  
Wei Peng ◽  
Xiaoxiao Ge ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Single Agent ◽  
Locally Advanced ◽  
Salivary Gland Cancer ◽  
Antibody Drug Conjugate ◽  
Her2 Positive

TPS1101 Background: MRG002 is an antibody drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG002 is presently being investigated in an ongoing phase I study for safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity in patients (pts) with solid tumors. Methods: MRG002 is evaluated as monotherapy for the treatment of pts with confirmed HER2 positive locally advanced or metastatic cancers, including breast cancer (BC), gastric cancer (GC), salivary gland cancer (SGC) and others. The primary objective is to determine the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D). Secondary objectives include evaluation of PK, tumor response, and immunogenicity. In the dose escalation phase with “3+3” design, approximately 24 pts will be enrolled to identify MTD. The starting dose of MRG002 is 0.3 mg/kg, followed by 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg. In the dose expansion phase, about 50 pts with HER2 positive advanced cancers will be enrolled to further evaluate the safety, antitumor activity, and PK at an appropriate confirmed dose. In this phase I study, each pt receives single agent MRG002 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. Pts with BC and GC should have HER2 positive advanced solid tumors per College of American Pathologists (CAP) guidelines. For other cancers, pts must have IHC status of 2+ or 3+, regardless of FISH results. Pts should have either failed or are ineligible for standard treatments. All pts must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac functions should be adequate. Observations include adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity, which is assessed every two treatment cycles. Further clinical trial details can be found on chinadrugtrials.org.cn (CTR20181778). Enrollment is ongoing since November 2018. Clinical trial information: CTR20181778 .

scholarly journals An Open-Label, Multicenter, Phase I/II Study of Single-Agent AT-101 in Men with Castrate-Resistant Prostate Cancer

2009 ◽  
Vol 15 (9) ◽  
pp. 3172-3176 ◽  
Author(s):  
Glenn Liu ◽  
W. Kevin Kelly ◽  
George Wilding ◽  
Lance Leopold ◽  
Kimberli Brill ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Single Agent ◽  
Open Label ◽  
Multicenter Phase ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

scholarly journals Intratumoral OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: a multicenter, phase I/II clinical trial

2021 ◽  
Vol 9 (4) ◽  
pp. e002224
Author(s):  
Bo Zhang ◽  
Jing Huang ◽  
Jialin Tang ◽  
Sheng Hu ◽  
Suxia Luo ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Single Agent ◽  
Intratumoral Injection ◽  
Advanced Solid Tumors ◽  
Multicenter Phase ◽  
Oncolytic Herpes Simplex Virus ◽  
Simplex Virus

BackgroundOH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors.MethodsIn this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (106, 107 and 108CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II.ResultsBetween April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1–2, except one case of grade 3 fever in the 108CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3+ and CD8+ cell density and programmed death-ligand 1 expression in the patients’ post-treatment biopsies relative to baseline.ConclusionsIntratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.

Pharmacodynamic evaluation of pCDC2 as the target engagement biomarker to assess activity of MK-1775 a Wee1 tyrosine kinase inhibitor.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13598-e13598
Author(s):  
Shelonitda Rose ◽  
Jonathan D. Cheng ◽  
Johnny Viscusi ◽  
Robert Iannone ◽  
Jan HM Schellens ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Locally Advanced ◽  
Target Engagement ◽  
Open Label ◽  
Post Dose ◽  
Dose Escalation Study ◽  
Skin Biopsies

e13598 Background: Wee1 kinase regulates the G2 checkpoint through phosphorylation of CDC2. MK-1775 is a first-in-class inhibitor of Wee1, and thereby reduces pCDC2 levels relative to CDC2. pCDC2therefore can be used as a target engagement (TE) biomarker to assess activity of MK-1775. This was investigated in a phase I first-in-man clinical trial of MK-1775. Methods: This is a multicenter, open-label, non-randomized phase I dose escalation study in patients with locally advanced or metastatic solid tumors. MK-1775 was administered orally in escalating doses as monotherapy, and either single dose or multi-dose in combination with chemotherapy including cisplatin, carboplatin and gemcitabine. Serial skin biopsies were performed at baseline and either 8, 24 or 48 hours following MK-1775 administration and analyzed by IHC for CDC2 and pCDC2. Based on preclinical efficacy experiments, TE was defined as a decrease of pCDC2 of at least 50% (or fold change > 0.50) from pre- to post-dose MK-1775. Results: To date a total of 176 patients have received at least one dose of MK-1775 either as monotherapy or in combination (single or multi-dose MK-1775) with chemotherapy at doses ranging from 25 mg to 1300 mg to define maximum tolerated dose. Dose dependent decreases in pCDC2 were observed in skin biopsies between pre-dose and post-dose treatment in all treatment groups. TE with monotherapy was achieved at 325 mg. TE with multi-dose MK-1775 in combination with cisplatin and carboplatin were achieved at 125 mg BID and 225 mg BID. Gemcitabinecombination treatment is on-going. In contrast, chemotherapy alone resulted in an increase of pCDC2. Conclusions: Based on preclinical data, in this first-in-man clinical trial of MK-1775, we were able to demonstrate TE required for maximal efficacy at tolerable doses of MK-1775 either as a single agent or in combination with chemotherapy. [Table: see text]

First-in-human phase I clinical trial of QBI-139, a human ribonuclease variant, in solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3113-TPS3113 ◽  
Author(s):  
Laura E. Strong ◽  
John A. Kink ◽  
Baigen Mei ◽  
Mark N. Shahan ◽  
Ronald T. Raines
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Model Systems ◽  
In Vivo Models ◽  
Multiple Tumor ◽  
Naturally Occurring

TPS3113 Background: RNA has been recognized as a drug target for cancer therapy, as evidenced by the ongoing clinical trials of RNAi and antisense therapies. An alternative approach that circumvents the delivery and stability issues of RNAi and antisense is to harness the activity of naturally occurring enzymes that degrade RNA. Variants of human ribonucleases (RNase) have been generated with diminished binding to their natural inhibitor inside cells, which allows the new proteins to kill cancer cells. QBI-139, a variant that retains 95% sequence identity to a naturally occurring RNase, has demonstrated efficacy as both a single agent and in combination against multiple tumor types in in vivo models of human cancer. A first in human phase I trial was designed and initiated for QBI-139. Methods: Since QBI-139 showed efficacy against multiple cancers in model systems, a first in human phase I trial was designed for patients with advanced solid tumors (NCT00818831). Patients receive QBI-139 by intravenous infusion once weekly for a cycle of three weeks. In the absence of disease progression or unacceptable toxicity, treatment can continue on the twenty one day cycle. The trial is a standard 3+3 design with cohorts of three to six patients receiving escalating doses of QBI-139 until the maximum tolerated dose (MTD) and/or recommended phase II dose is determined. The inclusion/exclusion criteria are typical for the patient population. Forty three patients have been treated to date (January 2012) without identification of dose limiting toxicity. The starting dose in the clinical trial was 3 mg/m2 while the most recently completed cohort was treated with a dose of 50.4 mg/m2. Dose escalation is ongoing. The primary outcome is to evaluate the toxicity and tolerability of QBI-139 in patients with advanced refractory solid tumors. This information will allow for identification of the maximum tolerated dose. Clinical exposure levels are being monitored by measuring the pharmacokinetics of QBI-139. Tumor response to QBI-139 will be measured using RECIST criteria. Since QBI-139 demonstrated broad efficacy in model systems, another outcome of the phase I trial may be identification of the indications for the next stage of clinical development.

A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3023-3023 ◽  
Author(s):  
Carlos Becerra ◽  
Jeffrey R. Infante ◽  
Lawrence E. Garbo ◽  
Michael S. Gordon ◽  
David A. Smith ◽  
...  
Keyword(s):  
Growth Factors ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Post Dose

3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m2) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m2) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.

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