Phase 1-2 study of TI-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3109-TPS3109 ◽  
Author(s):  
T.R. Jeffry Evans ◽  
Antoine Italiano ◽  
Ferry Eskens ◽  
Stefan Nicholas Symeonides ◽  
Alice Susannah Bexon ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Regulatory Protein ◽  
Objective Response ◽  
T Cell Response ◽  
Mouse Tumor ◽  
Dose Escalation Study ◽  
Advanced Malignancies ◽  
Anti Cancer

TPS3109 Background: The cell surface protein CD47 is expressed or over-expressed on many tumor types. CD47 binds to signal regulatory protein alpha (SIRPα) on macrophages resulting in a “don’t eat me” signal that blocks host cell phagocytosis of the tumor cells, thus allowing them to escape removal by the innate immune system. Recent data indicate that anti-CD47 antibodies also contribute to an effective anti-tumor T cell response in immune-competent mice. Therefore, anti-CD47 antibodies are a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. Ti-061 is a novel IgG4 humanized monoclonal antibody that specifically binds to CD47 with Kd values range from 100 – 500 pM. Ti-061 exhibits cross-species binding to cynomolgus monkey, mouse and rat CD47, enabling efficacy and toxicity testing across species. Ti-061 binds to CD47 on RBCs; however, it does not cause agglutination of RBCs in vitro from any of the species tested. Ti-061 exhibits anti-tumor activity in several in vivo mouse tumor models. This ongoing Phase 1-2 study will assess the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of Ti-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies. Methods: Part A is an open-label, dose-escalation study of Ti-061 administered as a weekly 1-hour IV infusion at doses ranging from 1 to 20 mg/kg. Once the MTD/RP2D or “active dose” is determined, patients with specific solid tumors and high CD47 expression will be enrolled in 4 or more expansion cohorts. Up to 160 patients with histologically confirmed solid tumors, ECOG PS 0-1, adequate blood counts (Hb≥ 10 g/dL), organ function, and archival or fresh tumor tissue will be enrolled in Part A, and will be treated until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is safety, which will be assessed using NCI-CTCAE v4.03. Secondary endpoints include PK, PD, objective response rate (ORR) and progression-free survival (PFS), which will be assessed using RECIST v1.1. The results of this study will support further development of Ti-061 in combination with checkpoint inhibitors (Part B) and other anti-cancer agents.

A phase I, dose-escalation study of ADG106, a fully human anti-CD137 agonistic antibody, in subjects with advanced solid tumors or relapsed/refractory non-Hodgkin lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3105-3105 ◽  
Author(s):  
Li Zhang ◽  
Hongyun Zhao ◽  
Yuxiang Ma ◽  
Xin Zheng ◽  
Ji Jiang ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Systemic Exposure ◽  
Pharmacokinetic Analysis ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Expansion Cohort ◽  
Dose Levels

3105 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody, targeting a unique epitope of CD137 with novel mechanism of actions for CD137 agonism, CD137 ligand antagonism and potent cross-linking via FcgRIIb. This phase 1 study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and preliminary efficacy. Methods: Eligible patients with age 18 to 75, ECOG ≤1, measurable lesion received intravenous infusion of ADG106 every 3 weeks for a maximum of 24 months. Accelerated titration was applied in 0.1mg/kg dose level and traditional Fibonacci 3+3 method was applied in 0.5, 1.5, 3.0, 5.0 and 10.0 mg/kg dose levels. A dose-expansion cohort will be started for dose levels that have been proved tolerable and with evidence of clinical or biological activity. Results: Data cutoff at Jan 17 2020, 15 patients [5 adenoid cystic carcinoma (ACC), 5 non-small cell lung cancer (NSCLC), 3 nasopharyngeal carcinoma, 1 malignant pleural mesothelioma and 1 follicular lymphoma] were enrolled and received treatment: 0.1mg/kg (n = 1), 0.5mg/kg (n = 3), 1.5mg/kg (n = 5), 3mg/kg (n = 3), and 5mg/kg (n = 3). Of these 15 patients, 6 with ongoing treatment, 9 discontinued (8 progression disease, 1 lack of clinical benefit). Medium treatment duration was 2 cycles (range 2-8). No dose limiting toxicities were observed. Seven (47%) patients experienced treatment-related AEs (TRAEs): rash (13%), pruritus (13%), nausea (7%), pyrexia (7%), hemoptysis (7%), mouth ulceration (7%), vomiting (7%), chest discomfort (7%), LDH increased (7%). All TRAEs were grade 1, no grade ≥3 occurred. One serious adverse event (anemia, not related) was observed. Pharmacokinetic analysis of ADG106 showed a half-life ranging from 5~10 days, with dose-dependent increase of systemic exposure. Treatment induced anti-drug antibodies were developed in 3 (20%) patients. No objective response was observed among the 14 evaluated patients. Disease control rate was 57% (8 stable disease), tumor shrinkage was observed in 3 (21%) patients (2 ACC, 1 NSCLC). Conclusions: ADG106 is safe and tolerable at doses up to 5 mg/kg in solid tumors and non-Hodgkin lymphoma. The dose expansion cohorts have started at selected doses. Clinical trial information: NCT03802955 .

scholarly journals Safety, antitumor activity and biomarkers of sugemalimab in Chinese patients with advanced solid tumors or lymphomas: results from the first-in-human phase 1 trial

2022 ◽  
Author(s):  
Jifang Gong ◽  
Junning Cao ◽  
Qingyuan Zhang ◽  
Nong Xu ◽  
Yanqiu Zhao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Chinese Patients ◽  
Fixed Dose ◽  
Phase 1 Trial ◽  
Advanced Malignancies ◽  
Biomarker Analysis ◽  
Phase 1B

Abstract Background This first-in-human phase 1 trial is to evaluate the safety, pharmacokinetics, preliminary efficacy, and biomarkers of sugemalimab, a full-length, fully human anti-PD-L1 monoclonal antibody, in Chinese patients with advanced malignancies. Methods Eligible patients with unresectable advanced or metastatic solid tumors or lymphomas were enrolled in phase 1a to receive sugemalimab following a modified 3 + 3 design. The primary endpoints included safety, tolerability, and the recommended Phase 2 dose (RP2D). In phase 1b, patients with 7 selected types of tumor received sugemalimab at the RP2D alone (monotherapy cohorts) or in combination with standard-of-care (SOC) chemotherapy (combination cohorts). The primary endpoint of phase 1b was investigator-assessed objective response rate (ORR). Results As of 19 February 2020, 29 and 178 patients were treated in phase 1a and 1b, respectively. No dose-limiting toxicities were observed in phase 1a, and the RP2D of sugemalimab was determined as 1200 mg fixed dose once every 3 weeks. Sugemalimab-related adverse events (AEs) were mostly (75.9%) grade 1–2 in phase 1a. Antitumor activity was observed across dose levels with an ORR of 24.1%. In phase 1b, 15.9% and 40.4% of patients in the monotherapy and combination cohorts, respectively, reported grade 3–5 sugemalimab-related AEs. Promising efficacy was observed in all combination cohorts, with ORRs ranging from 47.6 to 75.0%. Exploratory biomarker analysis did not indicate significant differences in responses at different PD-L1 expression/tumor mutation burden levels. Conclusions Sugemalimab was well-tolerated and showed promising antitumor activity as monotherapy or in combination with SOC chemotherapy in advanced malignancies. This trial was registered with ClinicalTrials.gov on Oct 18, 2017, number NCT03312842.

scholarly journals A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1425
Author(s):  
Filippo de Braud ◽  
Jean-Pascal H. Machiels ◽  
Daniela Boggiani ◽  
Sylvie W.H. Rottey ◽  
Matteo Duca ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Gamma Glutamyl Transferase ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Number Of Patients ◽  
Glutamyl Transferase

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.

scholarly journals Phase 1 dose escalation study of seribantumab (MM-121), an anti-HER3 monoclonal antibody, in patients with advanced solid tumors

2021 ◽  
Author(s):  
Crystal S. Denlinger ◽  
Vicki L. Keedy ◽  
Victor Moyo ◽  
Gavin MacBeath ◽  
Geoffrey I. Shapiro
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Clinical Trial Registration ◽  
Best Response

SummaryBackground Overactivation of human epidermal growth factor receptor 3 (HER3) triggers multiple intracellular pathways resulting in tumor cell survival. This Phase 1 study assessed the safety, efficacy, and pharmacokinetics (PK) of seribantumab, a fully human anti-HER3 monoclonal antibody. Methods Adult patients with advanced or refractory solid tumors were treated in six dose cohorts of seribantumab: 3.2, 6, 10, 15, or 20 mg/kg weekly, or 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose (40/20 mg/kg) using a modified 3 + 3 dose escalation strategy with cohort expansion. Primary objectives were identification of a recommended Phase 2 dose (RP2D) and determination of objective response rate. Secondary objectives were assessment of safety, dose-limiting toxicities, and PK. Results Forty-four patients (26 dose escalation; 18 dose expansion) were enrolled. Seribantumab monotherapy was well tolerated with most adverse events being transient and mild to moderate (grade 1 or 2) in severity; maximum tolerated dose was not reached. The highest dose, 40/20 mg/kg, was identified as RP2D. Best response was stable disease, reported in 24% and 39% of patients during the dose escalation and expansion portions of the study, respectively. Seribantumab terminal half-life was ≈100 h; steady state concentrations were reached after 3–4 weekly doses. Conclusions Seribantumab monotherapy was well tolerated across all dose levels. Safety and PK data from this study support further seribantumab investigations in genomically defined populations.Clinical trial registration NCT00734305. August 12, 2008.

scholarly journals Phase 1 Dose Escalation Study of Seribantumab (MM-121), an anti-HER3 Monoclonal Antibody, in Patients with Advanced Solid Tumors

2021 ◽  
Author(s):  
Crystal Denliger ◽  
Vicki L Keedy ◽  
Victor Moyo ◽  
Gavin MacBeath ◽  
Geoffrey I Shapiro
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Clinical Trial Registration ◽  
Best Response

Abstract BACKGROUND: Overactivation of human epidermal growth factor receptor 3 (HER3) triggers multiple intracellular pathways resulting in tumor cell survival. This Phase 1 study assessed the safety, efficacy, and pharmacokinetics (PK) of seribantumab, a fully human anti-HER3 monoclonal antibody.METHODS: Adult patients with advanced or refractory solid tumors were treated in six dose cohorts of seribantumab: 3.2, 6, 10, 15, or 20 mg/kg weekly, or 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose (40/20 mg/kg) using a modified 3+3 dose escalation strategy with cohort expansion. Primary objectives were identification of a recommended Phase 2 dose (RP2D) and determination of objective response rate. Secondary objectives were assessment of safety, dose-limiting toxicities, and PK.RESULTS: Forty-four patients (26 dose escalation; 18 dose expansion) were enrolled. Seribantumab monotherapy was well tolerated with most adverse events being transient and mild to moderate (grade 1 or 2) in severity; maximum tolerated dose was not reached. The highest dose, 40/20 mg/kg, was identified as RP2D. Best response was stable disease, achieved by 24% and 39% of patients during the dose escalation and expansion portions of the study, respectively. Seribantumab terminal half-life was ≈100 hours; steady state concentrations were reached after 3–4 weekly doses. CONCLUSIONS: Seribantumab monotherapy was well tolerated across all dose levels. Safety and PK data from this study support further seribantumab investigations in genomically defined populations. CLINICAL TRIAL REGISTRATION: NCT00734305.DATE OF REGISTRATION: August 12, 2008.

Phase 1, open-label, dose-escalation study of M3814 + avelumab ± radiotherapy (RT) in patients (pts) with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3169-TPS3169 ◽  
Author(s):  
Johanna C. Bendell ◽  
Michael Rahman Shafique ◽  
Bradford Perez ◽  
Sarah Chennoufi ◽  
Frank Beier ◽  
...  
Keyword(s):  
Dna Damage ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Metastatic Tumor ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Dose Levels

TPS3169 Background: DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage response (DDR) pathway for double-strand break (DSB) repair. DNA-PK inhibition augments DNA DSB damage generated by many antitumor therapies, including RT. DNA damage and repair impact the interaction of tumors with the immune system; combining immune checkpoint inhibitors (CPIs) with RT + DDR-targeted agents may modulate the tumor immune microenvironment, enhancing responsiveness to CPIs. M3814 (small molecule selective DNA-PK inhibitor) has demonstrated monotherapy activity in several tumor cell lines, and M3814 + RT combined with avelumab (programmed death ligand 1 mAb) significantly delayed tumor growth vs either agent alone + RT in MC38 syngrafts. This study will evaluate the clinical utility of M3814 combined with avelumab ± RT in pts with advanced solid tumors. Methods: NCT03724890 is a 2-part first-in-man study in adult pts with advanced or metastatic solid tumors. Part A is enrolling pts with measurable/evaluable solid tumors (RECIST v1.1); Part B will enrol pts with primary or metastatic tumor(s) in the lung which is/are amenable to be irradiated. In Part A, M3814 will be given orally twice daily. In Part B, M3814 + TRT will be given once daily, 5 days/wk for 2 wk. In both parts, pts will receive avelumab iv once every 2 wk from Day 1 until disease progression/unacceptable toxicity. Part B will initiate once the Safety Monitoring Committee declares the first dose level of Part A to have acceptable safety/tolerability. Primary objectives are to define the recommended Phase 2 dose (RP2D) of M3814 when combined with avelumab (Part A) and with avelumab + TRT (Part B) via dose-limiting toxicities (DLTs) occurring during the first 3/4 (Part A/B) wk of treatment. Secondary objectives include safety/tolerability, pharmacokinetics, immunogenicity, preliminary antitumor activity (BOR, PFS, OS). Sample size for each part depends on the number of DLTs/dose levels for M3814; dose escalation will be based on a Bayesian logistic regression model with overdose control. Part A aims to include 6–24 pts (≤4 dose levels), Part B 6–18 pts (≤3 dose levels). Recruitment began in Dec 2018. Clinical trial information: NCT03724890.

A phase I study evaluating COM701 in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2657-TPS2657
Author(s):  
Drew W. Rasco ◽  
Daniel A. Vaena ◽  
Ryan J. Sullivan ◽  
Jason J. Luke ◽  
Adam ElNaggar ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Mouse Tumor ◽  
Advanced Solid Tumors ◽  
Open Label

TPS2657 Background: There is a high unmet medical need for the treatment (tx) of patients (pt) who are refractory to or relapse following tx with checkpoint inhibitors. Newer checkpoint therapies with novel mechanisms of action that can activate T cells and demonstrate antitumor activity in this pre-tx pt population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis as are TIGIT and PD1. Inhibition of PVRIG leads to enhanced activation of T and NK cells, and PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will demonstrate antitumor activity in pts who are checkpoint inhibitor pre-tx. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate escalating doses of COM701 monotherapy IV Q3 weekly with single pt cohorts for the initial 4 and then 3+3 design. Key Inclusion Criteria: Age ≥18 yrs, histologically confirmed locally advanced/ metastatic solid malignancy and has exhausted available standard therapy, ECOG 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137 permissible. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years, symptomatic interstitial or inflammatory lung disease, untx or symptomatic central nervous system metastases. Primary objectives are safety and tolerability of COM701 as measured by the incidence of adverse events (AEs) and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701, and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary objectives are to characterize the immunogenicity and preliminary antitumor activity of COM701. Statistical Considerations: AEs graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. No DLTs have been observed in the single pt cohorts. Assessment of pts enrolled into cohort 5 is ongoing at the time of this submission. Clinical trial information: NCT03667716.

A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb) in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2577-2577
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Bo Gao ◽  
Kate Wilkinson
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Gastroesophageal Junction Cancer ◽  
Anti Cancer ◽  
Ongoing Phase

2577 Background: YH001 is a humanized anti -hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard “3+3” design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2020 data cut-off, 10 pts were enrolled and treated at 0.05 mg/kg (n = 2), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3) and 1 mg/kg (n = 2). The median age was 62 years (range 46-74). Baseline ECOG scores were 0 (n = 8), 1(n = 2) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-4) including 1 pt progressed after immunotherapy of pembrolizumab. There were no dose limiting toxicities (DLT) observed. No severe adverse events (SAEs), Grade (G) 3 or above adverse events (AEs) and AEs leading to treatment discontinuation were reported. Twelve drug related AEs were all G1/2 events including 2 G2 AEs (1 rash maculopapular at 0.05mg/kg, 1 hypothyroidism at 0.1mg/kg), 10 G1 AEs (1 hypotension, 1 dry skin, 1 pruritus at 0.05mg/kg; 1 rash, 1 rash macular, 1 hyperthyroidism, 2 rash pruritus at 0.1mg/kg, 2 fatigues at 0.3mg/kg). Among 7 patients having imaging tumor assessment by RECIST v1.1, there were 4 SD, including 1 at 0.05 mg/kg with tongue carcinoma at week 8 assessment, 1 at 0.1 mg/kg with nasopharyngeal carcinoma at week 8 and 15 assessment, 2 at 0.3 mg/kg with gastroesophageal junction cancer and uterus leiomyosarcoma at week 8. Conclusions: YH001 combined with Toripalimab is safe and tolerable up to 1 mg/kg dose level. Updated safety and preliminary efficacy data will be presented. Clinical trial information: NCT04481009.

403 Early results from a phase 1 study to evaluate safety, pharmacokinetics, and efficacy of AMG 404, a programmed death-1 (PD-1) antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A428-A428
Author(s):  
Timothy Price ◽  
Sant Chawla ◽  
Gerald Falchook ◽  
Hans Prenen ◽  
Iwona Lugowska ◽  
...  
Keyword(s):  
Partial Response ◽  
Solid Tumors ◽  
Clear Cell ◽  
Phase 1 ◽  
Cell Cancer ◽  
Objective Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Advanced Solid Tumors

BackgroundEnhancement of antitumor immunity through inhibition of the checkpoint PD-1 receptor has been effective in the treatment of many malignancies. AMG 404 is a monoclonal antibody (mAb) targeting PD-1. This phase 1, open-label, multicenter first-in-human study (NCT03853109) will evaluate the safety, tolerability, pharmacokinetics, and efficacy of AMG 404 monotherapy in adult patients with advanced solid tumors.MethodsThe primary study endpoint is dose-limiting toxicity (DLT) and safety; key secondary endpoints include pharmacokinetic parameters, objective response rate (assessed Q8W), duration of response, and progression-free survival. Key inclusion criteria include histologically or cytologically proven metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation for which standard therapies have been exhausted or not available. Prior anti-PD-(L)1 or other checkpoint inhibitors were not allowed. Five dose-finding cohorts, including 2 expansion cohorts, ranged from 3–20 patients each. AMG 404 was given until disease progression, intolerance, or consent withdrawal.ResultsAs of the data cutoff date of May 4, 2020, 62 patients received at least 1 dose of AMG 404 and were included in the safety and efficacy analysis sets. Fifty percent were men, 72% had ECOG 1 performance status, median age was 62 years (range: 28–83), and 42% had ≥3 lines of prior anticancer therapy. Median AMG 404 exposure was ~3 months (maximum: ~12 months). No DLTs were observed. Treatment-related adverse events (TRAEs) were reported for 29 patients (47%): those reported for ≥2 patients were fatigue (n=7); hypothyroidism (n=6); increased blood thyroid stimulating hormone and nausea (n=4 each); increased aspartate aminotransferase, decreased appetite, and pyrexia (n=3 each); and increased alanine aminotransferase, arthralgia, diarrhea, and increased weight (n=2 each). AEs leading to withdrawal of AMG 404 were reported for 3 patients (5%); all were serious and considered to be not related to AMG 404. Sixteen (26%) patients died on study; no deaths were considered related to AMG 404. Preliminary pharmacokinetic results were consistent with those of other therapeutic anti-PD-1 mAbs. Three patients had a confirmed partial response (pancreatic cancer, clear cell cancer, and pleomorphic sarcoma); an additional 4 patients had one scan with a partial response and are pending a confirmatory scan (clear cell renal carcinoma, undifferentiated nasopharyngeal carcinoma, sarcomatoid carcinoma of unknown primary, and colon cancer).ConclusionsAMG 404 is tolerable at the tested doses with no DLTs reported. All observed TRAEs are consistent with other anti-PD-1 therapies. Encouraging anti-tumor activity has been observed in heavily pretreated patients. The study is continuing enrollment into additional cohorts.Trial RegistrationNCT03853109Ethics ApprovalThe study was approved by the Ethics Board of each institution involved in this study and can be produced upon request.

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.

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