scholarly journals 455 Pegasus Lung, a platform study of SAR444245 (THOR-707, a pegylated recombinant non-alpha IL-2) with anti-cancer agents in patients with non-small cell lung cancer (NSCLC) and mesothelioma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A483-A483
Author(s):  
Robin Meng ◽  
Benjamin Besse ◽  
Melissa Johnson ◽  
Jaafar Bennouna ◽  
Luca Toschi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Informed Consent ◽  
Antitumor Activity ◽  
Safety Profile ◽  
Single Agent ◽  
Pharmacokinetic Profile ◽  
Clinical Results ◽  
Outpatient Setting ◽  
Primary Objective ◽  
Institutional Review Boards

BackgroundSAR444245 (THOR-707) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, SAR444245 showed anti-tumor benefits, but with no severe side effects, both as single agent and when combined with anti-PD1 comparing with historical data from aldesleukin. The HAMMER trial, which is the FIH study shows preliminary encouraging clinical results: initial efficacy and safety profile with SAR444245 monotherapy and in combination with pembrolizumab support a non-alpha preferential activity, validating preclinical models. The Pegasus Lung Ph2 study will evaluate the clinical benefit of SAR444245 in combination with other anticancer therapies for the treatment of patients with lung cancer or pleural mesotheliomaMethodsThe Pegasus Lung (NCT04914897) will enroll approximately 354 patients in 6 separate cohorts concurrently or sequentially. In cohorts A1 & A2, patients with first line (L) NSCLC will receive SAR444245 + pembrolizumab. In cohort A3, patients with 1L non-squamous NSCLC will receive SAR444245 + pembrolizumab + pemetrexed + carboplatin/cisplatin. In cohort B1 & B2 patients with 2/3L NSCLC who have progressed on a checkpoint inhibitor (CPI)-based therapy will receive SAR444245 + pembrolizumab, or SAR444245 + pembrolizumab + nab-paclitaxel. In cohort C patients with 2/3L CPI naïve mesothelioma will receive SAR444245 + pembrolizumab. SAR444245 is administered IV at a dose of 24 ug/kg Q3W in an outpatient setting until disease progression or completion of 35 cycles. Pembrolizumab is administered at a dose of 200 mg Q3W until PD or completion of 35 cycles. The study primary objective is to determine the antitumor activity of SAR444245 in combination with other anticancer therapies. Secondary objectives include confirmation of dose and safety profile, assess other indicators of antitumor activity, and assess the pharmacokinetic profile and immunogenicity of SAR444245. The study will be conducted in the US, Australia, France, Italy, Japan, Poland, South Korea, Spain, and Taiwan.AcknowledgementsThe Pegasus Lung study is sponsored by Sanofi.Trial RegistrationNCT04914897Ethics ApprovalThis study has been approved by applicable ethics committees or institutional review boards. All participants gave informed consent before taking part.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

scholarly journals 402 Pegasus GI, a platform study of SAR444245 (THOR-707, a pegylated recombinant non-alpha IL2) with anti-cancer agents of participants with advanced and metastatic gastrointestinal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A433-A433
Author(s):  
William Harris ◽  
Adyb Baakili ◽  
Yoon-Koo Kang ◽  
Brigitte Demers ◽  
Fatima-Zohra Menas ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Gastrointestinal Cancer ◽  
Safety Profile ◽  
Single Agent ◽  
Pharmacokinetic Profile ◽  
Clinical Results ◽  
Preclinical Study ◽  
Primary Objective ◽  
Anti Cancer ◽  
The Us

BackgroundSAR444245 (THOR-707) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, SAR444245 showed anti-tumor benefits, but with no severe side effects, both as single agent and when combined with anti-PD1 comparing with historical data from aldesleukin. Preclinical study demonstrated SAR444245 enhances ADCC function of cetuximab. The HAMMER trial, which is the FIH study, shows preliminary encouraging clinical results: initial efficacy and safety profile with SAR444245 monotherapy and in combination with pembrolizumab or with cetuximab support a non-alpha preferential activity, validating preclinical models. The Pegasus GI Ph 2 study will evaluate the clinical benefit of SAR444245 in combination with pembrolizumab or cetuximab for the treatment of participants with advanced or metastatic gastrointestinal cancer [esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) or gastro-esophageal junction adenocarcinoma (GEJ), Hepatocellular carcinoma (HCC) or colorectal cancer (CRC)]MethodsPegasus GI will enroll approximately 280 patients in 7 separate cohorts concurrently (4 cohorts) or sequentially (3 cohorts). In cohort A, 2–3 line (L) ESCC participants who have progressed after checkpoint inhibitor (CPI)-based therapy will receive SAR444245 + pembrolizumab. In cohorts B1, B2 & B3 participants with GC and GEJ cancers will receive SAR444245 + pembrolizumab. Cohort B1 & B2 will enroll 1–3L CPI-naïve patients. Cohort B3 will enroll 2-4L patients post CPI-based therapy). In cohort C, 2–3L HCC participants who have progressed after CPI-based therapy will receive SAR444245 + pembrolizumab. In cohorts D1 and D2, 3–6L CRC participants will receive SAR444245 + pembrolizumab (any RAS) or SAR444245 + cetuximab (RAS-wild type)SAR444245 is administered IV at a dose of 24 ug/kg Q3W until disease progression or completion of 35 cycles. Pembrolizumab is administered as per label, Q3W for up to 35 cycles. Cetuximab is administered per label, QW until PD.The study primary objective is to determine the antitumor activity of SAR444245 in combination with other anticancer therapies. Secondary objectives are to assess safety profile, other indicators of antitumor activity, the pharmacokinetic profile and immunogenicity of SAR444245. The study will be conducted in the US, France, Germany, Spain, Italy, Belgium, Netherlands, Poland, Russia, South Korea and ChinaAcknowledgementsThe Pegasus GI study is sponsored by SanofiEthics ApprovalAll applicable ECs are obtainedConsentAll participant consents are obtained

Early safety and efficacy from a phase I open-label clinical trial of CD137(4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
Siqing Fu ◽  
Wael A. Harb ◽  
Sapna Pradyuman Patel ◽  
Charles Lu ◽  
Daniel M. Halperin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Safety Profile ◽  
Single Agent ◽  
Human Study ◽  
Hepatic Metastases ◽  
Preliminary Evidence ◽  
Open Label ◽  
Grade 3 ◽  
Favorable Safety

2521 Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by >10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.

Pemetrexed in combination with paclitaxel: A phase I clinical and pharmacokinetic trial in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2051-2051 ◽  
Author(s):  
T. Graefe ◽  
C. Bolling ◽  
C. Lubbing ◽  
J. Latz ◽  
J. Blatter ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Thyroid Carcinoma ◽  
Phase Ii ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Best Response ◽  
Recommended Phase Ii Dose

2051 Background: Pemetrexed (Alimta [AL]) and paclitaxel (P) are clinically active in a variety of tumors. The primary objective of this trial was to determine the maximum tolerated dose (MTD) of the ALP combination; secondary objectives were: determination of dose-limiting toxicities (DLTs), definition of a recommended phase II dose, pharmacokinetic (PK) characterization and the anecdotal collection of antitumor activity. Methods: Escalating doses of P (3h infusion, d1 and d8) and AL (10 min infusion, d8 prior to P) were given in a 21d cycle. Results: 59 patients (pts) were enrolled. DLTs occurred at the following ALP (mg/m2) doses: 400/30 [G3 bilirubin (b), G3 and G4 thrombocytopenia (plts)]; 500/30 (G4 plts); 500/40 (G3 b); 500/75 (G4 ANC); 500/100 (G4 leukopenia, G4 ANC). With G4 leukopenia and G4 ANC in 4/6 pts and febrile neutropenia in 1 pt, the MTD was reached at the ALP (mg/m2) dose of 500/120. To confirm safety at the recommended dose-level, another 6 patients were treated at the ALP (mg/m2) dose of 500/100. 18 pts [mesothelioma (3), esophagus (2), lung (1), liver (1), renal (1), stomach (1), thyroid (9)] showed stable disease as best response. 4/14 (29%) pts with thyroid carcinoma showed long lasting partial responses [duration (months) 29+, 22, 18, 15]. One additional PR (2) was observed in a pt with penile carcinoma. AL PK when administered with P were consistent with those for AL administered as a single-agent. Conclusions: The ALP combination is safe and shows broad clinical activity. 500/100 mg/m2 is the recommended dose for further studies. Promising antitumor activity was observed in thyroid cancer. A phase II trial in thyroid carcinoma will be conducted. [Table: see text]

Outcomes for the elderly (≥70 years) from a three-arm phase III trial of gemcitabine in combination with carboplatin (GC) or paclitaxel (GP) versus paclitaxel plus carboplatin (PC) for advanced non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8052-8052
Author(s):  
R. H. Ansari ◽  
M. J. Edelman ◽  
C. P. Belani ◽  
M. A. Socinski ◽  
C. K. Obasaju ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Single Agent ◽  
The Elderly ◽  
Clinical Results ◽  
Phase Iii ◽  
Individual Treatment ◽  
Age Group ◽  
Standard Regimen ◽  
Platinum Based Chemotherapy

8052 Background: Approximately 50% of lung cancer patients (pts) are ≥ 70 y, however, this population has been historically underrepresented in clinical trials. Even among pts ≥ 70 y, doublet chemotherapy has been shown to be superior to single-agent therapy (Lilenbaum JCO 2005, Sederholm JCO, 2005), and the efficacy and safety of platinum-based chemotherapy doublets in NSCLC pts ≥ 70 years with good PS have been reported to be similar to those in younger pts (Fossella, ASCO 2003, #2528, Kelly, ASCO 2001, A-1313). The current analysis examined whether any differences were present by age in a three arm trial of GC or GP versus a standard regimen of PC. Methods: 1135 chemonaïve pts with stage IIIB or IV NSCLC were randomized to receive: G 1000 mg/m2 d 1,8 plus C AUC 5.5 d 1; or G 1000 mg/m2 d 1,8 plus P 200 mg/m2 d 1; or P 225 mg/m2 plus C AUC 6.0 d 1. Stratification was based on stage, baseline weight loss, and brain metastases. Cycles were repeated every 21 days up to 6 cycles or disease progression. Clinical results were retrospectively analyzed in by patient age. Results: See Table . Conclusions: In this trial of commonly used regimens for advanced NSCLC, pts 70–74 years of age had significantly longer survival than pts 75–79 years of age. Pts 80+ years of age also had lower survival than the 70–74 year age group, but this difference was not statistically significant. No pts 80+ years of age had brain metastases at study entry. There was no clear pattern with respect to the effectiveness of individual treatment regimens by age group. [Table: see text] [Table: see text]

IMAGE, a randomized phase Ib/II study of elisidepsin (E) as a single agent in pretreated advanced gastroesophageal (GE) cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 92-92 ◽  
Author(s):  
Ramon Salazar ◽  
Jean Philippe Metges ◽  
David Alan Anthoney ◽  
Gianluca Laus ◽  
Maria Alsina Maqueda ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase Ii ◽  
Single Agent ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Primary Objective ◽  
Phase Ib ◽  
Flat Dose

92 Background: E is a new marine compound with broad in vitro/in vivo antitumor activity. Low μM concentrations lead to cell-death through membrane permeabilization. E has shown evidence of activity in pre-treated GE patients (pts) in phase I trials. Methods: The primary objective was to determine the tolerability and efficacy of E in pts with GE cancer after 1-2 prior chemotherapy (CT) lines. Initially, dose was optimized (Phase Ib) in two different schedules: a fixed flat dose (FD) of intravenous (i.v) E (8 and 10 mg), in 24h, biweekly (Arm A) and i.v E (3.0 and 3.75mg), in 3h, weekly (Arm B). After dose optimization patients were included and stratified by histology to each optimal dose (Phase II) to determine the rate of progression-free survival at week 16 ± 1 (PFS4) in an intention to treat analysis. If at least two out of 15 pts reached PFS4, recruitment would continue to a maximum of 40 pts per arm. Results: A total of 45 pts were recruited, 12 pts into Phase Ib (Arm A/B: 6/6 pts) and 33 pts into Phase II (Arm A/B: 15/18 pts). Median age was 60 years (35–81 years), 39 were males and ECOG PS was 1 in 75% of pts. Tumour sites were gastric (32% pts), esophageal (39% pts) and esophago-gastric junction (30% pts). Ninety percent of pts had metastatic disease, 31.8% of which had liver metastasis; 55% of pts had two prior lines of CT . No DLTs occurred during the first cycle in the Phase Ib. The optimal dose for Arm A was 10 mg FD, 24h, biweekly; the optimal dose for Arm B was 3.75mg FD, 3h, weekly. Two patients reached PFS4 in Phase Ib (Arm A). Only one patient reached PFS4 in Phase II (Arm A). No objective responses were observed. Therefore, protocol criteria for further recruitment were not met. The safety profile showed grade 1-2 toxicity pruritus (29.5%), nausea (15.9%), vomiting (6.8%) and fatigue (25%). Grade 3-4 toxicity consisted of asymptomatic reversible liver enzyme increases in 20.5% of patients. Conclusions: E is a very tolerable drug with a unique mechanism of action. In the current setting of non-stratified advanced GE patients, E has insufficient antitumor activity to warrant further investigation. Clinical trial information: 2010-020325-40.

Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4071-4071 ◽  
Author(s):  
Zev A. Wainberg ◽  
Neil Howard Segal ◽  
Dirk Jaeger ◽  
Kyung-Hun Lee ◽  
John Marshall ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Safety Profile ◽  
Phase 1 ◽  
Primary Objective ◽  
Clinical Activity ◽  
Open Label ◽  
Sorafenib Treatment ◽  
Secondary Objective ◽  
Pugh Class ◽  
Grade 3

4071 Background: Durvalumab, an anti-PD-L1 mAb, has shown early and durable clinical activity with manageable safety in an ongoing Phase 1/2, multicenter, open-label study in pts with advanced solid tumors. Interim analyses from the HCC cohort in the dose-expansion part of this study are reported here. Methods: Patients with HCC (Child-Pugh class A) received durvalumab 10 mg/kg i.v. q2w for 12 months or until confirmed progressive disease, whichever occurred first. The primary objective was to evaluate the safety profile; secondary objective was to assess the antitumor activity (investigator-assessed RECIST v1.1). Clinical activity was evaluated for the total HCC population and by viral status. Results: As of Oct 24 2016, 40 HCC pts with median 23.9 (range 2.4–34.7) weeks follow-up received durvalumab. 93% had prior sorafenib. Treatment-related AEs occurred in 80.0% of pts, most commonly fatigue (27.5%), pruritus (25.0%) and elevated aspartate aminotransferase (AST) (22.5%). Grade 3–4 treatment-related AEs were reported in 20.0% of pts, most commonly elevated AST (7.5%) and elevated alanine aminotransferase (5.0%). 7 (17.5%) pts completed the initial 12-month treatment and 7 (17.5%) pts discontinued treatment because of an AE (none related to treatment). There were no deaths due to treatment-related AEs. Clinical activity is presented in the table. 4 pts achieved a PR; 2 were ongoing at data cut-off. Conclusions: Durvalumab had an acceptable safety profile and showed promising antitumor activity and OS in pts with HCC, particularly HCV+ pts. Clinical trial information: NCT01693562. [Table: see text]

Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: the case for studies in previously treated patients.

1992 ◽  
Vol 10 (3) ◽  
pp. 484-498 ◽  
Author(s):  
S C Grant ◽  
R J Gralla ◽  
M G Kris ◽  
J Orazem ◽  
E A Kitsis
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Small Cell ◽  
Small Cell Lung ◽  
Phase Ii Trials ◽  
Previously Treated Patients ◽  
Previously Treated

PURPOSE This review was undertaken (1) to determine the antitumor activity of agents studied in phase II trials in small-cell lung cancer (SCLC) patients, (2) to evaluate the adequacy of published trials, (3) to determine if previously treated patients are suitable for phase II trials in SCLC, and (4) to develop an improved design for phase II trials. DESIGN English-language, single-agent efficacy trials in SCLC, published from 1970 to 1990, were reviewed. Study design and reporting of results were assessed for clinical and statistical methodology. Response rates observed in previously treated patients were compared with those observed in previously untreated patients. RESULTS One hundred forty-one articles evaluating 57 agents in 3,042 patients were reviewed. Eleven drugs were active (defined as a response rate greater than or equal to 20% in a trial with greater than or equal to 14 assessable patients), and 12 were inactive. Due to methodologic problems with the clinical trials, the usefulness of the remaining 34 drugs (60%) remains uncertain. Deficiencies identified in trials include inappropriate sample sizes, poorly defined response criteria, and failure to report important prognostic factors. When studied in adequate trials, all agents known to be active in SCLC had an observed response rate greater than or equal to 10% in previously treated patients. CONCLUSIONS Over the past 2 decades, phase II trials in SCLC have failed in their primary task of effectively identifying agents that warrant further clinical study and rejecting inactive agents. If only previously treated patients had been entered into these trials, no useful agent would have been missed provided that a lower observed response rate had been used as evidence of antitumor activity. We propose a two-stage sequential study design, entering previously treated patients, for future phase II trials in SCLC.

An open-label phase 1b/2 study of surufatinib in combination with tislelizumab in subjects with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2677-TPS2677
Author(s):  
Arvind Dasari ◽  
John S. Kauh ◽  
Christopher Tucci ◽  
Shivani Nanda ◽  
Marek K. Kania ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Solid Tumors ◽  
Neuroendocrine Tumors ◽  
Cell Lung Cancer ◽  
Primary Objective ◽  
Small Cell ◽  
Small Cell Lung

TPS2677 Background: Surufatinib (S) is an inhibitor of VEGFR1, 2, & 3; FGFR1; and CSF-1R. In two phase 3 randomized trials (SANET-ep; NCT02588170 & SANET-p; NCT02589821) S demonstrated a manageable safety profile and statistically significant efficacy. Patients (pts) with extrapancreatic neuroendocrine tumors (epNETs) achieved a median progression free survival (PFS) of 9.2 v 3.8 months (mo) (hazard ratio [HR] 0.334; p<0.0001), and pts with pancreatic NETs (pNETs) achieved a median PFS of 10.9 v 3.7 mo (HR 0.491; p=0.0011), with S v placebo, respectively. S was recently approved for the treatment of pts with epNET in China. Tislelizumab (T) is a humanized immunoglobulin G4 anti-PD-1 monoclonal antibody engineered to minimize binding to Fc-gamma-receptor on macrophages. T is approved in China in combination with chemotherapy for squamous non-small cell lung cancer and has conditional approval for Hodgkin’s lymphoma and locally advanced or metastatic urothelial carcinoma with PD-L1 high expression. The objective of this study is to evaluate the safety and efficacy of combination therapy with S and T, which may have synergistic effects, where inhibition of angiogenesis along with stimulation of an immune response may enhance the overall antitumor activity. Methods: This study (NCT04579757) will include pts, ≥18 years of age, with advanced metastatic solid tumors, who have an Eastern Cooperative Oncology Group performance status of 0 or 1 and have progressed on or are intolerant to standard therapies. The primary objective of part 1 (dose escalation) will be to evaluate the safety and tolerability of S and T to determine the recommended phase 2 dose of the combination. The starting dose in part 1 will be 250 mg of S, orally, daily, and 200mg of T, intravenously, every 3 weeks. The dose of S will be escalated during part 1, while the dose of T will remain fixed. Endpoints include dose limiting toxicities, treatment emergent adverse events, serious adverse events, adverse events leading to discontinuation, electrocardiograms, clinical laboratory abnormalities and vital signs. Antitumor activity will be evaluated as a secondary objective. Six to 12 pts will be enrolled. The primary objective of part 2 (dose expansion) will be to evaluate the objective response rate (ORR) of S in combination with T per RECIST v1.1. The endpoint will be ORR at 12 weeks. Key secondary endpoints include PFS, disease control rate, duration of response, safety endpoints, and PK parameters. Approximately 95 pts with indications of interest will be enrolled: colorectal cancer, neuroendocrine tumors (thoracic and gastroenteropancreatic), small-cell lung cancer, gastric cancer, and soft tissue sarcoma (undifferentiated pleomorphic sarcoma and alveolar soft part sarcoma). Enrollment in the United States is open and ongoing, and enrollment in Europe is planned for fourth quarter 2021. Clinical trial information: NCT04579757.

Phase 1 and phase 2a, first-in-human (FIH) study, of DRP-104, a broad glutamine antagonist, in adult patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3149-TPS3149
Author(s):  
Melissa Lynne Johnson ◽  
Deborah Blythe Doroshow ◽  
Tanguy Y. Seiwert ◽  
Michael K. Gibson ◽  
Vamsidhar Velcheti ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Adult Patients ◽  
Glutamine Metabolism ◽  
Advanced Solid Tumors

TPS3149 Background: Dependence of cancer cells on glutamine has made glutaminolysis an attractive therapeutic target in cancer. Prior clinical trials evaluating glutamine analogues for the treatment of cancer were abandoned due to lack of efficacy and/or tolerability. DON (6-Diazo-5-oxo-L-norleucine) is an irreversible inhibitor of several enzymes that utilize glutamine as a metabolic substrate. In addition to direct anti-tumor efficacy, inhibition of glutamine metabolism in the tumor microenvironment has been shown to improve T-cell activation and tumor infiltration, increasing anti-tumor immune responses. As such, combining DON with an immune checkpoint inhibitor (ICI), has strong preclinical rationale. The investigational product DRP-104 (sirpiglenastat) is an inactive prodrug of DON designed to limit systemic DON exposure while targeting glutamine dependence in tumor cells. Methods: A phase 1/2a, FIH, multi-center, non-randomized, multi-cohort, open-label study of DRP-104 is currently open to accrual for patients with advanced solid tumors. This study will be conducted in 4 parts: A) Dose Escalation of IV and subQ DRP-104 (Run-In phase followed by modified Continual Reassessment Method) to define MTD/RP2D. Primary objective of dose escalation is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of DRP-104 as a single agent; B) Dose Expansion of IV and subQ DRP-104 for safety assessment while primary objective is to select and recommend phase 2 DRP-104 route of administration; C) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in 2 patient cohorts: patients with locally advanced/metastatic NSCLC with KEAP1, NFE2L2 and/or STK11 mutation and patients with unresectable or metastatic SCCHN, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 as a single agent; D) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in combination with atezolizumab in adult patients with advanced solid tumors previously treated with an ICI, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 in combination with atezolizumab; DRP-104 IV is infused TIW over 1 hour infusion for 2 consecutive weeks followed by 1 week off. DRP-104 subQ is administered BIW weekly. Study is currently open with 6 IV patients (Run-In Phase completed and at Dose Level 4) and 3 subQ patients at Dose Level 1 at time of submission. Clinical trial information: NCT04471415.

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