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.

Safety, pharmacokinetics, and antitumor activity of MEDI-573, an investigational monoclonal antibody that targets IGF-I and IGF-II, in adult patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2618-TPS2618 ◽  
Author(s):  
Paul Haluska ◽  
Michael E. Menefee ◽  
Elizabeth R. Plimack ◽  
Jonathan E. Rosenberg ◽  
Donald W. Northfelt ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Glucose Homeostasis ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Adult Patients ◽  
Human Antibody ◽  
Advanced Solid Tumors ◽  
Igf I

TPS2618 Background: MEDI-573 is an investigational dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF‑1R and insulin receptor-A (IR-A) signaling pathways. By sparing IR-B and its hybrid receptors, MEDI-573 may achieve antitumor activity without perturbing glucose homeostasis. Objectives of this phase 1 dose-escalation and expansion study are to evaluate safety and determine the maximum tolerated dose (MTD), optimal biologically effective dose, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI-573 in adult patients with solid tumors. Methods: Patients with advanced solid tumors, Karnofsky status ≥60, and adequate organ function were treated with escalating doses of MEDI-573 IV once weekly (0.5 to 15 mg/kg) or every 3 weeks (30 or 45 mg/kg q3w) using a 3+3 design. Three patients per dose level were evaluated for safety. A biomarker-rich dose-expansion arm tested weekly 5 or 15 mg/kg MEDI‑573 in patients with advanced bladder cancer. Results: Preliminary data are presented for 43 patients (25 M, 18 F), median age 64 years. No dose-limiting toxicities or serious toxicity patterns occurred at any dose level. Drug-related adverse events occurring in ≥10% of patients were fatigue (28%), decreased appetite (23%), nausea (16%), diarrhea (14%), and anemia (12%); the majority were ≤ grade 2. Perturbations in insulin and growth hormone were not observed. Clinically significant changes in serum glucose were rare. The MTD was not reached after completely enrolling patients through the highest dose, 45 mg/kg IV q3w. Serum exposure of MEDI-573 increased with increasing dose. Full suppression of IGF‑I/-II was achieved with weekly and q3w dosing. No neutralizing antibodies against MEDI‑573 were detected. Of 43 patients, 8 (19%) had stable disease ≥12 weeks. The longest exposure was 21 months in a patient with well-differentiated liposarcoma. Conclusions: MEDI-573 demonstrated an acceptable safety profile at all doses tested. No dose-limiting toxicity or serious toxicities, including those related to glucose homeostasis, were detected. These preliminary results support further clinical development.

Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3051-3051
Author(s):  
Nebojsa Skorupan ◽  
Mehwish Iqra Ahmad ◽  
Guillaume Joe Pegna ◽  
Cody J. Peer ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Primary Objective ◽  
Pseudomonas Exotoxin A ◽  
Recombinant Immunotoxin ◽  
Level 1 ◽  
Expansion Cohort ◽  
Almost All

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Igor Puzanov ◽  
Patricia LoRusso ◽  
Kyriakos P. Papadopoulos ◽  
Christopher T. Chen ◽  
Yvan LeBruchec ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

Phase I study of oral S-1 in combination with oxaliplatin (oxali) and bevacizumab (bev) in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4091-4091
Author(s):  
J. Zhang ◽  
K. Chung ◽  
C. Zergebel ◽  
P. Urrea ◽  
M. Quinones ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Cyanuric Acid ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Clinical Pharmacokinetics ◽  
Progression Of Disease ◽  
Recommended Phase Ii Dose

4091 Background: S-1 is a novel oral fluoropyrimidine (tegafur, CDHP and potassium oxonate) designed for enhanced DPD inhibition and reduced GI toxicity. Bev and oxali have demonstrated safety and synergistic anti-tumor activity with oral and IV fluoropyrimidines. The primary objective is to investigate the safety and maximum tolerated dose (MTD) of S-1 combined with bevacizumab and oxaliplatin in patients with advanced solid tumors. Secondary objective is to investigate the clinical pharmacokinetics (PK) of the components of S-1 (FT, CDHP, Oxo), 5-FU, a-fluoro-β-alanine, cyanuric acid, uracil, and oxali and to document any antitumor activity. Methods: ECOG 0/1 patients with advanced or metastatic solid tumors received oral S-1 starting at 20 mg/m2/dose BID x 14 days (classic 3+3 cohort dose escalation by 5mg/m2/dose until MTD), plus fixed doses of bev 7.5 mg/kg IV day 1, and Oxali 130 mg/m2 IV day 1 of every 3 week cycle, with discontinuation of oxali after 4 cycles. Reintroduction of oxali was allowed upon progression of disease. Toxicity, antitumor activity and PKs were assessed. The MTD was defined as the highest dose level at which < 33% of the patients experience a dose- limiting toxicity (DLT) during the first 2 cycles. Results: Of 22 evaluable patients, 3 patients were treated at 20mg/m2 S1 and 13 patients were treated at 25mg/m2 S1 without a DLT. At 30mg/m2, two patients experienced a DLT(Grade 3 diarrhea, Grade 4 mucositis). The MTD and recommended phase II dose of S-1 is 25mg/m2 in combination with oxali and bev. A median of 8 cycles of S-1 were initiated at the 25 mg/m2 dose level. Common MTD level toxicities included fatigue (62%), nausea (62%) and diarrhea (46%), with no grade 4 toxicities observed. Best responses (RECIST): stable disease(16 patients), partial response (2 patients), non-measurable disease (3 patients). The Day 8 AUC(0–8) of 5-FU at 20/25/30 mg/m2 dose level were 230±115 hr*ng/ml, 470±172 hr*ng/ml and 502±169 hr*ng/ml, respectively. Conclusions: The MTD combination of 25mg/m2 S-1, oxali and bev can be given safely. The study will be expanded to test S-1 one week on, one week off schedule in combination with oxali/bev every two weeks. No significant financial relationships to disclose.

Phase I dose-escalation, open-label study of HSP990 administered orally in adult patients with advanced solid malignancies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2561-2561
Author(s):  
Leticia De Mattos-Arruda ◽  
Lillian L. Siu ◽  
Javier Cortes ◽  
Yann Berge ◽  
Albiruni R A Razak ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Metabolic Response ◽  
Single Agent ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Oncogenic Signaling ◽  
Open Label ◽  
Solid Malignancies

2561^ Background: NVP-HSP990 is a synthetic small molecule that potently and selectively inhibits heat-shock protein 90. HSP990 leads to degradation of client proteins, offering potential simultaneous blockade of multiple oncogenic signaling pathways. The primary objective of this Phase l first-in-man study (NCT00879905) was to determine the single-agent MTD of HSP990 administered once (qw) or twice (biw) weekly to patients (pts) with advanced solid malignancies (preselected CYP2C9 genotypes only). Secondary objectives included safety, efficacy, PK, and biomarkers. Methods: HSP990 was administered orally qw or biw in 28-day cycles. Dose escalation was guided by a Bayesian logistic regression model. The MTD was determined by assessing DLTs in Cycle 1. Eligible pts included those with histologically confirmed advanced solid tumors that had progressed on standard therapy or for whom no standard therapy exists. Results: 64 pts (median age 57 yr: 44% male; 37.5% Stage IV; WHO PS 0/1) received HSP990. 53 pts received HSP990 qw at 2.5, 5, 10, 20, 30, 50 or 60 mg; and 11 pts received HSP990 biw at 25 mg. Median duration of exposure was 8 wks; 12 pts remained on treatment for >16 wks. DLTs occurred in 7 pts: 4/22 at 50 mg qw (including G3 diarrhea, G3 QTc prolongation, G4 ALT/AST elevations); 2/5 at 60 mg qw (including G3 tremors); and 1/11 at 25 mg biw (including G2 ataxia, G2 confusion, G2 visual hallucination). The 50-mg qw dose was declared as the MTD. Further dose escalation was not possible due to neurologic toxicity. Most common reported CTCAE G3/4 AEs were diarrhea (12.5%), increased ALT/AST (11% each), anemia, or cholestasis (6% each). HSP990 had Tmax of 3 h and T½ of ~20 h. Large inter-patient variability in PK exposures was observed. For qw dosing, approximate dose-dependent HSP70 induction was observed from 5−30 mg qw, which plateaued after 20 mg qw. There were no objective responses; however, 25 pts (39%) had SD. (RECIST v1.0). No pt showed a complete metabolic response (MR; by FDG-PET) and 11 pts (17%) showed a partial MR. All pts discontinued treatment, primarily due to disease progression (84%). Conclusions: The single-agent MTD of HSP990 in pts with advanced solid tumors was 50 mg qw. SD was observed in 39% of pts. Clinical trial information: NCT00879905.

scholarly journals Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase ◽  
Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

First-in-human phase I study of SY-5609, an oral, potent, and selective noncovalent CDK7 inhibitor, in adult patients with select advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3662-TPS3662 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Manish Sharma ◽  
Erika Paige Hamilton ◽  
Debra L. Richardson ◽  
Graeme Hodgson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Cell Cycle Control ◽  
Single Agent ◽  
Genetic Alterations ◽  
Adult Patients ◽  
Molecular Evidence ◽  
Advanced Solid Tumors ◽  
Rb Pathway

TPS3662 Background: SY-5609 is an oral, noncovalent, highly selective and potent inhibitor of cyclin-dependent kinase 7 (CDK7), a key regulator of 2 biological processes that play critical roles in driving tumor development: transcription and cell cycle control. Evaluation of SY-5609 as a single agent in PDX models from a range of solid tumors, including breast, ovarian, lung and colorectal tumors, revealed robust antitumor activity including complete regressions, and activity in models known to be resistant to standard of care therapy. Models with genetic alterations in RB pathway genes demonstrated deep ( > 90% TGI) and sustained SY-5609-induced tumor regressions following treatment discontinuation, in contrast to models without genetic alteration in RB pathway genes, suggesting that tumor cells with aberrant cell-cycle control may be particularly sensitive to SY-5609 treatment. The study is designed to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of SY-5609, to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and preliminary antitumor activity of SY-5609, and to explore candidate biomarkers predictive of response to SY-5609. Methods: This is a multi-center, open-label Phase 1 trial expected to enroll approximately 60 adult patients with select advanced solid tumors for which standard treatment is no longer effective. The dose escalation phase of the trial is open to adult patients with ovarian, breast, colorectal, or lung cancer, and patients with any solid tumor histology with molecular evidence of deregulated RB cell cycle control. SY-5609 is being administered orally once daily, for each 4-week cycle. Initially, patients will be enrolled into single-patient accelerated titration cohorts; subsequent cohorts will transition to a 3 + 3 design. Following completion of DLT evaluation at a given dose level, additional patients may be enrolled at that dose to further characterize safety, PK, PD, and early clinical activity. Data from this trial will support dose selection for planned evaluations of antitumor activity of SY-5609 as a single agent and in combination. Clinical trial information: NCT04247126 .

Sign in / Sign up

Export Citation Format

Share Document