A phase I, open-label, multicenter, single-dose escalation and multi-dose study of a monoclonal antibody targeting CEACAM1 in subjects with selected advanced or recurrent malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3094-3094
Author(s):  
Roni Shapira ◽  
Jeffrey S. Weber ◽  
Ravit Geva ◽  
Mario Sznol ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Drug Disposition ◽  
Phase 1 ◽  
Primary Objective ◽  
Immune Checkpoints ◽  
Open Label ◽  
Trial Testing ◽  
Dose Study ◽  
Cea Gene ◽  
Grade 3

3094 Background: The carcinomembryonic antigen cell adhesion molecule 1 (CEACAM1, CD66a) is a member of the CEA gene family. CEACAM1 interacts homophilically and heterophilically with CEACAM5, and is involved in various anti-proliferative activities. CEACAM1 is expressed on a variety of epithelial and hematological cells, including multiple types of cancer and activated lymphocytes. High CEACAM1 expression in some tumor types is known to be associated with poor disease prognosis. Recently it was demonstrated CEACAM1 is co-expressed on exhausted lymphocytes with other immune checkpoints such as TIM-3 and may regulate downstream activity. CM24 is a novel humanized α-CEACAM1-specific antibody with nM affinity to the N terminal domain of CEACAM1, which blocks intercellular CEACAM1 interactions. Methods: The primary objective was to test the safety and tolerability of CM24 in adult patients with advanced or recurrent cancer. Secondary objectives included assessment of CM24 PK and PD profiles, anti-tumor response and the recommended Phase 2 dose. Patient received IV infusion of CM24 at 7 dose levels ranging between 0.01 and 10 mg/kg in a cycle of 4 doses administered q2wks followed by a 6-week observation only period and additional 6 cycles. Results: 27 patients (median pretreatment of 4 prior regimens; range 2-8, 11 colorectal, 7 melanoma, 4 ovarian, 3 gastric, 2 NSCLC; 13 males, 14 females, mean age of 60 years), were included. Treatment with CM-24 was overall well-tolerated without DLTs up to 10 mg/kg. The most frequent AE was grade 1-3 increased alanine aminotransferase (7 subjects) and the most severe AE was grade 3/4 increase in gamma-glutamyltransferase (4 subjects). Drug-related AEs were observed in 63% of the subjects with grade 3-5 occurred in 3.7%. Eight subjects (29.6%) had stable disease as the best overall response. Median overall survival was 4 (3.4, 8.0) and 6.2 (2.7, 10.2) months for the 3 and 10 mg/kg doses, suggesting dose response. Cmax, AUC and t1/2 increased with increasing dose with the longest t1/2 of 11.2 days obtained at 10mg/kg. The average target occupancy of CM24 at 3mg/kg and 10mg/kg were 75% and 93%, respectively. Conclusions: PK and target-mediated drug disposition analysis suggest that doses higher than 10mg/kg are needed for target saturation at a q2 week regimen while a q3 week regimen is less optimal. A phase 1/2 clinical trial testing CM24 in combination with anti-PD-1 therapy in patients with NSCLC including assessment of CEACAM1 expression is warranted. Clinical trial information: NCT02346955 .

Early safety from a phase 1, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 438-438 ◽  
Author(s):  
J. Randolph Hecht ◽  
Miklos Pless ◽  
Antonio Cubillo ◽  
Aitana Calvo ◽  
Steven Raman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Liver Tumors ◽  
Disease Incidence ◽  
Phase 1 ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

438 Background: T-VEC is a genetically modified HSV-1 oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF, and stimulate anti-tumor immune responses. This study evaluates the safety of intrahepatic injection (inj) of T-VEC in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated dose. Eligible pts were ≥ 18 years (y) old, had progressive HCC or breast cancer (BC), colorectal cancer (CRC), gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer with liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 1) or 108 PFU/mL (cohort 2) every 21 (±3) days (Q21D), or up to 8 mL of the maximum tolerated concentration (MTC) Q21D (cohort 3). Inj volume was based on lesion size. Results: Results from cohorts 1 and 2 of group A are reported. 14 pts were treated; 12 (3 BC, 9 CRC) were DLT-evaluable: Median age was 65.5 y (range: 33, 73); median number of inj was 3; 1 pt received all 12 inj. MTC was 108 PFU/mL. There was 1 DLT, grade 3 aspartate aminotransferase (AST)/grade 2 bilirubin increase (inc), after 1 dose. In all treated pts, 4 (28.6%) had grade 3/4 treatment-related adverse events (TRAEs): anemia and inc gamma-glutamyltransferase, alanine aminotransferase (ALT), and AST. There were 2 deaths attributable to disease. Incidence of serious AEs (SAEs) is shown (Table). Conclusions: The MTC was 108 PFU/mL Q21D after initial inj at 106 PFU/mL. Repeated intrahepatic inj of T-VEC at the FDA-approved concentration for intralesional inj of melanoma was deemed tolerable and feasible in pts with liver mets. Additional investigation in combination with a PD-1 inhibitor is planned. Clinical trial information: NCT02509507. [Table: see text]

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]

Early results of TROPHY-U-01 Cohort 2: Sacituzumab govitecan (SG) in platinum-ineligible patients (pts) with metastatic urothelial cancer (mUC) who progressed after prior checkpoint inhibitor (CPI) therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5027-5027 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Scott T. Tagawa ◽  
Rohit K. Jain ◽  
Manojkumar Bupathi ◽  
Arjun Vasant Balar ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Primary Objective ◽  
First Line ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Early Results ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Grade 3

5027 Background: SG is an antibody-drug conjugate consisting of a humanized monoclonal anti–Trop-2 antibody coupled to the cytotoxic agent, SN-38, via a unique hydrolyzable linker. The epithelial cell surface antigen, Trop-2, demonstrates greater expression between UC vs normal tissue, and is a promising target. In a phase 1/2 basket study (IMMU-132-01), SG showed an overall response rate (ORR) of 31% and manageable toxicity in 45 pts with mUC who had a median of 2 (range 1–6) prior therapy lines (Tagawa 2019 ASCO GU). Recent interim results for cohort 1 of the TROPHY-U-01 study in 35 pts with mUC who progressed on platinum and CPI therapy demonstrated an ORR of 29% in pts with a median of 3 prior treatment lines (range 2–6) (Tagawa 2019 ESMO). The most common grade ≥3 treatment-related AE (TRAE) was neutropenia. Methods: TROPHY-U-01 (NCT03547973) is a global, open-label, phase 2 trial evaluating the antitumor activity of SG (10 mg/kg, days 1 and 8 of 21-day cycles) in pts with advanced UC with measurable disease and ECOG PS 0 or 1. Cohort 2 includes platinum-ineligible pts who progressed after CPI therapy in the first-line metastatic setting. The primary objective is ORR evaluated with RECISTv1.1 by central review. Secondary objectives include progression-free survival, overall survival, and duration of response. Results: 18 pts with baseline tumor assessment (50% male; median age 79 y [range 57–87], 67% visceral metastases; 28% liver metastases) received a median of 2 (range 1–5) prior therapies. At a median follow-up of 6 months, ORR was 28% (5/18) with 4 confirmed PRs, and 1 PR pending confirmation. The majority of pts (61% [11/18]) had target lesion reduction. The safety profile was consistent with prior reports. Key grade ≥3 TRAEs were neutropenia (39%), fatigue (33%), diarrhea (28%), leukopenia (22%), anemia (17%), and febrile neutropenia (11%). No events of interstitial lung disease, ocular toxicities, or grade > 2 neuropathy were reported. There were no treatment-related deaths. Conclusions: In cisplatin-ineligible pts, the ORR for currently approved first-line CPI treatments is ~23–29% (Balar 2017 Lancet; Vuky 2018 ASCO). These preliminary data with SG show a manageable safety profile with an encouraging ORR of 28% and support the development of SG in platinum-ineligible pts with mUC who have progressed after CPI therapy. Clinical trial information: NCT03547973 .

Bicalutamide with or without metformin for biochemical recurrence in prostate cancer patients (BIMET-1).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 85-85
Author(s):  
Marijo Bilusic ◽  
Matthew R. Zibelman ◽  
Pooja Ghatalia ◽  
Susan Wroblewski ◽  
Ravi Amrit Madan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Total Duration ◽  
Epidemiological Studies ◽  
Primary Objective ◽  
Duration Of Treatment ◽  
Open Label ◽  
Carcinogenic Agent ◽  
Randomized Phase Ii ◽  
Grade 3

85 Background: Metformin (MET) may play a role as an anti-proliferative and anti-carcinogenic agent. Epidemiological studies have demonstrated that MET is associated with decreased prostate cancer (PCa) incidence, including decreased PCa specific mortality in diabetic men with PCa. Preclinical studies have shown synergistic effect of MET with bicalutamide, thus prompting this clinical trial evaluating the combination (NCT02614859). Methods: This was an open label, randomized, phase II trial of pts with biochemically recurrent PCa, PSA doubling time 3-9 months, normal testosterone, and BMI > 25. Pts were randomized (2:1) either to MET 1000 mg twice daily orally or observation for initial 8 weeks. Bicalutamide 50 mg orally daily was added to both arms after 8 weeks. Total duration of treatment was 32 weeks. The primary objective was to determine number of pts with undetectable PSA ( < 0.2 ng/mL) at the end of study with key secondary objectives of evaluating PSA declines of ≥ 85%, PSA responses to MET alone and safety. An early stopping rule for futility was set at 39 pts, but due to slow accrual, an unplanned interim analysis was undertaken. Results: 28 patients were randomized between December 2015 and September 2019. Treatment was well tolerated with no dose reductions or treatment discontinuation. No Grade 3 treatment-related adverse events were observed. Conclusions: PSA responses were seen in 50% pts with MET monotherapy after 8 weeks. Although well tolerated, there was no difference in PSA at 32 weeks between the two arms. The trial will be stopped early due to poor accrual and inability to achieve its primary endpoint. Ongoing larger studies of MET in PCa (STAMPEDE) will define it’s utility in prostate cancer. Clinical trial information: NCT02614859. [Table: see text]

scholarly journals ACTR-54. OPEN-LABEL PHASE 1 CLINICAL TRIAL TESTING PERSONALIZED AND TARGETED INTERVENTION WITH SKULL REMODELLING SURGERY TO MAXIMIZE LEVELS OF TTFIELDS INTENSITY FOR HIGHER TREATMENT BENEFIT - THE OPTIMAL TTF STUDY

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi12-vi12
Author(s):  
Anders Rosendal Korshoej ◽  
Frederik Lundgaard Hansen ◽  
Lukacova Slavka ◽  
Søren Ole Stigaard Cortnum ◽  
Yasmin Lassen-Ramshad ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase 1 ◽  
Targeted Intervention ◽  
Open Label ◽  
Treatment Benefit ◽  
Phase 1 Clinical Trial ◽  
Trial Testing ◽  
Open Label Phase

A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2624-2624
Author(s):  
Manish R. Patel ◽  
Aung Naing ◽  
Howard A. Burris III ◽  
Chia-Chi Lin ◽  
Giuseppe Curigliano ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Cancer Therapies ◽  
Open Label ◽  
Efficacy Measures ◽  
Grade 3 ◽  
Dual Mechanism

2624 Background: KY1044, is a fully human IgG1 anti ICOS antibody designed to stimulate Teffs and to deplete ICOS high Tregs in the tumor microenvironment. Methods: Patients with advanced/metastatic malignancies received escalating doses of KY1044 as a single agent and in combination with atezolizumab 1200 mg by IV infusion every 3 weeks until disease progression or unacceptable toxicity. Dose escalation was guided by a modified toxicity probability interval design. The primary objective was to determine safety, tolerability, and maximum tolerated dose. Cohorts that were tolerated were later enriched with more subjects. AEs were classified according to CTCAE v5 and efficacy measures performed according to RECIST v1.1 every 8 weeks for the first 16 weeks and then every 12 weeks. Results: As of 16-Dec-2020, a total of 103 patients have been enrolled in the study (38 patients as monotherapy in 6 cohorts at doses ranging from 0.8 to 240 mg and 65 in combination with atezolizumab in 5 cohorts at doses 0.8 – 80 mg). 63% and 55% of patients received ≥4 prior anti-cancer therapies in the single agent and combination cohorts, respectively. All cohorts were completed without DLTs during the first 21 days of treatment. In the KY1044 single agent cohorts, 47.4% of patients experienced treatment-related AEs (TRAEs), all were grades 1 or 2. In the combination cohorts, TRAEs were observed in 58% of patients. Most of the TRAEs were grade 1 or 2 apart from 8 TRAEs that were ≥grade 3 occurring in <8% of patients. Infusion-related reactions, pyrexia and lymphopenia were the most commonly occurring TRAEs in ≥10% of patients. TRAE leading to dose interruptions occurred in 1 patient in the single agent cohort and in 4 patients in the combination cohort. Only 1 patient discontinued treatment due to myositis that was considered related to the combination. Preliminary KY1044 PK data from 69 patients agree with the PK model predictions. Median treatment duration for all enrolled patients was 9 weeks. Treatment duration ≥16 weeks was observed in 24% (9/38) and 27% (17/64) patients in the single agent and combination cohorts, respectively. Five objective responses, including 1 CR in triple negative breast cancer (TNBC) and 4 PRs in TNBC, head and neck squamous cell carcinoma, penile and pancreatic cancer were observed. Four of the 5 responding patients were still on treatment at the data cut, with 3 patients on treatment for >43 weeks (range 45 to 66 weeks). Conclusions: KY1044 is well tolerated as single agent and in combination with atezolizumab. Objective responses have been observed in this phase 1 part of the study. The phase 1 expansion and phase 2 part of the study is ongoing. Clinical trial information: NCT03829501.

First-in-human administration of CEB-01, a novel drug delivery implant matrix, in patients with recurrent or locally advanced retroperitoneal soft tissue sarcoma (RPS) after surgery: Preliminary safety and pharmacokinetics report.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11554-11554
Author(s):  
José Antonio Gonzalez ◽  
Ana Sebio ◽  
Paula Cerdà ◽  
Francesc Cano ◽  
José Antonio Tornero ◽  
...  
Keyword(s):  
Phase 1 ◽  
Locally Advanced ◽  
Primary Objective ◽  
Low Grade ◽  
Open Label ◽  
Biodegradable Implant ◽  
Time To Recurrence ◽  
Local Surgery ◽  
Grade 3 ◽  
Expansion Cohort

11554 Background: RPS local recurrence after radical surgery (SX) is frequent and a major cause of death. Locally delivered CHT by a biocompatible and biodegradable implant matrix (CEB-01) loaded with SN-38 and placed in the surgical bed during SX may increase local control and survival in RPS patients with reduced systemic toxicity. Methods: This is a multicentre, open label, first-in-human phase 1 trial comprising a dose-escalation phase (3 cohorts with total SN-38 doses of 9, 18 and 36 mg respectively), followed by an expansion cohort at the recommended phase 2 dose (RP2D). Recurrent or locally advanced RPS patients candidates for local surgery, with no option of systemic treatment, ECOG < 2, life expectancy > 6 months, and normal organ function are eligible. Primary objective is to determine RP2D, defined as the dose level at which less than 33% of patients present dose limiting toxicity (DLT) in a minimum of 6 at-risk patients during the first two weeks after SX. DLT is defined as any Grade ≥3 toxicity. Secondary objectives include safety, time to recurrence, biomarkers, pharmacokinetics (PK) and quality of life (QoL). Here we report preliminary safety, efficacy, and PK data for the initial patients enrolled. Results: First cohort of 9 mg SN-38 was completed in february 2021, with the inclusion of three patients with dedifferentiated liposarcoma, (grade 2-3) Patients were male, age 65 to 74, with ECOG of 0-1. Optimal SX were performed for recurrent/metastatic disease (2 patients) or locally advanced disease (1 patient) with complete (R0) and optimal (R1) outcomes. There were no surgical complications attributed to the SN-38 treatment. One patient suffered from grade 2 (Dindo Clavien classification) intestinal subocclusion due to SX complication resolved with medical treatment at day 5. Frequency and severity of adverse events (AE) was low. All the patients presented transitory abdominal discomfort and seroma. AEs consisted of one catheter infection and one hypomagnesemia, both grade 3. Only one treatment related AE (TRAE) consisting of alopecia grade 1 was reported. There were no DLTs observed during the first administrations of CEB-01 (9 mg SN38). SN38 and its glucuronidated SN-38 systemic levels were low, reaching a peak (Cmax) of 0.60 and 3.3 ng/mL at 2 and 6 hours respectively, and were detectable 27 days after CEB-01 implantation in the surgical bed, at 0.1 and 0.6 ng/mL respectively. Conclusions: CEB-01 biocompatible and resorbable implant matrix loaded with SN38 has proven to be safe upon first human administrations in RPS patients, with scarce low grade AEs and TRAE. Preliminary PK indicates low, prolonged, systemic SN-38 exposure as expected. Currently the second cohort of this trial is open for recruitment. Clinical trial information: NCT04619056.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

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