A phase I study of intravesical Ad-IFN in superficial bladder cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16048-e16048
Author(s):  
C. P. Dinney ◽  
W. F. Benedict ◽  
D. L. Cutler ◽  
M. F. Fisher ◽  
M. A. O'Donnell
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Prolonged Exposure ◽  
Superficial Bladder Cancer ◽  
Response Duration ◽  
Maximum Tolerated Dose ◽  
Interferon Α ◽  
Anticholinergic Medication ◽  
Open Label

e16048 Background: Intravesical BCG (Bacillus Calmette-Guérin) is the gold standard for treatment of superficial bladder cancer. Recurrence is a significant problem. Intravesical interferon α (IFN) demonstrated complete response (CR) in ∼40% patients with most relapsing <1 year. Intravesical Ad-IFN takes advantage of the bladder to allow prolonged exposure to high concentrations of IFN; this is expected to potentiate durable therapeutic responses. Syn3 is an excipient used to increase adenoviral vector (Ad) transfection. Methods: The phase I study is a nonrandomized, open-label, rising-dose, multi-center study of Ad-IFN in patients with papillary bladder cancer, or carcinoma in situ refractory to BCG. Patients with T1 were not enrolled unless they refused cystectomy. A minimum of 3 subjects were enrolled at each dose level. Adverse events and lab abnormalities were graded according to CTC version 3 criteria. The occurrence of treatment-related Grade 3 or Grade 4 toxicity is considered dose-limiting toxicity (DLT). The maximum tolerated dose is defined as the dose which results in DLT in ≤1/6 subjects. Urine from pre-treatment, posttreatment days 0–7, 10, 14, and 28 were tested for IFN, Syn3, Ad-IFN DNA, and research biomarkers. Blood was assayed for IFN, Syn3, Ad-IFN DNA, anti- adenovirus and anti-IFN antibodies. Results: Intravesical administration of 3×109, 1×1010, 3x1010, 1×1011, or 3×1011 particles/ml of Ad-IFN (75ml) in 1mg/ml Syn3 is safe with only minor initial urgency controlled with anticholinergic medication. Of the 13 evaluable patients, 6 are CR, defined as a negative cytology and biopsy at 3 months. CR patients were offered a second dose. Response duration is variable with longest >1 year. Urinary IFN was seen for all patients in a dose-dependent fashion. TRAIL, IP-10, M65, and M30 were also seen. Conclusions: Initial safety and response activity justify further clinical development. [Table: see text]

A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Ying Cheng ◽  
Ying Liu ◽  
Jinhua Xu ◽  
Jing Zhu ◽  
Ying Wang ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Renal Cancer ◽  
Phase I Study ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

A first-in-human phase I study of CZ48, a lactone ring protected oral camptothecin, in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2578-2578
Author(s):  
Devalingam Mahalingam ◽  
Montaser F. Shaheen ◽  
John Sarantopoulos ◽  
Steven Weitman ◽  
Beppino C. Giovanella ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Poor Correlation ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label

2578 Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m2, advancing to 2560mg/m2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m2 and escalated to 1g/m2on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3+3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and Cmax or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson's correlation coefficient ϱ=0.476, p<0.01) and CZ48 Cmax(ϱ =0.51, p<0.01). Evidence of clinical activity with stable disease ≥ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m2 and 576 mg/m2. Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.

scholarly journals A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Siqing Fu ◽  
David E. Piccioni ◽  
Hongtao Liu ◽  
Rimas V. Lukas ◽  
Santosh Kesari ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Cytotoxic T Lymphocyte ◽  
Wilms Tumor ◽  
Biological Marker ◽  
Human Leukocyte ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Advanced Malignancies

AbstractWT2725 is a Wilms’ tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56–81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309–648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6–19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.

Phase I results from a study of lapatinib with gemcitabine and cisplatin (GC) in advanced/metastatic bladder cancer.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 252-252 ◽  
Author(s):  
Gedske Daugaard ◽  
Lisa Sengeløv ◽  
Mads Agerbaek ◽  
Cora N. Sternberg ◽  
Carla Van Herpen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Primary Phase ◽  
Her2 Status ◽  
Metastatic Bladder Cancer ◽  
Standard Chemotherapy Regimen ◽  
Ecog Ps

252 Background: Lapatinib (Tykerb, Tyverb) is a potent EGFR and ErbB2 inhibitor approved for the treatment of breast cancer. GC is a standard chemotherapy regimen for advanced/metastatic bladder cancer and there are preclinical and clinical data suggesting the role of EGFR and HER2 in urothelial carcinoma. This phase I study examined the safety of lapatinib in combination with GC in patients (pts) with bladder cancer. Methods: The primary phase I objective was to determine the maximum tolerated dose of lapatinib 750–1,250 mg that could be administered safely with GC in bladder cancer pts. A 3+3 dose escalation was used with lapatinib 750 mg, 1000 mg and then 1250 mg. Lapatinib was dosed daily and G (1000 mg/m² days 1, 8, 15) + C (70 mg/m² day 2) every 28 days. Results: 18 pts with median age 63 yrs (range 50-77) and ECOG PS 0/1 (66.7% with WHO-PS 0 and 33.3% with WHO-PS 1) were included. 3/6, 3/5 and 6/7 pts completed at least one cycle according to the protocol and received lapatinib 750 mg, 1000 mg and 1250 mg + GC, in cohorts 1, 2 and 3, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 or 2 (3 pts each); in cohort 3 (2 x 3 pts), 1 of 6 pts had DLT (Gr4 related febrile neutropenia and renal failure). One discontinued due to pt decision after 1 cycle. Ten pts received 6 cycles and one 7 cycles. The response rate among the 11/12 eligible patients was 73% (1 CR, 7 PR, 3 SD and 1 not assessable). Further toxicity data together with responses in relation to EGFR and HER2 status will be presented. Conclusions: Within the limits of a phase I study, lapatinib 750–1,250 mg + GC appears safe and tolerable with considerable activity at the maximum planned dose in bladder cancer. Clinical trial information: NCT00623064.

Phase I Study of Forodesine (BCX1777), An Oral PNP Inhibitor In Patients with Relapsed or Refractory T/NK Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1796-1796 ◽  
Author(s):  
Kunihiro Tsukasaki ◽  
Michinori Ogura ◽  
Hirokazu Nagai ◽  
Jun Taguchi ◽  
Tatsuya Suzuki ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase I Study ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study

Abstract Abstract 1796 Background: Forodesine is a rationally designed potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to elevation of plasma deoxyguanosine (dGuo) and intracellular accumulation of dGTP levels and then apoptosis mainly in T cells. Oral forodesine has shown clinical activity in patients with cutaneous T-cell lymphoma (CTCL) (M. Duvic et al, ASH 2007). The objective of this phase I study was to evaluate the safety, PK profile, and efficacy of oral forodesine in patients with recurrent or refractory T/NK malignancies in Japan. Methods: An open-label dose-escalation study of forodesine, 100 to 300 mg/body qd for 4 weeks, was conducted to evaluate safety profile (dose-limiting toxicities, DLT), tolerability and PK profile as primary endpoints. Forodesine was administered until disease progression or unacceptable toxicity is observed. Relapsed or refractory T/NK malignancies with PS 0 to 1 and without major organ dysfunction were eligible. Results: Overall, 13 Japanese patients, 8 males and 5 females, with a median age of 69 (range 30–77) years were enrolled in the study: 5 patients in the 100mg cohort, 3 in the 200mg cohort and 5 in the 300mg cohort. Patients’ histopathologic subtypes were as follows: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (6 patients), anaplastic large cell lymphoma (ALCL) (3), primary cutaneous ALCL (C-ALCL) (2) and mycosis fungoides (MF) (2). Median stage and prior treatment regimen were IIIA (range IA-IVA) and 2 (range 1, 8), respectively. No DLT was observed and a maximum tolerated dose was never defined. The most common toxicities of grade 2 or less were constipation (39 %), rash (31%), lymphopenia (31 %), neutropenia (23 %), nausea (23 %), peripheral edema (23 %), LDH elevation (23 %) and leukopenia (23 %). The toxicities of grade 3 or greater were lymphopenia (62 %), anemia (15 %), leukopenia (8 %), thrombocytopenia (8 %) and viral infection (8 %). Median baseline, nadir, and last visit lymphocytes counts (1,000/μL) were 0.69 (95% CI: 0.56, 1.18), 0.35 (95% CI: 0.14, 0.60) and 0.60 (95% CI: 0.24, 0.95), respectively. Plasma levels for forodesine showed less than dose-proportional increase in exposure as mean AUC at Day 1 was 1,948 (ng·h/mL) in the 100mg cohort, 4,608 (ng·h/mL) in the 200mg cohort, and 4,596 (ng·h/mL) in the 300mg cohort. The levels for dGuo displayed a similar trend, with mean AUC at Day 1 4,023 (ng·h/mL) in the 100mg cohort, 5,705 (ng·h/mL) in the 200mg cohort, and 6,074 (ng·h/mL) in the 300mg cohort. One patient with ALCL reached complete response (CR) in the 100mg cohort and 2 patients with MF reached partial response in the 200mg cohort. In addition, 4 patients with stable disease (SD) were observed: 1 patient with PTCL-NOS in the 100mg cohort, 1 with C-ALCL in the 200mg cohort and 2 with C-ALCL and PTCL-NOS in the 300mg cohort. As of Aug, 2010, 2 patients with ALCL (CR patient in the 100mg cohort) and PTCL-NOS (SD patient in the 300mg cohort) have continued the treatment for more than 510 days and 290 days, respectively. Conclusion: Oral forodesine was well tolerated at all the dose levels tested with similar PK findings to those in the CTCL study in USA, demonstrating potential efficacy against relapsed or refractory T/NK lymphomas including PTCL for the first time. Based on these promising data, we are planning a phase I /II study of forodesine in patients with relapsed or refractory PTCL. Disclosures: No relevant conflicts of interest to declare.

Phase I Study of Weekly Oxaliplatin in Relapsed or Refractory Pediatric Solid Malignancies

2008 ◽  
Vol 26 (27) ◽  
pp. 4394-4400 ◽  
Author(s):  
Birgit Geoerger ◽  
François Doz ◽  
Jean-Claude Gentet ◽  
Michele Mayer ◽  
Judith Landman-Parker ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Weekly Schedule ◽  
Open Label ◽  
Solid Malignancy ◽  
Phase Ii Studies ◽  
Solid Malignancies ◽  
Two Phases

Purpose To explore feasibility, maximum-tolerated dose (MTD), and recommended dose (RD) for phase II studies of weekly oxaliplatin for the treatment of relapsed or refractory pediatric solid malignancies. Patients and Methods Eligible patients were 6 months to 21 years old, had a diagnosis of a solid malignancy, and had experienced treatment failure with at least two or more previous lines of therapy. The phase I study was multicentric, open-label, and nonrandomized. It foresaw two phases: a dose-escalation phase (comprising six levels) to find the RD and an extension at the RD to evaluate the cumulative toxicity. Oxaliplatin was administered intravenously over 2 hours on days 1, 8, and 15 of a 28-day cycle. Results Forty-five patients were enrolled: 29 patients in the dose-escalation phase and 16 patients in the extension at the RD. Median age was 9.5 years (range, 2.8 to 20.0 years) and 7.8 years (range, 1.8 to 19.2 years), respectively. The dose-limiting toxicities during the first treatment cycle were grade 3 (G3) sepsis at 50 mg/m2, G3 dysesthesia at 90 mg/m2, and G3 dysesthesia and G3 paresthesia at 110 mg/m2, thus the MTD and RD was 90 mg/m2. No case of ototoxicity was reported. Stable disease was reported in seven patients (16.3%), and confirmed partial response was observed in two patients (4.7%), one with neuroblastoma and one with osteosarcoma. Conclusion Oxaliplatin administered in a weekly schedule has an acceptable safety profile, different from cisplatin and carboplatin, and shows activity in children with relapsed or refractory solid tumors, suggesting further investigation in pediatric malignancies.

Phase I Trial of Intravesical Docetaxel in the Management of Superficial Bladder Cancer Refractory to Standard Intravesical Therapy

2006 ◽  
Vol 24 (19) ◽  
pp. 3075-3080 ◽  
Author(s):  
James M. McKiernan ◽  
Puneet Masson ◽  
Alana M. Murphy ◽  
Manlio Goetzl ◽  
Carl A. Olsson ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Superficial Bladder Cancer ◽  
Transitional Cell ◽  
Maximum Tolerated Dose ◽  
Intravesical Therapy ◽  
Systemic Absorption ◽  
Microtubule Depolymerization ◽  
Grade 3

Purpose Up to 50% of patients treated with intravesical agents for superficial bladder cancer will experience recurrence. Response rates to second-line intravesical therapies range from 20% to 40%. For these high-risk patients, novel agents are necessary to prevent recurrence. Docetaxel is a microtubule depolymerization inhibitor with unique physiochemical properties, making it an excellent candidate for investigation as an intravesical agent. Patients and Methods This phase I trial included patients with recurrent Ta, T1, and Tis transitional cell carcinoma who experienced treatment failure with at least one prior intravesical treatment. Docetaxel was administered as six weekly instillations at a starting dose of 5 mg, with a dose-escalation model used until a maximum tolerated dose (MTD) was achieved. Primary end points were dose-limiting toxicity (DLT) and MTD. Efficacy was evaluated by cystoscopy with biopsy, cytology, and computed tomography imaging. Results Eighteen patients (100%) completed the trial, and the distribution of stages included six patients with Tis, seven with Ta, and five with T1 disease. No grade 3 or 4 DLTs occurred in 108 infusions, and no patient had systemic absorption of docetaxel. Eight (44%) of 18 patients experienced grade 1 or 2 toxicities, with dysuria being the most common. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy. None of the patients who experienced relapse had disease progression. Conclusion Intravesical docetaxel exhibited minimal toxicity and no systemic absorption in the first human intravesical clinical trial. This suggests that docetaxel is a safe agent for further evaluation of efficacy in a phase II trial.

A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3026-3026 ◽  
Author(s):  
Nicolas Isambert ◽  
Antoine Hollebecque ◽  
Yann Berge ◽  
Hein van Ingen ◽  
Silvano Brienza ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Hsp90 Inhibitor ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study

3026 Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]

Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2562-2562 ◽  
Author(s):  
Manish R. Patel ◽  
Gerald Steven Falchook ◽  
Judy Sing-Zan Wang ◽  
Esteban Rodrigo Imedio ◽  
Sanjeev Kumar ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Human Monoclonal Antibody ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Drug Induced ◽  
Recommended Phase Ii Dose

2562 Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]

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