Phase I study of pucotenlimab (HX008), an anti-PD-1 antibody, for patients with advanced solid tumors

Background: Pucotenlimab is a humanized immunoglobulin G4 (IgG4) anti programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) with a S228P hinge mutation and an engineered Fc domain. Preclinical data suggests that pucotenlimab exerts antitumor effects. In this phase I study, which was prospectively registered on www.chinadrugtrials.org.cn (CTR20180125), the safety, maximum tolerated dose, preliminary antitumor activity, pharmacokinetics, and immunogenicity of pucotenlimab were evaluated in patients with advanced solid tumors. Methods: Patients with advanced solid tumors refractory to standard therapies were recruited. In a 3+3 dose escalation study, 13 patients received pucotenlimab intravenously every 3 weeks (Q3W) until disease progression or unacceptable toxicity occurred at doses of 1 mg/kg, 3 mg/kg, 10 mg/kg, and 200 mg. 17 additional patients were assigned in the expansion period. Results: A total of 30 patients were enrolled. No dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common treatment-related adverse events of any grade were proteinuria (40%), fatigue (36.7%), weight loss (26.7%), fever (26.7%), increased aspartate aminotransferase (26.7%), rash (23.3%), and anorexia (20.0%). Partial responses occurred in five patients, with an objective response rate of 16.7%. Pharmacokinetics analysis showed rapid absorption followed by slow terminal elimination, with a mean half-life of 17.1–23.5 days across all dose groups. Conclusions: Pucotenlimab had an acceptable toxicity profile at doses up to 10 mg/kg and the maximum tolerated dose was not reached. Based on the pharmacokinetics, efficacy, and safety profile, 3 mg/kg Q3W or 200 mg Q3W are optimal for further drug development.

Download Full-text

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3015 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3015-3015

Author(s):

Andrew Eugene Hendifar ◽

Sant P. Chawla ◽

Doris Quon ◽

Victoria S Chua ◽

Lita Fernandez ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase I Study ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Minor Response ◽

Grade 3

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3026 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3026-3026 ◽

Cited By ~ 1

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]

Download Full-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.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3101 ◽

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.

Download Full-text

Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000870 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000870

Author(s):

Aung Naing ◽

Joseph P Eder ◽

Sarina A Piha-Paul ◽

Claude Gimmi ◽

Elizabeth Hussey ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Trial ◽

Ex Vivo ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Advanced Solid Tumors ◽

Antitumor Effects ◽

Dual Inhibitor ◽

Indoleamine 2,3 Dioxygenase

BackgroundM4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.MethodsIn preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsIn mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).ConclusionsThere were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration numberNCT03306420.

Download Full-text

A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3592 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3592-3592 ◽

Cited By ~ 6

Author(s):

C. Sweeney ◽

C. Verschraegen ◽

G. Chiorean ◽

F. Lee ◽

S. Jones ◽

...

Keyword(s):

Breast Cancer ◽

Phase I ◽

Solid Tumors ◽

Kinase Inhibitor ◽

Antiangiogenic Therapy ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Curative Therapy ◽

Grade 3

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2578 ◽

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.

Download Full-text

Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2544 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2544-2544

Author(s):

Suzanne Fields Jones ◽

Carla Kurkjian ◽

Manish R. Patel ◽

Jeffrey R. Infante ◽

Howard A. Burris ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase Ii ◽

Stable Disease ◽

Phase I Study ◽

Standard Dose ◽

Maximum Tolerated Dose ◽

Unknown Primary ◽

Advanced Solid Tumors ◽

Grade 3

2544 Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n=3); 240 mg (n=5); 360 mg (n=6). No DLTs were observed until the 3rd dose level (treatment delay ≥3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.

Download Full-text

Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.475 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 475-475

Author(s):

Johanna C. Bendell ◽

Lowell L. Hart ◽

Shubham Pant ◽

Jeffrey R. Infante ◽

Suzanne Fields Jones ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Phase I Study ◽

Standard Dose ◽

Heat Shock Protein 90 ◽

Competitive Inhibitor ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Grade 3

475 Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90, with demonstrated activity in a variety of preclinical models. Further preclinical evidence suggests potential synergy between inhibition of HSP90 and fluorouracil treatment (Burkitt et al. 2007). This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Patients with refractory solid tumors for which capecitabine was an appropriate therapy received AUY922 with capecitabine in a standard 3+3 dose escalation. Capecitabine 1000mg/m2 was administered twice daily for days 1-14 of 21-day cycles, with escalating doses of AUY922 administered by intravenous (IV) infusion on days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 patients were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n = 6). There were no DLTs observed until the 6th dose level (grade 3 diarrhea). Common adverse events (all grades) included: diarrhea (61%), nausea (57%), fatigue (43%), hand-foot skin reaction (39%), anorexia (39%), vomiting (35%), rash (30%), and darkening vision (22%). Myelosuppression was uncommon, with no instances of grade ≥3 thrombocytopenia, and only 2 patients (9%) with grade 3/4 neutropenia (1 patient each). Of the 19 patients evaluable for response per RECIST 1.1, unconfirmed partial response (PR) was noted in 3 patients (13%; colorectal, 1; breast, 1; stomach, 1), with 1 additional confirmed PR (4%; colorectal); two of these had progressed on prior fluorouracil. Stable disease was noted in 8 patients (35%). Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

Download Full-text

Phase I study to assess the safety, tolerability, pharmacokinetics/pharmacodynamics and preliminary efficacy of SC10914 in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6047 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6047-6047

Author(s):

Jifang Gong ◽

Jinhai Tang ◽

Yongmei Yin ◽

Dingwei Ye ◽

Jian Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase I ◽

Cancer Patients ◽

Solid Tumors ◽

Phase I Study ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Adequate Organ Function ◽

Grade 3 ◽

Wbc Count

6047 Background: SC10914 is a highly selective inhibitor of PARP enzymes, including PARP1 and PARP2. SC10914 has a similar structure with olaparib. We conducted a phase I study to assess the safety, tolerability, PK/PD and preliminary efficacy of SC10914 in patients with advanced solid tumors. Methods: This is a phase I dose-escalation study with 3+3 design, we enrolled patients at 4 sites in China. Eligible patients were diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists; had measurable disease; had adequate organ function. Patients received SC10914 daily at ten escalating doses from 30 mg QD to 500 mg TID in a 28-day cycle. We obtained blood for PK and CA125 assessments. Toxic effects were assessed by CTCAE 4.03 criteria and tumour responses ascribed by RECIST 1.1 and CA125 was assessed by GCIG criteria. Results: As of January 2020, 52 patients were enrolled, of which 14 were males and 38 were females. Ten doses were escalated to 500mg TID, and no DLT was observed, and MTD was not obtained. The incidence of grade 3/4 AEs and SAEs that were related to SC10914 were 34.6% (18/52) and 13.5% (7/52). Grade 3/4 adverse reaction happened in at least two patients were anaemia/reduced hemoglobin (10/52, 19.2%), decreased WBC count (5/52, 9.6%), neutropenia (3/52, 5.8%), thrombocytopenia (2/52, 3.8%), and decreased lymphocyte count (2/52, 3.8%). A total of 17 gBRCAm evaluable ovarian cancer patients were enrolled, 6 of them had PR, the ORR was 35.3% (6/17). 10 gBRCAm ovarian cancer patients were enrolled in TID groups (including 2 patients who received BID doses at the beginning and changed to 300 mg TID dose after several cycles of treatment), 5 of them had PR, the ORR was 50% (5/10). The ORR of 400 mg TID group was 66.7%(4/6). PK data showed that the exposure of SC10914 was increased with dose increasing at the dose of 30 mg to 250 mg. The half-life of SC10914 was about 2-5 hours. Conclusions: SC10914 was safe in patients with advanced solid tumors. The main toxicity was blood-related adverse reactions. SC10914 was effective in gBRCAm ovarian cancer patients. 400 mg TID might be RP2D. Clinical trial information: NCT02940132.

Download Full-text

Phase I Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, Administered Daily in Patients With Advanced Solid Tumors

10.21203/rs.3.rs-522994/v1 ◽

2021 ◽

Author(s):

Yoon-Koo Kang ◽

Min-Hee Ryu ◽

Yong Sang Hong ◽

Chang-Min Choi ◽

Tae Won Kim ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Safety Profile ◽

Phase I Study ◽

Angiogenesis Inhibitor ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Potential Clinical Benefit ◽

Dose Levels

Abstract Rivoceranib is a highly potent and selective inhibitor of VEGFR-2 and subsequent angiogenesis through this receptor signaling pathway. This phase I study was the first global study with rivoceranib outside of China in Korean and Caucasian patients and was designed to determine the safety profile (including maximum tolerated dose), pharmacokinetics, and efficacy in patients with advanced solid tumors. Thirty-one adult patients with advanced malignant solid tumors were enrolled to investigate 6 dose levels of rivoceranib. Twenty-five patients were initially enrolled to 5 dose levels of rivoceranib from 81 to 685 mg and an additional 6 patients were later enrolled in a supplemental study to evaluate the 805 mg dose level. Rivoceranib was very well tolerated. At the 805 mg dose level, 2 dose-limiting toxicities were observed but the 685 mg dose was well tolerated over multiple cycles of therapy. The maximum tolerated dose for rivoceranib was 685 mg (equivalent to 850 mg rivoceranib mesylate) and recommended for further study in patients with advanced solid tumors. The most common adverse events were hypertension (all grades %/≥G3%: 58/29), nausea (42/0), diarrhea (39/0), anorexia (32/3), and fatigue (29/6). Rivoceranib pharmacokinetics were proportional across all dose levels but interpatient variability was high. Of the 31 patients enrolled, 21 were evaluable for efficacy. In this evaluable group, partial response was recorded in 5 patients, stable disease in 10, and disease progression in 6. Results indicate the potential clinical benefit of daily rivoceranib in patients with advanced malignant solid tumors with a tolerable safety profile.Trial registration: NCT01497704 (ClinicalTrials.gov) registered on December 22, 2011 and NCT02711969 (ClinicalTrials.gov) registered on March 17, 2016.

Download Full-text