A phase I study of vorinostat (VOR) in combination with capecitabine (CAP) in patients (pts) with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3576-3576 ◽  
Author(s):  
P. Tang ◽  
A. Oza ◽  
C. Townsley ◽  
L. Siu ◽  
G. Pond ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Zinc Ion ◽  
Advanced Solid Tumors ◽  
Prior Therapy ◽  
Disease Stabilization ◽  
Grade 3 ◽  
Tumor Types

3576 Background: VOR (suberoylanilide hydroxamic acid; SAHA) is a small molecule inhibitor of histone deacetylase (HDAC) that binds directly to the enzyme’s active site in the presence of a zinc ion. Aberrant HDAC activity has been implicated in a variety of cancers. The combination of 5-fluorouracil and VOR is synergistic in preclinical tumor models. Methods: This phase I study evaluated safety, tolerability, and the recommended phase II dose (RPTD) of VOR and CAP in pts with advanced solid tumors. VOR was administered orally daily while CAP was administered orally bid on days 1–14 of a 21 d cycle. Results: Three dose levels have been evaluated (VOR (mg/d)/CAP (mg/bid)): 300/750, 300/1,000 and 400/1,000. Twenty-three pts have been treated: 6M/17F, median age 59 (range 41–73), ECOG 0:1:2 = 9:13:1, prior therapy 1:2:3 or more = 3:7:13. Pts had colorectal cancer (n=6), nasopharyngeal (n=3) and various other tumors. A total of 104 cycles have been administered, with median = 2 (range 1–15). One dose limiting toxicity (DLT) (grade 3 diarrhea) occurred in 6 patients at dose level 1. No DLT were observed at dose level 2, and 2 DLTs (grade 3 fatigue and grade 3 nausea/vomiting) occurred at dose level 3. RPTD was determined to be VOR 300 mg/d and CAP 1,000 mg/bid. Most common toxicities of any grade and at least possibly attributable (n=22) are: thrombocytopenia (59% of pts), fatigue (55%), nausea (55%), vomiting (50%), hypoalbuminemia (45%), anemia (41%), diarrhea (41%), anorexia (41%), elevated creatinine (36%), lymphopenia (36%), hyponatremia (36%), and hyperglycemia (36%). Common grade 3 toxicities included: hand-foot syndrome (23% of pts), diarrhea (14%), fatigue (14%), and lymphopenia (14%). One pt died on study from ventricular fibrillation due to sotalol and hypocalcemia from pre-existing hypoparathyroidism. Five patients with various tumor types had PR (2 confirmed, 3 unconfirmed) (2 nasopharyngeal, 1 each of ovarian, endometrial and squamous cell carcinoma of head and neck). In addition, disease stabilization was seen in 12 patients. Conclusions: VOR and CAP are well tolerated, and this combination is active in several tumor types. Further evaluations of VOR and CAP are warranted. No significant financial relationships to disclose.

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

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.

A phase I study of the humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) TheraCIM-h-R3 (nimotuzumab) in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13054-13054
Author(s):  
A. M. Brade ◽  
L. Siu ◽  
A. M. Oza ◽  
B. Southwood ◽  
M. De Borja ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Eligibility Criteria ◽  
Skin Biopsies ◽  
Grade 3

13054 Background: Nimotuzumab is a humanized mAb against the extracellular ligand binding domain of EGFR. Although well tolerated when combined with radiotherapy in previous studies, the pharmacodynamics (PD) of nimotuzumab has not been elucidated. This phase I study was designed to evaluate the safety, tolerability and PD of nimotuzumab. Methods: Eligibility criteria included advanced solid tumors refractory to standard therapy and performance status of ECOG 0–2. Nimotuzumab was administered intravenously weekly × 6 and then every other week (6 weeks = 1 treatment cycle). Tumor and skin biopsies were obtained at baseline and after 2 weeks of treatment. Results: To date, 9 patients (7 m/2 f, median age 60, 7 colorectal cancer, ECOG 0:1:2 = 5:3:1, prior therapy 1:2:3+ = 1:3:5) have been treated on the first 2 dose levels (100 mg and 200 mg) for a total of 13 treatment cycles. The most common toxicities, mainly grade 1- 2, were lymphopenia (n = 8 patients), fatigue (n = 8), abnormal liver function tests (n = 7) and anemia (n = 6). Observed grade 3 toxicities include: pain (n = 3), hyponatremia (n = 2), elevated ALP (n = 2), fatigue (n = 1), hyperglycemia (n = 1) and hyperkalemia (n = 1). One patient at the first dose level experienced grade 3 fatigue, at least possibly attributable to nimotuzumab, and thus considered as a dose-limiting toxicity (DLT). No DLT were observed in the expanded cohort and dose level 2. No skin toxicities were observed. Stable disease was seen in 3 patients with colorectal cancer. PD from tumor and skin biopsies will be presented, and may clarify the reason for the lack of skin toxicity. Conclusions: Overall nimotuzumab was well tolerated, with disease stabilization observed in heavily pretreated patients. Accrual continues at dose level 3 (400 mg) with one further planned dose level (800 mg). [Table: see text]

Phase I study of intravenous decitabine in combination with oral vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas (NHL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3528-3528 ◽  
Author(s):  
A. Stathis ◽  
S. Hotte ◽  
H. Hirte ◽  
E. X. Chen ◽  
S. Webster ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Gastrointestinal Symptoms ◽  
Advanced Solid Tumors ◽  
Sequential Administration ◽  
Disease Stabilization ◽  
Sequential Schedule ◽  
Hodgkin's Lymphomas ◽  
Tumor Types

3528 Background: Decitabine (D), a hypomethylating agent, and vorinostat (V), a histone deacetylase inhibitor, belong to two different classes of drugs with an epigenetic effect. The ideal dose scheduling of these drugs remains controversial. This phase I study aims to determine the recommended phase II dose (RPTD) of the combination, their toxicity profile, pharmacokinetic (PK) interaction and preliminary clinical activity. Methods: Patients (pts) with advanced solid tumors or relapsed/refractory NHL are eligible. Two different schedules of D and V are being evaluated: sequential administration of D followed by V and concurrent administration of D and V. Dose escalation of D and V on the sequential schedule is described in Table. Results: To date, 27 pts have been entered into dose levels 1, -1, 1a, 1b, -1b, -2b of the sequential schedule. Demographics: median age 61 (range 31–76), F:M = 13:14, ECOG 0:1:2 = 8:16:3, tumor types: 24 solid tumor and 3 NHL. Pts received a total of 77 cycles with a median of 2 cycles (range 1–8). Adverse events (AE) of grade 3 or higher of at least possible attribution to the study treatment were neutropenia (16 pts), thrombocytopenia (4), febrile neutropenia (2), fatigue (2), and 1 pt each for constipation, dehydration, nasal bleeding, elevated alanine aminotransferase, and hyponatremia. Dose limiting toxicities (DLT) consisted mainly of myelosuppression, constitutional and gastrointestinal symptoms occurred in 7/27 (26%) of pts so far. Disease stabilization for 4 or more cycles was observed in 7 out of 22 (31.8%) evaluable pts (two with breast and one each of thymus, colon, pancreatic, appendix and non-small cell lung cancers). Conclusions: The sequential combination of D and V seems to be tolerable after some adjustments in the doses and duration of drug administration. Prolonged disease stabilization has been observed in multiple tumor types. Accrual is ongoing and RPTD will likely be dose level -1b or -2b. ( Supported by NCI Grant No. U01CA132123.) [Table: see text] No significant financial relationships to disclose.

Phase I study of sirolimus plus gemcitabine in patients with advanced solid tumors: A Spanish Group for Research on Sarcomas (GEIS) study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3096-3096
Author(s):  
Juan Martin Liberal ◽  
Marta Gil ◽  
Laura Jimenez ◽  
Maria Ochoa de Olza ◽  
Carmen Munoz ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Mtor Pathway ◽  
Advanced Solid Tumors ◽  
Level 3 ◽  
Skin Biopsies ◽  
Grade 3 ◽  
Dose Levels

3096 Background: In preclinical studies, combination of sirolimus with gemcitabine enhances apoptosis in vitro and increases anti-tumor efficacy in vivo. Methods: Patients with advanced solid tumors, age 18-70 years, no prior mTOR inhibitor or gemcitabine, ECOG PS 0-1, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of the combination of sirolimus and gemcitabine. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Sirolimus was given po continuously. Gemcitabine was given iv 10mg/m2/minute on days 1 and 8 every 3 weeks. Dose levels 1, 2 and 3 corresponded to sirolimus 2, 2 and 5mg/24h plus gemcitabine 800, 1000 and 1000mg/m2 respectively. After observing DLTs at higher dose level and poorer mTOR signaling inhibition at lower doses, a new cohort of sirolimus 5mg/24h plus gemcitabine 800 mg/m2 was added. Skin biopsies pre and post treatment were performed to assess the inhibition of mTOR pathway. Results: 19 patients were enrolled: median age 51 years (36-70); gender 12M, 7F. Median number of cycles was 4. Patients were treated at 4 dose levels, the MTD was reached at level 3 and the RD was: sirolimus 5mg/24h and gemcitabine 800mg/m2. 3 DLTs were observed, 1 at dose level 2 and 2 at dose level 3: transaminitis grade 3, thrombocytopenia grade 3 and thrombocytopenia grade 4. Other toxicities grade 1-2 included anemia, neutropenia, asthenia, mucositis and high cholesterol levels. 2 patients achieved partial response (1 uterine cervix cancer and 1 colon cancer). Immunohistochemistry of pS6 in skin biopsies showed significative inhibition of mTOR pathway at RD. PK parameters estimated were in agreement with those previously reported in the literature. No influence of sirolimus administration on gemcitabine clearance was found. Conclusions: Combination of sirolimus and gemcitabine is feasible and safe, allowing administration of active doses of both agents and achieving mTOR signaling inhibition. A phase II study to assess the activity of this combination in sarcomas is ongoing.

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

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
Shubham Pant ◽  
Lowell L. Hart ◽  
Johanna C. Bendell ◽  
Jeffrey R. Infante ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Hsp90 Inhibition ◽  
Grade 3 ◽  
Dose Levels

3564 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. Preclinical evidence suggests potential synergy between HSP90 inhibition and fluorouracil. 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: Pts with refractory solid tumors received AUY922 with capecitabine in a standard 3+3 dose escalation. Dose levels were capecitabine 1000mg/m2 PO BID d 1-14 of 21-day cycles, with escalating doses of AUY922 IV 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 pts 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). No DLTs were observed until the 6th dose level (grade 3 diarrhea). Related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (43%; 17%), fatigue (30%; 13%), nausea (39%; 0), hand-foot skin reaction (30%; 5%), anorexia (30%; 4%), vomiting (30%; 0), and darkening vision (26%; 0). Vision darkening, a class effect of HSP90 inhibitors, was reversible with drug hold and retreatment was possible. Two pts (9%) had hematologic G 3/4 events of neutropenia. Of the 19 pts evaluable for response, partial response was noted in 4 patients (colorectal, 2; breast, 1; stomach, 1); 2 had progressed on prior fluorouracil, and remained on treatment for 13-35 wks. Stable disease was noted in 8 pts (35% [colorectal, 5; pancreas, 2; breast, 1]) with a median duration of 25.5 wks (range: 11-44+). All 5 colorectal pts were refractory to 5-FU. Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, particularly as seen in pts previously resistant to fluorouracil, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

A phase I study of pegylated doxorubicin (DOX) and weekly topotecan (TOP) in patients (pts) with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12018-12018
Author(s):  
G. A. Masters ◽  
M. Guarino ◽  
C. Schneider ◽  
D. Biggs ◽  
S. Grubbs
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Level 1 ◽  
Grade 3 ◽  
Ecog Ps

12018 Background: The primary endpoint of this prospective phase I study of DOX-TOP in pts with advanced solid tumors was to identify the maximum tolerated dose and dose-limiting toxicities (DLT) of this combination. Other objectives included a description of additional toxicities and efficacy in this patient population with refractory cancers. Pharmacokinetic sampling of TOP plasma levels will be reported separately. Methods: Eligible pts had advanced solid tumors and had either failed standard chemotherapy (chemo) or were pts for whom no standard therapy existed. They had ECOG PS = 0–2, adequate organ function, and gave written, informed consent. Initial doses included DOX 40 mg/m2 day 1 and TOP 2 mg/m2 days 1, 8 and 15 q 28 days. TOP was to be escalated in cohorts of pts. DLT was defined as febrile neutropenia, grade 4 thrombocytopenia, any grade 3 non-hematologic toxicity, or the inability to receive subsequent treatment due to ongoing toxicity. Treatment was held for ANC < 1000 or platelets < 75,000. Results: Fourteen pts have been enrolled on this phase I study, all of whom were evaluable for toxicity. There were 12 males and 2 females, and the median age was 57 years (range 25–86). Four had ECOG PS = 0, 9 had PS = 1, and 1 had PS = 2. Cancer types included head and neck (3), renal (2), and breast, pancreas, liver, esophagus, germ cell tumor, sarcoma, and others (one each). In the 6 pts treated at dose level 1, toxicities included grade 3 anemia (1) and neutropenia (2), and grade 4 neutropenia (1). DLT consisted of grade 4 thrombocytopenia (1) and inability to deliver day 15 TOP in 3/6 pts at this dose. Thus, TOP was reduced to 1.5 mg/m2 weekly for dose level -1, and 8 pts have been treated. Toxicities included grade 3 anemia (1)and neutropenia (2), and grade 4 neutropenia (1) and thrombocytopenia (1). Enrollment continues at this dose level to confirm tolerability. No patient achieved an objective response to therapy, but 2 pts have stable disease for up to 4 cycles. Conclusions: DOX-TOP can be safely combined in pts with advanced solid tumors, with hematologic toxicity as the DLT. The preliminary recommended phase II dose is DOX 40 mg/m2 and TOP 1.5 mg/m2. We plan to explore an additional dose level of DOX 30 mg/m2 and TOP 2 mg/m2. Phase II evaluation is contemplated in selected tumor types. [Table: see text]

A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2026-2026 ◽  
Author(s):  
E. I. Heath ◽  
A. Alousi ◽  
J. P. Eder ◽  
M. Valdivieso ◽  
L. S. Vasist ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Minor Response ◽  
Level 3 ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

2026 Background: Ispinesib, a novel cytotoxic agent inhibiting the kinesin spindle protein (KSP) has demonstrated significant antitumor activity in multiple murine tumor models. The primary objectives of the study were to assess the safety and tolerability of SB-715992, to determine the dose limiting toxicity (DLT), and the maximum tolerated dose (MTD). Methods: Ispinesib was administered days 1–3 intravenously over 1 hour every 21 days, starting at a dose of 1 mg/m2/day. Traditional 3-patient cohort trial design was utilized with dose levels of 2, 4, 6, 8 mg/m2/day. Results: Twenty-seven patients (24 Caucasians, 3 African-Americans, 16 males, 11 females) with various tumor types were enrolled; colorectal (7), renal (5), bladder (2), lung (2), pharynx (2), pancreas (2), others (7). Grade 3/4 toxicities were noted starting at the 4 mg/m2 dose level with two patients developing grade 4 neutropenia; one for < 5 days, one for > 5 days (with grade 3 leukopenia). At the 6 mg/m2 dose level, grade 3 neutropenia and leukopenia were reported. At the 8 mg/m2 dose level, 3 of 3 patients had grade 4 neutropenia and leukopenia. The 6 mg/m2 dose level was declared the MTD. Toxicities seen in the additional 6 patients included grade 1 fatigue (1/6), grade 1 infusion- related flushing (1/6), grade 3 febrile neutropenia (1/6), and grade 4 neutropenia and leukopenia (1/6). The MTD cohort has been expanded to 10 evaluable patients for confirmation of tolerability and pharmacodynamic endpoints including phosphohistone 3 (PH3), cyclin E, and TUNEL assay on serial tumor biopsies. Preliminary pharmacokinetic data appear linear, but not dose proportional. As predicted, between days 1 and 3, accumulation ranged from 40 to 106%. Exposures appear comparable between cycles 1 and 2. Stable disease in 2 patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. Conclusions: Treatment with ispinesib at the MTD of 6 mg/m2/day x 3 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.

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

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.

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

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.

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

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.

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