A phase I clinical and pharmacokinetic study of flavopiridol administered concurrently with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13515-13515
Author(s):  
R. D. Meng ◽  
R. D. Carvajal ◽  
A. N. Tse ◽  
M. A. Shah ◽  
H. Dials ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Response To Treatment ◽  
Fixed Dose ◽  
Colorectal Cancers ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Modified Folfox6 ◽  
Grade 3

13515 Background: Flavopiridol, a potent cyclin-dependent kinase inhibitor, enhances oxaliplatin-induced apoptosis in HCT116 colon cancer cells in vitro, especially with concurrent therapy. Significant tumor regressions were also observed in HCT116 xenografts treated with flavopiridol and oxaliplatin therapy versus either therapy alone. Methods: Therefore, an ongoing phase I trial in advanced solid tumors was designed in which flavopiridol at a fixed dose (40 mg/m2 over 1 hour) was administered concurrently with escalating doses of oxaliplatin (60 mg/m2 -> 80 mg/m2 over 2 hours), given as part of a modified FOLFOX6 regimen at standard doses every 14 days. Patients then received escalating doses of infusional 5-fluorouracil over 48 hours (900 mg/m2/day -> 1200 mg/m2/day). Standard phase I eligibility criteria apply. Prior FOLFOX or oxaliplatin was allowed. Results: Median characteristics of nineteen evaluable patients: age 54 (39–77), KPS 80% (70–90), 9 males/10 females, 3 prior regimens (range 1 to 10). The combination has been well-tolerated, with 1 dose limiting toxicity occurring with oxaliplatin at 85 mg/m2 and infusional 5-fluorouracil at 1200 mg/m2/day (grade 3 hyponatremia and grade 3 syncope). Pharmacokinetic studies for flavopiridol indicate no appreciable difference in Cmax despite escalation of oxaliplatin dose. We have observed 1 partial response to treatment in pancreatic cancer. Stable disease has been seen in 5 patients, including 1 breast cancer (3 months), 1 gastric cancer (2 months), 1 anal cancer (7 months) and 2 colorectal cancers (5+ months), with one patient previously treated with oxaliplatin. Conclusions: The combination of flavopiridol and modified FOLFOX6 can be given safely without a significant increase in toxicity. The pharmacokinetic data for flavopiridol remains unchanged despite escalating doses of oxaliplatin. Activity has been observed in several tumor types, with promising activity noted for colorectal cancers even with prior oxaliplatin chemotherapy. Therefore, further dose escalation of flavopiridol is currently planned. No significant financial relationships to disclose.

A phase I study of oral belinostat (PXD101) in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14092-14092 ◽  
Author(s):  
W. K. Kelly ◽  
T. Yap ◽  
J. Lee ◽  
U. Lassen ◽  
E. Crowley ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Standard Therapy ◽  
Tumor Imaging ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Grade 3

14092 Background: Belinostat (PXD101) is a hydroxamate HDAC inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. In Phase I studies in patients (pts) with advanced cancer, IV belinostat is well-tolerated up to 1000 mg/m2 daily x5. Preliminary results of an oral formulation of belinostat showed that the oral bioavailability was 20 - 50%. This Phase I trial of oral belinostat will determine the maximal tolerated dose (MTD) of once and twice daily dosing, tolerability and pharmacokinetics (PK) in pts with advanced solid tumors. Methods: Sequential cohorts of 3–6 pts with advanced solid tumors refractory to standard therapy or for which no standard therapy exists were administered belinostat 250–500mg once or twice daily in 4 week cycles. Fasting (day 1) and non-fasting (day 7) pharmacokinetic studies were performed on all patients along with serial ECGs to evaluate any potential effects on QTc prolongation. Patients were evaluated with routine blood work weekly and tumor imaging at the end of cycle 1 then every other cycle. Results: Sixteen pts have been treated in 3 dose levels at 250mg QD (6 pts), 500mg QD (6 pts) and 250mg BID (4 pts). The median number of cycles of therapy is 1 (range 1–5), nine pts continue to be treated. The most common reasons for discontinuation were adverse event (3 pts) and PD (3 pts). No DLTs were identified at 250mg QD or 250mg BID. DLTs of grade 3 dehydration and grade 3 fatigue were reported at 500mg QD. In pts from the first 3 dose cohorts, there were no grade 4/5 events reported. Other Grade 3 toxicities were fatigue (2 pts), abdominal pain (1 pt), ataxia (1 pt), prolonged INR (1 pt), prolonged PTT (1 pt) and confusion (1 pt). Symptoms were transient and usually resolved after drug was held. In > 500 ECG’s collected, there were no QTcF > 500 ms, and no QTcF increase > 60 ms above baseline. To date, the best clinical response observed has been SD in 7 patients. Conclusions: Oral belinostat at doses of 250mg QD and 250mg BID given on a continuous schedule appears to be well tolerated. Alternative dosing schedules are being explored to further dose escalate the belinostat. Updated safety, activity and pharmacokinetic data will be presented on these and alternate dose schedules. [Table: see text]

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

2000 ◽  
Vol 18 (20) ◽  
pp. 3545-3552 ◽  
Author(s):  
Corinne Couteau ◽  
Marie-Laure Risse ◽  
Michel Ducreux ◽  
Florence Lefresne-Soulas ◽  
Alessandro Riva ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

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.

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

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3592-3592 ◽  
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.

Phase I dose-escalation study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as single‑agent and in combination with temozolomide in patients with advanced solid tumors (NCT00920595).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3052-3052 ◽  
Author(s):  
Mario Campone ◽  
Ruth Plummer ◽  
Peter Stephens ◽  
Zahir Brakchi ◽  
Louiza Aissat-Daudigny ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Excision Repair ◽  
Single Agent ◽  
Recommended Dose ◽  
Parp Inhibition ◽  
Advanced Solid Tumors ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Grade 3

3052 Background: Poly-ADP-ribose (PAR) polymerases (PARPs) are essential in cellular processing of DNA damage via the base excision repair pathway. CEP-9722, an orally available PARP1-2 inhibitor, demonstrated single-agent antitumor activity and synergy with temozolomide (TMZ) in xenograft models. This phase I study evaluated the pharmacokinetics, pharmacodynamics, and the maximum tolerated dose (MTD) of CEP-9722 in monotherapy and combination with TMZ. Methods: Adult patients with advanced solid tumors were enrolled in cohorts of 3-6 patients to receive a 14-day cycle of CEP-9722 (days 1-5), followed by 28-day cycles of CEP-9722 (days 1-5) plus TMZ (150 mg/m2 days 1-5). The dose of CEP-9722 was 150 mg/day in the first cohort and was escalated depending on the occurrence of dose-limiting toxicities (DLTs) during cycles 1 and 2. The safety, pharmacokinetics, and pharmacodynamics (PAR levels in peripheral blood mononuclear cells) of CEP-9722 were analyzed. Results: Overall, 26 patients (18F,8 M) 18 to 71 years of age were enrolled in 5 cohorts of 3-9 patients and treated with CEP-9722 at 150-1000 mg/day. The MTD of CEP-9722 in combination with TMZ (150 mg/m2) was reached at 1000 mg/day. The recommended dose was 750 mg/day. A total of 9 patients were treated at the recommended dose. DLTs were observed in 2 patients during cycle 1 (1 grade 3 myositis at 750 mg/day and 1 grade 3 asthenia at 1000 mg/day) and 2 patients during cycle 2 (1 grade 3 asthenia at 300 mg/day and 1 persistent grade 2 weight loss at 1000 mg/day). Overall during this study, 4 grade 3 treatment-related adverse events were observed. The pharmacokinetics showed high intra- and inter-patient variability at all doses. The pharmacodynamic analysis demonstrated PARP inhibition at all doses, but the high inter- and intra-patient variability prevented any conclusion regarding a dose / PARP inhibition relationship. Conclusions: TheMTD of CEP-9722 when administered with TMZ was 1000 mg days 1-5 and the combination CEP-9722/TMZ was well tolerated. In addition, a clear signal of PARP inhibition was demonstrated.

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 dose escalation study of recombinant interleukin-21 (rIL-21; BMS-982470) in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced or metastatic solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3112-TPS3112 ◽  
Author(s):  
Laura Quan Man Chow ◽  
Michael S. Gordon ◽  
Theodore F. Logan ◽  
Scott J. Antonia ◽  
Shailender Bhatia ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Clinical Outcomes ◽  
Dose Escalation ◽  
Fixed Dose ◽  
Weekly Schedule ◽  
Advanced Solid Tumors ◽  
Biologic Activity

TPS3112 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2. Nivolumab, a PD-1 receptor blocking antibody, has shown durable antitumor activity in pts with various solid tumors in two phase I clinical trials. The cytokine rIL-21 has also shown antitumor activity in selected solid tumors. We hypothesized that combining rIL-21-induced stimulation of T-cell and NK-cell function in conjunction with T-cell checkpoint blockade using nivolumab could enhance biologic activity resulting in improved clinical outcomes, as compared with either agent alone. We describe a novel phase I study investigating the biologic activity and clinical outcomes of the combination in pts with advanced solid tumors. Methods: This ongoing study (N=160) includes a dose escalation phase (Part 1) using a 3 + 3 design followed by an expansion phase (Part 2). In Part 1 (N=60), successive pt cohorts with advanced solid tumors are being treated with escalating doses of rIL-21 (10, 30, 50, 75, or 100 µg/kg IV) on two distinct schedules (Arms A and B) in combination with fixed-dose nivolumab (3 mg/kg q 2 weeks) in 6 week cycles. Arm A administers rIL-21 on a weekly schedule, given on day 1 in weeks 1–4 of the 6 week cycle. Arm B administers rIL-21 at 3x per week during weeks 1 and 3 of the 6 week cycle. In Part 2, pts with renal cell carcinoma (N=50) or non-small cell lung carcinoma (N=50) will each be randomized to treatment at the maximum tolerated dose (MTD) or maximum administered dose, if no MTD is determined, for Arm A or Arm B. Therapy for pts who are stable or responding in Parts 1 and 2 may be continued for up to 2 years or until treatment discontinuation criteria are met. Primary objectives are to evaluate the safety of rIL-21 + nivolumab, and to define the MTD of the 2 schedules. Secondary and exploratory objectives include a preliminary assessment of the antitumor activity, pharmacokinetics, immunoregulatory activity (peripheral blood, tumor) and immunogenicity of this combination. Clinical trial information: NCT01629758.

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 call for global harmonization of phase I oncology trials: Results from two parallel, first-in-human phase I studies of DS-7423, an oral PI3K/mTOR dual inhibitor in advanced solid tumors conducted in the United States and Japan.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2536-2536
Author(s):  
Tomoya Yokota ◽  
Johanna C. Bendell ◽  
Patricia LoRusso ◽  
Takahiro Tsushima ◽  
Ved Desai ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
The United States ◽  
Maximum Tolerated Dose ◽  
Serum Glucose ◽  
Advanced Solid Tumors ◽  
Dual Inhibitor ◽  
Phase I Studies ◽  
Akt Phosphorylation ◽  
Grade 3

2536 Background: The aim of this study was to determine the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of DS-7423, a novel inhibitor of PI3K/mTOR, in US and Japanese population. We further compared toxicities and recommended phase 2 dose (RP2D) of DS-7423 and approved oncology drugs in the two populations. Methods: We conductedparallel, first-in-human studies in US and Japan in patients with advanced solid tumors. We conducted a Pubmed search of pivotal and corresponding phase I studies to compare the RP2D and final approval doses of molecularly targeted agents (MTA) between US and Japan. Results: 69 patients were enrolled (n = 42 from US and n = 27 from Japan). Between populations, the only difference at baseline was body weight (BW) and body mass index (BMI). Dose-limiting toxicities included grade 3 rash (48 mg), grade 3 stomatitis (240 mg), grade 3 lung infection (240 mg), grade 4 hyperglycemia (240mg), grade 3 fatigue (320 mg), and grade 3 dehydration (320mg). The MTD and RP2D was 240 mg/d in both populations. Frequent treatment-related adverse events included diarrhea, fatigue, decreased appetite, rash, and stomatitis. No remarkable difference in AUC and Cmax were observed between populations. Prolonged stable disease was seen in cholangiocarcinoma, thymic cancer, non-small cell lung cancer, squamous cell carcinomas, carcinoid, and sarcoma. DS-7423 demonstrated PD effects on serum glucose, C-peptide and Akt phosphorylation and 18F-FDG uptake in tumors. The final RP2D of 17 MTA approved in US and Japan from 2001 to 2015 was near identical. The approved doses in both regions were identical. Conclusions: Despite differences in BW, BMI, and ethnicity, DS-7423 showed no difference in PK, PD, toxicity or efficacy between populations. We found near identical RP2D in phase I oncology studies and approved doses in pivotal studies. This supports increased international collaboration in the conduct of phase I oncology trials. Clinical trial information: NCT01364844, Japic CTI, 12766.

Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Junning Cao ◽  
Pin Zhang ◽  
Paul L. de Souza ◽  
Bo Gao ◽  
Mark Voskoboynik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Response To Treatment ◽  
Clinical Activity ◽  
Dose Cohort ◽  
Phase Ii Studies ◽  
Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

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