A phase I/II study of biweekly docetaxel (D) in combination with fixed-dose cisplatin plus fluorouracil (CF) in patients (pts) with advanced esophageal cancer (AEC) (JCOG0807).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15016-e15016
Author(s):  
Shuichi Hironaka ◽  
Yasuhiro Tsubosa ◽  
Junki Mizusawa ◽  
Takayuki Kii ◽  
Ken Kato ◽  
...  
Keyword(s):  
Phase I ◽  
Peer Review ◽  
Primary Endpoint ◽  
Performance Status ◽  
Treatment Compliance ◽  
Phase Iii ◽  
Fixed Dose ◽  
Open Label ◽  
Eligibility Criteria ◽  
Grade 3

e15016 Background: Thougha triplet chemotherapy with D plus CF (DCF) has shown promising activity, high incidence of adverse events (AEs) especially in febrile neutropenia (FN) was observed in previous studies for head and neck cancer (TAX323, 324) and gastric cancer (TAX325). To reduce its AEs with keeping activity, we conducted a multicenter open-label phase I/II study of biweekly D plus CF for AEC. Methods: Eligibility criteria included histologically proven AEC with measurable disease, age 20 to 75, non-resectable or recurrent disease, performance status (PS) 0 to 1. Pts received escalating doses of D (dose level (DL) 1: 30 mg/m2, DL 2: 40 mg/m2, on days 1, 15) in combination with fixed dose of CF (cisplatin 80 mg/m2 on day 1, fluorouracil 800 mg/m2on days 1-5) repeated every 4 weeks with 3+3 design in phase I part (P-I). The primary endpoint of P-I was dose limiting toxicity (DLT) and that of phase II part (P-II) was response rate (RR) defined by central peer review. Based on a SWOG two stage design (p0=35%, p1=50%; one-sided a=0.1, β =0.2) at least 22 responders among 50 eligible pts should be observed to satisfy the primary endpoint. Results: Between Feb 2009 and Mar 2010, 62 pts were enrolled for P-I and P-II. In P-I, 10 pts were enrolled with DLT of 0/3 in DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended dose for P-II was determined as DL1. Thus, 3 (P-I) and additional 52 pts (P-II) were analyzed: 53 for efficacy (excluded 2 ineligible pts) and 55 for safety. Pts characteristics were as follows: male/female 49/6, age median 61 (range 44 to 75), PS 0/1 39/16. The RR was 62% (95% confidence interval, 48-75%, p<0.0001) by central peer review. Median OS and PFS were 11.1 and 5.8 months. Grade 3/4 toxicity was observed in neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%) and nausea (11%). No grade 3/4 FN was observed. Treatment related death occurred in one patient due to pneumonitis. Conclusions: Biweekly D (30mg/m2) combined with CF showed promising activity and tolerability. A phase III study comparing CF with DCF is warranted. Clinical trial information: UMIN000001737.

Randomized phase II trial of ficlatuzumab with or without cetuximab in pan-refractory, advanced head and neck squamous cell carcinoma (HNSCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6015-6015
Author(s):  
Julie E. Bauman ◽  
Nabil F. Saba ◽  
Denise Roe ◽  
Jessica R. Bauman ◽  
John M. Kaczmar ◽  
...  
Keyword(s):  
Lower Bound ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Performance Status ◽  
Primary Objective ◽  
Phase Iii ◽  
Platinum Resistance ◽  
Eligibility Criteria ◽  
Immune Biomarkers ◽  
Hpv Status

6015 Background: Cetuximab (C), an anti-EGFR monoclonal antibody (mAb), is approved for advanced HNSCC but benefits a minority. Crosstalk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways is a known resistance mechanism. HGF is also immunosuppressive within the tumor microenvironment. A Phase I study confirmed the safety of C and ficlatuzumab (F), an IgG1 anti-HGF mAb, with preliminary efficacy and biomarker data suggesting that dual pathway inhibition may overcome tumor-intrinsic or immune cetuximab resistance. Methods: The primary objective of this phase II randomized, non-comparative trial was to evaluate the efficacy of F (20 mg/kg every 2 wks), with or without C (500 mg/m2 every 2 wks), in pan-refractory, advanced HNSCC. Eligibility criteria included recurrent/metastatic HNSCC, performance status (PS) 0-1, C resistance (defined as progression on or within 6 months of exposure), and resistance to or ineligibility for platinum and anti-PD1 mAb. Randomization was stratified by HPV status and center. The primary endpoint was median progression-free survival (mPFS). An arm was deemed worthy of further study if the lower bound of the 90% 1-sided confidence interval (CI) excluded the historical control of 2 months. Secondary objectives included overall response rate (ORR) in the overall and HPV-stratified populations. A Bayesian continuous monitoring rule for futility was applied. Results: 60 patients were randomized and 58 treated between Jan 2018 and Dec 2020 (27 to F; 33 to FC). Baseline characteristics were balanced across major prognostic variables including age, PS, HPV status, platinum resistance, and PD1 mAb exposure. Median time since prior cetuximab was 3.5 months (range 0-48 months). Grade ≥3 adverse events attributed to F included: pneumonitis (2); edema (3); diarrhea (1); LFT elevation (1); rash (2); electrolyte abnormality (2). The Table presents efficacy data. The F arm stopped for futility after 26 evaluable subjects accrued. The FC arm completed accrual and met the primary endpoint; 32 evaluable subjects had mPFS of 3.6 months (lower bound 90% 1-sided CI: 2.3 months) and ORR of 19% (6/32). All responses were in HPV- subjects, including 2 complete (CR) and 4 partial responses (PR) to the FC combination and 1 PR to F monotherapy. The mPFS and ORR for the HPV- population (n = 16) on FC were 3.8 months and 38% (6/16). Mechanistic signaling and immune biomarkers are under analysis. Conclusions: The well-tolerated FC combination met the primary PFS endpoint in pan-refractory, advanced HNSCC with notable activity in HPV- HNSCC, warranting phase III investigation. Clinical trial information: NCT03422536. [Table: see text]

A phase I/II study of pemetrexed plus cisplatin in Japanese patients with malignant pleural mesothelioma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18152-18152
Author(s):  
K. Gemba ◽  
K. Yamazaki ◽  
H. Kunitoh ◽  
T. Hida ◽  
K. Nakagawa ◽  
...  
Keyword(s):  
Phase I ◽  
Performance Status ◽  
Asian Population ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Phase Iii ◽  
Vitamin Supplementation ◽  
Eligibility Criteria ◽  
Histologic Diagnosis ◽  
Level 1

18152 Background: Pemetrexed (pem) is globally used for the treatment of malignant mesothelioma (MPM) in combination with cisplatin (cis). Pharmacokinetic (PK) difference of pem/cis between Western and Asian population (pop) so far remains unknown. To investigate safety/efficacy of pem/cis therapy and PK profiles of pem/cis for Japanese (Jpn) MPM patients (pts), we designed a phase I/II study. Methods: Primary objectives in phase (Ph) I part were to determine a recommended dose (RD), and in Ph II part were to examine the efficacy of the RD and safety. PK profiles were to be analyzed as a secondary objective. A cohort of 6 pts, starting from a dose of pem 500 mg/m2 and cis 75 mg/m2 (level 1: LV1), was used in the dose-escalation Ph I. The efficacy of the RD was to be evaluated in at least 18 pts in the study. Key eligibility criteria were: histologic diagnosis of MPM incurable by surgery, no prior systemic chemotherapy, and a performance status 0–1. Under full vitamin supplementation, pem was administered as a 10-min. infusion on day 1 of a 21-day cycle, followed by cis administration as a 2-hr. infusion 30 min. after pem administration. For comparison of PK profiles, PK data of this study and a Western phase III study were analyzed by pop PK approach. Results: In Ph I, 13 pts were enrolled: 7 in LV1 and 6 in level -1 (LV-1: pem 500 mg/m2 and cis 60 mg/m2). Two dose-limiting toxicities were observed in LV1: pneumonitis and neutropenia. The RD were then determined to be LV1. In Ph II, 12 pts were enrolled in LV1. For safety, one drug-related death was reported among 25 pts due to worsening of underlying pneumonia observed before enrollment. The most common G3/4 toxicities were neutropenia and hemoglobin decrease. For efficacy, a partial response was achieved for 7 of 19 pts who received LV1. Response rate was 36.8% (95% CI: 16.3- 61.6). PK profiles of pem/cis in Jpn pts were similar to those in Western. The results of other secondary objectives, e.g., progression-free survival, QOL, and pulmonary function test, will be presented in the conference. Conclusions: The profiles of efficacy/safety/PK shown in this study are almost comparable to those in Western pts, and indicate that pem/cis therapy will be a promising therapy for Jpn MPM pts. No significant financial relationships to disclose.

Axitinib or bevacizumab (bev) plus FOLFOX or FOLFIRI as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 478-478 ◽  
Author(s):  
J. C. Bendell ◽  
C. Tournigand ◽  
M. Bednarczyk ◽  
A. Swieboda-Sadlej ◽  
I. Chung ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Performance Status ◽  
Progression Free Survival ◽  
Second Line ◽  
Open Label ◽  
Vegf Inhibitors ◽  
Multiple Tumor ◽  
Dosing Regimens ◽  
Grade 3 ◽  
Line Chemotherapy

478 Background: Axitinib (AG-013736,AG), an oral selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, shows activity in multiple tumor types including those refractory to front-line chemotherapy. Methods: This multicenter, open-label, randomized phase II trial compared AG and bev in combination with FOLFOX or FOLFIRI in second-line mCRC. Pts previously treated with irinotecan were randomized to mFOLFOX6 plus AG 5 mg BID or bev 5 mg/kg q2wk; pts who received oxaliplatin were randomized to FOLFIRI with AG or bev at the same doses, with stratification by performance status and prior bev therapy. Primary endpoint was progression-free survival (PFS). Results: 171 pts were randomized from March 2008 to July 2009. There were no significant differences in PFS or median overall survival (mOS) between the AG and bev arms with FOLFOX or FOLFIRI. However, there was a trend towards reduced mOS in the FOLFIRI arms with AG compared to bev, and a trend towards improved mOS with AG+FOLFOX vs bev+FOLFOX. There were more treatment discontinuations (DCs) and a higher incidence of grade ≥3 adverse events (AEs) in the AG arms (diarrhea, asthenia, fatigue; Table). Conclusions: This study did not meet the primary endpoint, showing similar PFS with AG compared to bev when added to second-line chemotherapy. A potential factor in these results was earlier DCs in the AG versus bev arms, likely secondary to increased AEs. While VEGF inhibitors may have a role in second-line treatment of mCRC, at current dosing regimens AG-based chemotherapy shows no improvement in outcome compared to bev. [Table: see text] [Table: see text]

Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA10008-LBA10008 ◽  
Author(s):  
George D. Demetri ◽  
Peter Reichardt ◽  
Yoon-Koo Kang ◽  
Jean-Yves Blay ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind Study ◽  
Open Label ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Multikinase Inhibitor

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG. Results: Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p<0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common > grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). Conclusions: This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.

FOLFIRI plus bevacizumab (bev) as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC) who have failed first-line bev plus oxaliplatin-based therapy: The randomized phase III EAGLE study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3516-3516 ◽  
Author(s):  
Hiroshi Tamagawa ◽  
Shigeyoshi Iwamoto ◽  
Takao Takahashi ◽  
Masato Nakamura ◽  
Yoshinori Munemoto ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Primary Endpoint ◽  
Therapy Response ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Significance Level ◽  
Line Therapy ◽  
Grade 3

3516 Background: The phase III ML18147 study (NCT00700102) showed a survival benefit for the continuation of bev after 1st-line bev-containing therapy in pts with mCRC. Continuation of bev beyond disease progression in this setting was approved by the FDA in Jan 2013. In the randomized, phase II SPIRITT study (NCT00418938) assessing 2nd-line treatment for mCRC, progression-free survival (PFS) was longer in the bev arm compared with the panitumumab arm, but the difference was not statistically significant. We describe the results of EAGLE, a multicenter, randomized phase III study evaluating the optimal dose of 2nd-line bev in Japan (UMIN000002557). Methods: Pts were randomized 1:1 to receive bev 5 mg/kg (Arm A) or 10 mg/kg (Arm B) plus FOLFIRI Q2W. Key eligibility criteria: age ≥20 years, mCRC, ECOG PS ≤1, and treatment failure to prior 1st-line bev plus oxaliplatin-based therapy (≥4 cycles). The primary endpoint was PFS. Secondary endpoints included time to treatment failure (TTF), PFS from 1st-line therapy, response rate (RR) and safety. The planned sample size was 370 pts to detect 30% risk reduction with 90% power assuming a two-sided significance level of 0.05. Results: 387 pts were randomized between Sep 2009 and Jan 2012; 367 pts formed the full analysis set (Arm A 179 pts; Arm B 188 pts). Baseline characteristics were well balanced between the treatment arms. Respectively for Arm A and B, PFS was 6.2 and 6.3 months (HR 1.03, 95% CI: 0.82-1.30; p=0.815), TTF 5.3 and 5.3 months (HR 1.08, 95% CI: 0.87-1.33; p=0.485), PFS from 1st-line therapy 17.6 and 17.8 months (HR 0.99, 95% CI: 0.78-1.25; p=0.919) and RR 11.7% and 10.1%. Frequently reported AEs in Arm A and B, respectively, were: hypertension (13.0%, 18.1%), proteinurea (36.8%, 35.2%), GI perforation (4.7%, 3.1%), grade 3/4 neutropenia (46.1%, 39.9%), grade 3/4 fatigue (7.8%, 10.9%), and grade 3/4 anorexia (5.7%, 5.2%). Treatment-related deaths occurred in 2 pts in each arm. Conclusions: The study did not meet its primary endpoint. PFS in Arm A was comparable to that reported in the ML18147 study. Safety in both arms was consistent with previously reported studies. Clinical trial information: UMIN000002557.

Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4503-4503 ◽  
Author(s):  
David C. Smith ◽  
Thomas Gajewski ◽  
Omid Hamid ◽  
Jeffrey S. Wasser ◽  
Anthony J. Olszanski ◽  
...  
Keyword(s):  
Phase I ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Advanced Disease ◽  
Alternative Therapy ◽  
Phase Iii ◽  
Open Label ◽  
Advanced Urothelial Carcinoma ◽  
Grade 3 ◽  
Line Of Therapy

4503 Background: Pembrolizumab (P), a PD-1 inhibitor, is active and well tolerated in platinum-treated, advanced urothelial carcinoma (UC). Epacadostat (E) potently and selectively inhibits indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study of E + P in pts with advanced tumors. We report phase I/II efficacy and safety outcomes for the UC cohort at an October 29, 2016 data cutoff. Methods: Adult pts with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate), and no prior checkpoint inhibitor therapy were eligible to participate. In phase I, pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1–evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: A total of 40 pts (phase I, n = 5; phase II, n = 35) were evaluated. Median age was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease. Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable pts were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). PFS and biomarker analyses are ongoing. The most common TRAEs (≥10% of 40 pts) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of pts (rash was the only grade ≥3 TRAE to occur in > 1 pt [n = 3]). Three pts discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). Conclusions: E + P was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in pts with advanced UC. A phase III UC study is planned. Clinical trial information: NCT02178722.

Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment for advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4514-4514 ◽  
Author(s):  
H. Narahara ◽  
W. Koizumi ◽  
T. Hara ◽  
A. Takagane ◽  
T. Akiya ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Primary Endpoint ◽  
Standard Treatment ◽  
High Response Rate ◽  
Phase Iii ◽  
Rank Test ◽  
Open Label ◽  
Eligibility Criteria ◽  
Phase Iii Study

4514 Background: S-1 has been widely used against advanced gastric cancer (AGC) not only as monotherapy but also in combination with other cytotoxic compounds. Results of a phase I/II study combining S-1 + cisplatin (CDDP) were very encouraging with a high response rate (RR) of 76%, and the MST (Median Survival Time) of 383 days (Koizumi W et al, Br J Cancer, 2003). Based on these results, a phase III study comparing S-1 alone with S-1 + CDDP has been conducted to further evaluate the efficacy and safety for S-1 + CDDP as a standard treatment for AGC. Methods: This is a randomized, controlled, open-label, parallel, multicenter study. Patients (pts) are randomized to one of two treatment arms. Arm A: Pts receive oral S-1 (40 mg/m2) twice daily 28 days followed by 14 days rest. Arm B: Pts receive oral S-1 (40 mg/m2) twice daily 21 days followed by 14 days rest plus CDDP (60 mg/m2) iv on day 8. Eligibility criteria included unresectable/recurrent AGC, age 20–74, no prior chemotherapy for AGC. Primary endpoint was overall survival (OS). Main secondary endpoints included RR, time to treatment failure (TTF) and toxicity. Based on planned sample size of 284 pts, the trial was designed to have 90% power to detect an improvement in median OS from 8 to 12 months (2-sided log-rank test; significance level 0.05). Results: 305 pts (Arm A/B, 152/153) were randomized between Mar 2002 and Nov 2004. The eligible pts were 299 (Arm A/B, 150/149). Median age was 62.0/61.5 yrs. At a 2 yrs follow-up since last patient in, the MST for Arm A was 335.5 days (95%CI: 292.0 - 402.0) and for Arm B was 396.0 days (95%CI: 342.0 - 471.0). The OS for Arm B was superior to Arm A (log-rank p=0.0366, hazard ratio: 0.774, 95% CI: 0.608 - 0.985). RR was 31.1% for Arm A and 54.0% for Arm B. In Arm A vs Arm B, the most common grade 3/4 toxicities were: leucopenia, 2.0% vs 11.5%; neutropenia, 10.7% vs 39.9%; anemia (decreased Hb), 4.0% vs 25.7%; nausea, 1.3% vs 11.5%; anorexia, 6.0% vs 30.4%. No treatment related death was observed. Conclusions: The combination treatment of S-1 and CDDP met primary endpoint of OS, and was found to be effective and well tolerated in pts with AGC. Accordingly, this regimen can be regarded as one of first-line standard treatment for AGC. No significant financial relationships to disclose.

Phase I study of pemetrexed (P) and pegylated liposomal doxorubicin (PLD) in patients with refractory breast, ovarian, primary peritoneal, or fallopian tube cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13515-e13515
Author(s):  
D. A. Richards ◽  
D. Loesch ◽  
S. J. Vukelja ◽  
H. H. Wu ◽  
W. J. Hyman ◽  
...  
Keyword(s):  
Phase I ◽  
Performance Status ◽  
Pegylated Liposomal Doxorubicin ◽  
Open Label ◽  
Ecog Performance Status ◽  
Fallopian Tube Cancer ◽  
Dose Escalation Study ◽  
Specific Patient ◽  
Phase Ii Studies ◽  
Grade 3

e13515 Background: P and PLD are clinically active as single agents and synergistic in preclinical models. This phase I, open-label trial determined the maximum tolerated dose (MTD) and safety profile of P followed by PLD in patients (pts) with breast or gynecologic cancers. Methods: Using standard phase I (3+3 dose escalation) study design, cohorts of 3–9 pts received escalating doses of P followed by PLD in 28-day cycles: P 400–500 mg/m2 on Days 1 and 15 and PLD 30–45 mg/m2 on Day 1. All pts received folic acid (350–1000 μg daily) and vitamin B12 (1000 μg) until 21 days after last dose of P. Pts continued until dose-limiting toxicity (DLT) or disease progression (PD) occurred. Results: From 11/05 to 1/08, 29 pts were registered/treated. Median age: 60.6 years (range, 47.5–80.1); ECOG performance status 0/1: 28%/72%; primary disease sites: ovarian (55%), breast (35%), peritoneal (10%); prior therapies: chemotherapy (100%), surgery (72%), hormones/biologics (35%), radiation (21%). Dosing results are shown below. At dose level (L) 2 and L3, 1 pt/cohort had DLTs; L5 was added and 3/3 pts had DLTs; 4 more pts were treated at L4 (1 pt replaced). Most frequent drug-related Grade 3–4 hematologic toxicities: neutropenia (86%), leukopenia (59%), thrombocytopenia (48%), anemia (41%). Most frequent drug-related Grade 3–4 nonhematologic toxicities: hand-foot syndrome (14%), hypokalaemia (10%). Major reasons for discontinuation: PD (48%), toxicity (28%), pt request (14%). Overall best responses (n=24): 5 pts (21%) had partial response (PR), 14 pts (58%) had stable disease (SD), 2 pts (8%) had PD, 3 pts (13%) were not evaluable. All 5 PR and 8 SD pts were ovarian; 5 SD and both PD pts were breast. Conclusions: P followed by PLD was reasonably tolerated in this heavily-pretreated population. The MTD was P 500 mg/m2 and PLD 40 mg/m2. These dose levels may be carried forward to phase II studies in more specific patient populations. [Table: see text] [Table: see text]

Phase 2 trial of Lu-177-DOTATATE in inoperable pheochromocytoma/paraganglioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4159-TPS4159 ◽  
Author(s):  
Frank Lin ◽  
Jaydira Del Rivero ◽  
Jorge A. Carrasquillo ◽  
Abhishek Jha ◽  
Melissa K Gonzales ◽  
...  
Keyword(s):  
Amino Acid ◽  
Performance Status ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Progression Free Survival ◽  
Fixed Dose ◽  
Phase 2 ◽  
Open Label ◽  
Ecog Performance Status ◽  
Eligibility Criteria

TPS4159 Background: Pheochromocytoma/paraganglioma (PHEO/PGL) is a rare malignancy that arises from chromaffin cells of typically the adrenal medulla but can also be of extra-adrenal origin. These tumors produce excessive catecholamines such as epinephrine and norepinephrine which causes labile hypertension, tachycardia, and flushing. Lu-177-DOTATATE (Lu-177-dodecanetetraacetic acid‐tyrosine-3-octreotate) is a radiolabeled somatostatin analog that is FDA approved for somatostatin receptor-positive neuroendocrine tumors. It is being being investigated in PHEO/PGL, which overexpress somatostatin receptors. Amino acid solutions containing lysine/arginine (L/A) are routinely co-administered with Lu-177-DOTATATE for renal radioprotection, although solutions containing other amino acids are also used. Methods: This is a prospective, single center, open label Phase 2 study evaluating the efficacy of Lu-177-DOTATATE in PHEO/PGL. Ninety patients will be enrolled, divided into two cohorts of 45 patients each ( SDHx mutation vs. apparent sporadic). Lu-177-DOTATATE is given at a fixed dose of 200 mCi with a co-administration of L/A amino acid solution q8 weeks for 4 cycles. The primary endpoint is the progression-free-survival (PFS) rate at 6 months. Secondary endpoints include response rate, overall survival, time to progression, quality of life measures, and examination of potential biomarkers such as biochemical profiles, Ga-68-DOTATATE PET, and F-18-FDG PET scans. Eligibility criteria include inoperable disease (including non-metastatic), histological confirmation of PHEO/PGL, evidence of disease progression by RECIST 1.1, ECOG performance status of 1 or better, and a positive Ga-68-DOTATATE PET scan. Exclusion criteria include prior treatment with systemic radionuclide therapy such as I-131-MIBG, brain parenchymal metastases, and standard organ dysfunction limitations. Interim analysis using a Simon two-stage optimal design will be performed separately for each cohort after enrollment of 18 patients. First patient accrual to this ongoing study was in the Fall of 2017, and as of February 2019, fourteen patients have been accrued. Preliminary results will be reported at the completion of stage 1 for each cohort. Clinical trial information: NCT03206060.

Abstract 178: Byvalson Fixed-Dose Combination for the Treatment of Hypertension: A Comprehensive Review

2017 ◽  
Vol 10 (suppl_3) ◽  
Author(s):  
Charles E Wight ◽  
Nicole Jara ◽  
Chelsea Harlan ◽  
Paul Petrillo ◽  
Mara N Poulakos
Keyword(s):  
Blood Pressure ◽  
Phase I ◽  
Phase I Study ◽  
Fixed Dose Combination ◽  
Phase Iii ◽  
Fixed Dose ◽  
Open Label ◽  
Phase Iii Trial ◽  
Treatment Of Hypertension ◽  
Dose Combination

Purpose: Byvalson (nebivolol and valsartan), FDA approved in June 2016 for the treatment of hypertension, is the first combination beta blocker and ARB fixed-dose combination medication available. Two-thirds of patients with hypertension require more than one drug to achieve BP control. The combination of two antihypertensive medications has been associated with greater BP control, compliance, and reduced adverse effects. Nebivolol is a highly selective β1-adrenergic receptor antagonist with vasodilator properties and valsartan is an ARB. The objective of this study is to evaluate clinical efficacy and safety of this combination of BP-lowering medications in the treatment of hypertension. Methods: A comprehensive literature search was conducted to date utilizing MEDLINE and PUBMED with the following search terms: “nebivolol”, “valsartan”, and “hypertension” to retrieve clinical trials. The following three studies were found: a phase I randomized, open-label study investigating pharmacokinetic and pharmacodynamic interactions between nebivolol and valsartan; and two phase III studies evaluating the safety and efficacy of combination treatment: one is an open-label, single-arm study over 52 weeks and the other is a phase III randomized, placebo-controlled study comparing fixed-dose combination to nebivolol and valsartan alone over 8 weeks. Analysis of the study designs, methods, results, statistical analyses, and conclusions were properly conducted for appropriateness and validity. Results: The pharmacokinetic and pharmacodynamics parameters in the phase I study involving 30 patients had statistically significant steady-state PK interactions deemed not clinically significant, significant reductions in blood pressure (p≤0.005) and other PD interactions. A phase III trial (n=4161) showed significantly greater reductions from baseline at 8 weeks in DBP in the fixed-dose combination group than both nebivolol 40 mg (mean difference –1.2 mm Hg [95% CI, –2.3 to –0.1; p=0.030] and valsartan 320 mg (–4.4 mm Hg [95% CI, –5.4 to –3.3]; p<0.0001). SBP reductions were also significant (p<0.01). Another phase III trial (n=810) showed significant reductions from baseline at 52 weeks for SBP (-25.5±15.9 mm Hg) and for DBP (-19.0±8.7 mm Hg). 75.7% of nebivolol/valsartan and 57.8% of nebivolol/valsartan/HCTZ patients achieved a BP goal of <140/90. Conclusion: Both phase III trials evaluating the combination treatment of nebivolol and valsartan demonstrated long term safety, efficacy, and tolerability with significant reductions in systolic and diastolic blood pressure compared with monotherapy. The phase I study showed limited PK interactions, additive PD effects, and tolerability in healthy volunteers. As an initial therapy in patients with inadequately controlled blood pressure, Byvalson 5/80 mg taken orally once daily is a safe and effective treatment for the hypertension.

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