A multicenter random assignment phase II study of irinotecan and flavopiridol versus irinotecan alone for patients with p53 wild-type gastric adenocarcinoma (NCI 8060).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14586-e14586 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Laura H. Tang ◽  
Stephen Shibata ◽  
David Paul Kelsen ◽  
Michal Segal ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Gastric Adenocarcinoma ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Single Agent ◽  
Progression Free Survival ◽  
Sequential Therapy ◽  
Wild Type

e14586 Background: Preclinical studies demonstrate that tumors wild-type for p53 (p53wt) are refractory to irinotecan relative to non-functional or mutant p53, and that sequential therapy with flavopiridol, a cyclin dependent kinase inhibitor that inhibits homologous recombination and DNA repair, and irinotecan overcomes p53 mediated drug resistance in vivo. This phase II study is designed to assess cell cycle mediated drug resistance in p53wt gastric cancer, and test the hypothesis that administration of flavopiridol following irinotecan can overcome resistance to irinotecan. Methods: Pts with advanced p53wt (≤ 20% nuclear IHC staining using D07 antibody) gastric adenocarcinoma and disease progression on non-irinotecan chemotherapy regimen were randomized in 2:1 fashion to irinotecan 100 mg/m2 followed 7 h later by flavopiridol 60 mg/m2 administered over 1h or irinotecan 100 mg/m2 administered weekly on a 2 week on/1 week off schedule. Response assessment is performed every 2 cycles and the primary endpoint is 3-month progression free survival (PFS). Pre- and post-treatment biopsies were obtained for molecular assessments of p53 mediated drug resistance. Results: To date 30 of 55 patients screened were p53wt (54%), 19 pts were randomized to receive irinotecan + flavopiridol (n=13) and irinotecan (n=6). Median characteristics of 19 evaluable patients: age 61 (44 to 76), KPS 80% (70 to100), 13 male, 1 prior regimen (1 to 2). The common treatment emergent toxicities were anemia (Grade 2/3 21%), neutropenia (grade 2/3 31%, grade 4 .05%), nausea (grade 2/3 21%) and fatigue (grade 2/3 37%). With irinotecan + flavopiridol 1/13 (8%) confirmed partial response was seen and 5 month disease stabilization in 3/13 (23%) patients. No responses were seen with single agent irinotecan. The median PFS was similar, 1.6 mos irinotecan + flavopiridol vs 1.3 mos in irinotecan group (p=0.21). Conclusions: 54% of gastric cancers are p53wt. Correlative tissue analysis including p53 sequencing, p21, Rad51 is ongoing. Due to lack of activity with irinotecan alone, an amendment to a single arm irinotecan + flavopiridol study is planned.

scholarly journals CTIM-15. PRELIMINARY RESULTS OF A PHASE II STUDY OF NIVOLUMAB WITH HYPOFRACTIONATED RE-RADIATION AND BEVACIZUMAB FOR RECURRENT MGMT METHYLATED GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii36-ii36
Author(s):  
Christian Grommes ◽  
Minesh Mehta ◽  
Alexandra Miller ◽  
Mariza Daras ◽  
Anna Piotrowski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Disease Recurrence ◽  
Primary Objective ◽  
Significant Finding ◽  
Trial Treatment

Abstract Standard of standard of care for glioblastoma (GBM) remains unsatisfactory with universal disease recurrence and a median survival of < 2 years. Immune checkpoint inhibitors (ICI) have shown limited single-agent activity in GBM thus far. GBMs with methylated MGMT promoter and no baseline corticosteroid dependence may be most likely to derive benefit from ICI. The combination of ICIs with radiation has shown promising activity in other human cancers. Combining nivolumab and re-RT/bevacizumab in GBM may augment ICI activity through immunogenic effects of radiation, may reduce the risk of radiation necrosis by addition of bevacizumab at the time of radiation, and may reduce the need for corticosteroids. In this multicenter phase II study, nivolumab is combined with re-irradiation and optional concurrent bevacizumab followed by nivolumab in patients with first recurrence of IDH-wildtype and MGMT methylated glioblastoma. Primary objective is to improve 1-year overall survival (OS) from 33 (based on EORTC 26101) to 50%. Nine-three patients are required to show a significant finding with an α of 0.05 and 81% power. Thirteen of 93 patient (14%) have been enrolled with a median age of 59 (range 42–71) with a median KPS of 90 (range 70–90). Treatment has been tolerated well without any grade ≥ 4 toxicities and only one grade 3 (amylase elevation). The most common adverse events were pruritus and hypothyroidism in 3/13 (23%). The median progression-free survival (PFS) is 7 months with a 6months PFS of 55.6%. The 12months OS is 66.7%. Patients with recurrent MGMT methylated, IDH-wildtype glioblastoma tolerate trial treatment with acceptable toxicities. Clinical efficacy in the first patients enrolled shows a promising effect. Enrollment is ongoing.

scholarly journals First-line single-agent panitumumab in frail elderly patients with wild-type RAS unresectable colorectal cancer: a phase II study protocol OGSG 1602

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Tetsuji Terazawa ◽  
Takeshi Kato ◽  
Masahiro Goto ◽  
Daisuke Sakai ◽  
Yukinori Kurokawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Elderly Patients ◽  
Phase Ii ◽  
Study Protocol ◽  
Frail Elderly ◽  
Phase Ii Study ◽  
Single Agent ◽  
Wild Type ◽  
First Line

Sorafenib With Interferon Alfa-2b As First-Line Treatment of Advanced Renal Carcinoma: A Phase II Study of the Southwest Oncology Group

2007 ◽  
Vol 25 (22) ◽  
pp. 3296-3301 ◽  
Author(s):  
Christopher W. Ryan ◽  
Bryan H. Goldman ◽  
Primo N. Lara ◽  
Philip C. Mack ◽  
Tomasz M. Beer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Renal Carcinoma ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Performance Status ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Interferon Alfa

Purpose This phase II study evaluated the activity of combined treatment with interferon alfa-2b and sorafenib, a Raf and multiple receptor tyrosine kinase inhibitor, in patients with advanced renal carcinoma. Patients and Methods Eligible patients had metastatic or unresectable renal carcinoma with a clear-cell component, no prior systemic therapy, performance status 0 to 1, and measurable disease. Treatment consisted of interferon alfa-2b 10 × 106 U subcutaneously three times weekly and sorafenib 400 mg orally bid. The primary end point was confirmed Response Evaluation Criteria in Solid Tumors response rate. Results Twelve (19%) of 62 assessable patients achieved an objective confirmed response. An additional 31 (50%) had an unconfirmed partial response or stable disease as best response. The median progression-free survival was 7 months (95% CI, 4 to 11 months). The most common adverse events were fatigue, anorexia, anemia, diarrhea, nausea, rigors/chills, leukopenia, fever, and transaminase elevation. Von Hippel-Lindau gene mutations were detected in four (22%) of 18 archival tumor specimens. Conclusion The confirmed response rate for the combination of sorafenib and interferon in advanced renal carcinoma is greater than expected with either interferon or sorafenib alone. The toxicity of this combination is dominated by adverse events common to interferon that limit further development of this regimen.

A phase II study of sunitinib administered in a continuous daily regimen in patients with cytokine-refractory metastatic renal cell carcinoma (mRCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4529-4529 ◽  
Author(s):  
P. H. De Mulder ◽  
J. Roigas ◽  
S. Gillessen ◽  
S. Srinivas ◽  
P. Pisa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
Colon Perforation ◽  
Efficacy Data ◽  
Significant Difference ◽  
Hand Foot Syndrome

4529 Background: Renal cell carcinomas are known for their vascularity and production of high levels of VEGF. Sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor of multiple receptors including VEGFR, PDGFR, KIT, RET, and FLT3, has previously demonstrated significant efficacy in 168 patients (pts) with mRCC, with a 42% objective response rate (ORR) at 50 mg/day in 6-week (wk) cycles of 4 wks on treatment followed by 2 wks off. This study sought to determine the efficacy and safety of single-agent sunitinib in mRCC when administered in a continuous 37.5 mg/day regimen. Methods: Pts with histologically proven mRCC, refractory to a cytokine-based regimen, were enrolled in this open-label, multicenter, phase II study. Eligibility criteria included measurable disease, ECOG PS 0/1, and adequate organ function. Pts were randomized to receive sunitinib in the morning (AM) or in the evening (PM) at a dose of 37.5 mg/day, with individual doses subsequently titrated based on tolerability. The primary endpoint was RECIST-defined ORR. Secondary endpoints includedprogression-free survival, adverse events (AEs) and quality of life measures. Results: A total of 88/100 planned pts have been randomized to date: AM (43) and PM (45), and enrollment will be completed by end January 2006. 44 pts have been on continuous sunitinib treatment at 37.5 mg/day for >16 wks (3), >12 wks (9), >8 wks (12), and >4 wks (20). 2 pts (2.3%) discontinued (colon perforation and renal insufficiency) and 9 (10.2%) dose reduced to 25 mg/day due to grade 2/3 AEs: mucositis (2), hand-foot syndrome (2), thrombocytopenia (2), asthenia (1), nausea/diarrhea (1), and neutropenia (1). Preliminary efficacy data show some tumor shrinkage in the majority of patients evaluated at 4 wks, with 3 initial partial responses. There has been no significant difference between pts who received AM or PM doses. The most commonly reported AEs were mucositis, fatigue, hair/skin discoloration, and hand-foot syndrome. Conclusions: Sunitinib administered at a continuous dose of 37.5 mg/day was generally well tolerated; only a few patients required treatment breaks and/or dose reduction. Preliminary efficacy data are encouraging. Mature data will be presented. [Table: see text]

A phase II study of enzastaurin as second- or third-line treatment of non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7543-7543 ◽  
Author(s):  
G. Bepler ◽  
Y. Oh ◽  
H. Burris ◽  
A. Cleverly ◽  
M. Lahn ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Line Treatment ◽  
Platinum Based Chemotherapy ◽  
Third Line ◽  
Third Line Treatment

7543 Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKC and the PI3K/AKT pathway, induces tumor cell apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Over-expression and activity of PKC and PI3K/AKT are associated with poor prognosis and treatment resistance in NSCLC. This multicenter phase II trial of enzastaurin as second- and third-line treatment of NSCLC determined the rate of progression-free survival (PFS) at 6 months (mos). Secondary objectives included safety and the rate of overall survival (OS) at 12 mos. Methods: Eligibility included metastatic (stage IV and wet IIIB) NSCLC and prior platinum-based chemotherapy. Patients (pts) received 500 mg of oral enzastaurin, once daily, until disease progression or unacceptable toxicity occurred. All pts were eligible for 2nd or 3rd line treatment. Results: In the 54 pts enrolled [54% M, 46% F; median age: 63 (range: 43–82); 22.2% stage III, 77.8% stage IV, ECOG PS=2], adenocarcinoma was the most frequent diagnosis (67%). Prior therapies included radiotherapy (74%) and EGFR inhibitors (28%). At the final analysis, the median PFS was 1.9 mos (95% CI: 1.7–1.9), and the PFS rate at 6 mos was 14% (95% CI: 4.4%–23.6%). The median OS was 9.9 mos (95% CI: 6.5–14.6). The OS rate at 12 mos was 46.3% (95% CI: 32.1%–60.5%). Nineteen pts (35%) had stable disease (SD); none had a complete or partial response. Ten (19%) pts were on-study for =6 cycles, 3 of whom continued for >10 months. The most common toxicity, fatigue (grade =2, n=15), occurred within 1 week of enrollment and was not reported in pts with SD. Grade =3 toxicities observed were ataxia (n=1), fatigue (n=2), thrombo-embolism (n=1), and anemia (n=1). Two pts discontinued due to fatigue and dizziness. Five pts died on-study and 4 within 30 days of discontinuation due to PD. Post-study chemotherapy (n=28) included bevacizumab, erlotinib, pemetrexed, gemcitabine, cisplatinum and paclitaxel. Conclusion: Although no objective tumor responses occurred, 14% of the pts were progression-free at 6 months. Based on encouraging survival and tolerability data, further evaluation of enzastaurin as a single agent or in combination, is warranted in NSCLC. No significant financial relationships to disclose.

A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: A trial of the PMH Phase II Consortium

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5576-5576
Author(s):  
S. Welch ◽  
H. J. Mackay ◽  
H. Hirte ◽  
G. F. Fleming ◽  
R. Morgan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Open Label ◽  
Second Stage ◽  
Best Response ◽  
Grade 3 ◽  
Ecog Ps

5576 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Vascular endothelial growth factor (VEGF) overexpression in EC correlates with poor outcome, thus targeting VEGF is a rational therapeutic approach. We have conducted a two-stage open-label phase II study in advanced EC with sunitinib, an oral tyrosine kinase inhibitor of multiple VEGF receptors. Methods: Eligible pts have recurrent or metastatic EC and have received up to 1 prior chemotherapy (CT) regimen for metastatic disease. Sunitinib is given at 50 mg daily (OD) for 4 consecutive weeks (wks) followed by 2 wks off. Dose could be reduced to 37.5 mg OD and then 25 mg OD in the setting of toxicity. Imaging is repeated every 12 wks. Primary objectives are objective response rate (ORR by RECIST) and rate of 6-month progression-free survival (PFS). If 1 or more responses occur in the first 15 evaluable pts, the study would continue to a second stage (total = 30 pts). Secondary objectives are time to progression (TTP), overall survival (OS), and safety. Results: We report the results of the first stage of this study. Sixteen pts have been treated (median age: 63; range 41–74) with 37 cycles of sunitinib (median 2; range: 1–7). Baseline ECOG PS was 0 (7 pts), 1 (8 pts), or 2 (1 pt). Histology was endometrioid (7 pts), serous (5 pts), clear cell (1 pt), or mixed/other (3 pts). Most pts had high-grade histology (G3: 8; G2: 4; G1: 2; GX: 2). Nine pts had prior adjuvant CT, 8 pts had 1 prior CT for advanced EC, 4 pts had prior hormones and 7 pts had prior radiotherapy. Partial response was achieved by 2 pts (ORR = 12.5%), and 2 other pts had a best response of stable disease; 3 of these pts remained progression-free > 6 months. Median TTP = 2.5 months (95% CI: 2.47-NR), and median OS = 6.2 months (95% CI: 5.1-NR). Grade 3/4 adverse events (AE) in >10% of pts were fatigue (7 pts, 44%) and hypertension (5 pts, 31%). Dose reduction was required for 11 of 16 pts (69%). Two pts were inevaluable after receiving <2 cycles due to AE (grade 4 hyponatremia; grade 3 fatigue) and 1 other pt has yet to complete 2 cycles. Conclusions: Sunitinib shows preliminary activity in EC. This trial will proceed to a second stage of accrual to further explore the efficacy and safety of sunitinib in advanced EC. [Table: see text]

Phase II study of efficacy of bevacizumab and erlotinib in inoperable previously untreated hepatocellular carcinoma (HCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15557-e15557
Author(s):  
R. Govindarajan ◽  
E. Siegel ◽  
I. Makhoul ◽  
S. Williamson
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Synergistic Activity ◽  
Time To Progression ◽  
Class A ◽  
Pugh Class

e15557 Background: New treatment options are needed for patients with inoperable and metastatic HCC. Sorafenib, a RAF kinase inhibitor, prolongs the time to progression and overall survival compared to best supportive care (5.5 and 10.7 months respectively). Angiogenesis plays important role in the development and progression of HCC. Erlotinib, an EGFR tyrosine kinase inhibitor that down-regulates expression of Vascular Endothelial Growth Factor (VEGF), and bevacizumab, a monoclonal anti-VEGF antibody, have synergistic activity in arresting angiogenesis. The objective of the study was designed to evaluate the efficacy of the combination of bevacizumab and erlotinib. The pre-determined endpoint for a positive result is a 27 week PFS of > 20%. Methods: A phase II study was conducted for newly diagnosed unresectable or metastatic HCC, Child-Pugh class A or B cirrhosis with bilirubin <2.0 mg/dL, transaminases < 5 x ULN, Platelet count >75,000 K/UL and ECOG PS 0–2 who had no prior systemic therapy and were not candidates for liver transplantation. Erlotinib was administered continuously at a daily dose of 150 mg, and bevacizumab was administered at a dose of 15 mg/kg intravenously every three weeks. Subjects were evaluated for disease progression by RECIST criteria. Results: At the time of analysis, 21 subjects were enrolled (16 Child- Pugh class A, 5 class B). 16 were evaluable. The median age was 60 Yrs.(range 33–81). Four subjects (27%) were progression-free at 27 weeks of enrollment (95% CI 8%- 55%). Median (quartiles) time to progression was 10.3 (9.0–57.1) weeks. The median (quartiles) overall survival (OS) was 59.7 (range 24.6- 92.6) weeks. Grade-3 events observed were (no.): fatigue (4), dehydration (2), hematemesis (1), diarrhea (1), nausea (1), and dyspnea (1). Grade-4 events (no.) observed were: myocardial infarction (1), atrial fibrillation (1), and ventricular tachycardia (1); pulmonary edema (1). Conclusions: The results met the predetermined study end point of progression free survival at 27 weeks of > 20%. The combination of bevacizumab and erlotinib should be further evauated as treatment option for patients with HCC. [Table: see text]

Phase II study of biweekly administration of CPT-11 and gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer in Japan.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15150-e15150
Author(s):  
Ryoji Takada ◽  
Tatsuya Ioka ◽  
Nobuko Ishida ◽  
Takuo Yamai ◽  
Nobuyasu Fukutake ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Phase Ii Study ◽  
Single Agent ◽  
Progression Free Survival ◽  
Current Standard ◽  
Free Survival ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Grade 3

e15150 Background: The current standard therapies for metastatic pancreatic adenocarcinoma in Japan are the single-agent Gemcitabine (Gem) or S-1 and Gem plus erlotinib. Irinotecan (CPT-11) is one of the promising drugs for Gem-refractory PC pts. Both Irinotecan and Gem have shown activity against these diseases with different mechanisms and are non-cross-resistant with each other. Japanese pts have the different metabolism with Irinotecan rather than pts in western countries. Methods: The aim of this phase II study was to evaluate the efficacy and safety of CPT-11 and Gem in Japanese pancreatic cancer pts. Patients with MPC and PS 0-2 were enrolled in this phase II trial. CPT-11, 100mg/m (2), was administered in 90 min. and Gem, 1000mg/m (2), was administered in 30 min. soon after CPT-11 on day1. Chemotherapy was repeated biweekly. Results: From May 2002 to May 2006 40 pts, with median age of 62 (40-74) years, were enrolled in this study. The overall response rate (RR) was 15% with disease control rate of 50%. The median progression-free survival (PFS) was 4.0 months (range: 1.0-15.0 months), and median overall survival (OS) was 7.5 months (range: 3.0-24.0 months). Grade 3/4 anemia, leucopenia occurred in 26.3, 5.2% of pts. The most common non-hematologic toxities were fatigue, diarrhea, nausea/vomiting and anorexia. Grade 3 diarrhea and nausea occurred in 10.5% of pts. Conclusions: The combination chemotherapy with Gem and CPT-11 showed favorable RR as expected and the treatment was manageable in Japanese pts with MPC. We plan to evaluate this combination chemotherapy for MPC pts after progression of FOLFIRINOX in near the future. Clinical trial information: UMIN000009963.

IMAGE, a randomized phase Ib/II study of elisidepsin (E) as a single agent in pretreated advanced gastroesophageal (GE) cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 92-92 ◽  
Author(s):  
Ramon Salazar ◽  
Jean Philippe Metges ◽  
David Alan Anthoney ◽  
Gianluca Laus ◽  
Maria Alsina Maqueda ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase Ii ◽  
Single Agent ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Primary Objective ◽  
Phase Ib ◽  
Flat Dose

92 Background: E is a new marine compound with broad in vitro/in vivo antitumor activity. Low μM concentrations lead to cell-death through membrane permeabilization. E has shown evidence of activity in pre-treated GE patients (pts) in phase I trials. Methods: The primary objective was to determine the tolerability and efficacy of E in pts with GE cancer after 1-2 prior chemotherapy (CT) lines. Initially, dose was optimized (Phase Ib) in two different schedules: a fixed flat dose (FD) of intravenous (i.v) E (8 and 10 mg), in 24h, biweekly (Arm A) and i.v E (3.0 and 3.75mg), in 3h, weekly (Arm B). After dose optimization patients were included and stratified by histology to each optimal dose (Phase II) to determine the rate of progression-free survival at week 16 ± 1 (PFS4) in an intention to treat analysis. If at least two out of 15 pts reached PFS4, recruitment would continue to a maximum of 40 pts per arm. Results: A total of 45 pts were recruited, 12 pts into Phase Ib (Arm A/B: 6/6 pts) and 33 pts into Phase II (Arm A/B: 15/18 pts). Median age was 60 years (35–81 years), 39 were males and ECOG PS was 1 in 75% of pts. Tumour sites were gastric (32% pts), esophageal (39% pts) and esophago-gastric junction (30% pts). Ninety percent of pts had metastatic disease, 31.8% of which had liver metastasis; 55% of pts had two prior lines of CT . No DLTs occurred during the first cycle in the Phase Ib. The optimal dose for Arm A was 10 mg FD, 24h, biweekly; the optimal dose for Arm B was 3.75mg FD, 3h, weekly. Two patients reached PFS4 in Phase Ib (Arm A). Only one patient reached PFS4 in Phase II (Arm A). No objective responses were observed. Therefore, protocol criteria for further recruitment were not met. The safety profile showed grade 1-2 toxicity pruritus (29.5%), nausea (15.9%), vomiting (6.8%) and fatigue (25%). Grade 3-4 toxicity consisted of asymptomatic reversible liver enzyme increases in 20.5% of patients. Conclusions: E is a very tolerable drug with a unique mechanism of action. In the current setting of non-stratified advanced GE patients, E has insufficient antitumor activity to warrant further investigation. Clinical trial information: 2010-020325-40.

Phase II study of cabozantinib (cabo) in patients (pts) with recurrent/metastatic endometrial cancer (EC): A study of the Princess Margaret, Chicago, and California phase II consortia.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5524-5524 ◽  
Author(s):  
Neesha C. Dhani ◽  
Hal W. Hirte ◽  
Julia V. Burnier ◽  
Angela Jain ◽  
Marcus O. Butler ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Mutational Analysis ◽  
Single Agent ◽  
Progression Free Survival ◽  
Current Data ◽  
Pik3ca Mutations ◽  
Primary Endpoints ◽  
Hand Foot Syndrome ◽  
Grade 3

5524 Background: Recurrent/metastatic EC has a poor prognosis with no standard 2ndline therapy. Cabo is a multi-targeted kinase inhibitor of MET, VEGFR, TIE2, AXL & KIT, relevant in epithelial-stromal cross-talk. The role of MET/HGF in aggressive EC biology, where transient benefit of VEGF-targeting is due to MET/HGF, TIE2 & AXL, provides rationale for MET targeting in EC. Methods: PHL86 (NCI#9322/NCT01935934) is a multi-centre, phase II trial of cabo (60mg oral daily dose) in pts with EC recurring within a year of adjuvant chemotherapy (ctx), or with progression after 1 line of ctx for metastatic disease. Experimental (E) cohort was stratified by histology (serous (SER) vs endometroid (END)) in a Simon two-stage design for co-primary endpoints of response rate ( > 30%) & 12-week progression-free-survival (PFS) ( > 55%). Activity was defined as > 7 partial responses (PRs) or > 15 instances of 12 wk-PFS in 36 pts. Pts with rare histology EC were treated in a parallel exploratory (Ex) cohort. Results: From May 2013 to Nov 2016, 102 pts (E: 71; Ex: 31) have been treated with cabo after prior radiation (59) and/or ctx (no. lines: 1(77); 2(22)). Cabo was well tolerated with common toxicities of fatigue, nausea, diarrhea & hand-foot syndrome. Most frequent Grade 3/4 toxicity was hypertension (32/101 pts). Fistula/perforation occurred in 4 of 71 SER/END pts & 4 of 31 Ex pts; no risk factors were identified. In 33 END pts, 6 PRs & 24 instances of > 12-wk PFS were observed; median PFS is 4.8 mths (95% CI: 4.4 – 6.4) with estimated 6-mth PFS of 43% (95% CI: 27 to 59%). In 34 SER pts, 4 PRs & 20 instances of > 12-wk PFS were observed; median PFS is 4.0 mths (95% CI: 2.7 – 4.7) with estimated 6-mth PFS of 30% (95% CI: 15 to 46%). 4 pts have had PFS > 12 mths, 1 SER pt remains on study after 25mths. Mutational analysis demonstrated presence of KRAS with PTEN or PIK3CA mutations in 9 (SER/END) pts, of whom 8/9 pts met 12-wk PFS endpoint, with a median PFS 5.9 mth (4.1 to 15.4). Conclusions: Cabo has single agent activity in END and SER EC with durable disease control. Concurrent mutation in KRAS/PTEN/PIK3CA may enrich for response. The current data support further evaluation of cabo in EC. Clinical trial information: NCT01935934.

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