EFFORT: EFFicacy Of adavosertib in parp ResisTance: A randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5505-5505
Author(s):  
Shannon Neville Westin ◽  
Robert L. Coleman ◽  
Bryan M. Fellman ◽  
Ying Yuan ◽  
Anil K. Sood ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dose Reduction ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Cell Cycle Checkpoint ◽  
M Cell ◽  
Peritoneal Cancer ◽  
Grade 3

5505 Background: Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 and 2 and is involved in regulation of the intra-S and G2/M cell cycle checkpoint arrest for premitotic DNA repair. The Wee1 inhibitor, adavosertib, has demonstrated activity alone and in combination with olaparib in PARP inhibitor (PARPi)-resistant preclinical models. We sought to evaluate efficacy of adavosertib (A) with or without olaparib (O) in a phase II noncomparative study of recurrent PARPi-resistant ovarian cancer. Methods: Women with recurrent ovarian, fallopian tube or primary peritoneal cancer with documented progressive disease on a PARPi were eligible. All patients (pts) had measurable disease and adequate end organ function. On the A arm, pts received A 300mg PO daily on days 1-5 and 8-12 of a 21-day cycle. On the A/O arm, pts received A 150mg PO BID on days 1-3 and 8-10 and O 200mg PO BID on days 1-21 of a 21-day cycle. Primary endpoint was objective response per RECIST 1.1 and was assessed every 2 cycles. Clinical benefit rate (CBR) was defined as proportion of pts with objective response or stable disease > 16 weeks. Progression free survival (PFS) was assessed using the Kaplan Meier method and calculated from date of treatment initiation to earliest date of progression, death, or last visit. Results: 116 pts were screened with 80 pts enrolled and randomized (A: n=39, A/O: n=41). Median age was 60 years (range 36-76) and the majority of pts had platinum resistant disease (64%) and high grade serous histology (98%). Pts received a median of 4 prior therapies (range 1-11) and 48% had germline or somatic BRCA mutations. There were 35 pts evaluable for response in each arm. Table demonstrates efficacy data. On the A arm, Grade 3/4 toxicities occurred in 51% of pts, most commonly neutropenia (13%), thrombocytopenia (10%), and diarrhea (8%). 28 (72%) pts required at least one dose interruption and 20 (51%) required dose reduction. On the A/O arm, Grade 3/4 toxicities occurred in 76% of pts, most commonly thrombocytopenia (20%), neutropenia (15%), diarrhea (12%), fatigue (12%), and anemia (10%). 36 (88%) of pts required at least one dose interruption, 29 (71%) required dose reduction, and 4 (10%) did not restart due to toxicity. Conclusions: A given alone and in combination with O demonstrated efficacy in pts with PARPi-resistant ovarian cancer. Although grade 3 and 4 toxicities were observed on both arms, these were generally manageable with supportive care, dose interruptions and dose reductions as needed. Additional translational analyses are ongoing to clarify which pts received clinical benefit. Clinical trial information: NCT03579316. [Table: see text]

scholarly journals Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours

2019 ◽  
Vol 122 (4) ◽  
pp. 483-490 ◽  
Author(s):  
Corran Roberts ◽  
Victoria Y. Strauss ◽  
Sylwia Kopijasz ◽  
Charlie Gourley ◽  
Marcia Hall ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Progression Free Survival ◽  
Breast Cancer Patients

Abstract Background Tumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin. Methods This phase II single-arm trial investigated the activity of 6MP 55–75 mg/m2 per day, and methotrexate 15–20 mg/m2 per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS). Results In total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9–14.5), median PFS 1.9 months (1.7–2.8). Conclusions The overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit. Trial registration NCT01432145 http://www.ClinicalTrials.gov.

scholarly journals Abiraterone in patients with recurrent epithelial ovarian cancer: principal results of the phase II Cancer of the Ovary Abiraterone (CORAL) trial (CRUK – A16037)

2020 ◽  
Vol 12 ◽  
pp. 175883592097535
Author(s):  
Susana Banerjee ◽  
Holly Tovey ◽  
Rebecca Bowen ◽  
Elizabeth Folkerd ◽  
Lucy Kilburn ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Clinical Activity ◽  
Low Grade ◽  
Open Label ◽  
Grade 3

Background: Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis. The Cancer of the Ovary Abiraterone (CORAL) trial was designed to evaluate the clinical activity of abiraterone in EOC. Patients & Methods: CORAL was a multi-centre, open-label, non-randomised, 2-stage phase II clinical trial. Eligible patients had progression within 12 months of last systemic therapy and no prior hormonal anti-cancer agents. Patients received abiraterone 1000 mg daily plus 5 mg prednisone until progression. The primary endpoint was objective response rate (ORR) according to combined Response Evaluation Criteria in Solid Tumours/Gynaecological Cancer Intergroup (RECIST/GCIG) criteria at 12 weeks. Secondary endpoints included clinical benefit rate (CBR) at 12 weeks. Results: A total of 42 patients were recruited; median age 65 (range 34–85) years; 37 (88.1%) had high-grade serous tumours; 20 (48%) had at least three prior lines of therapy; 29/40 (72.5%) were AR+. In stage 1, 1/26 response was observed (in an AR+, low-grade serous EOC); response lasted 47 weeks. Overall, 12 week ORR was 1/42 (2%), CBR was 11/42 (26%) (8/29 (28%) in AR+ patients). Disease control was ⩾6 months for 4/29 (14%). One patient (AR+, low-grade serous) had a RECIST response at 82 weeks. Four (10%) had grade ⩾3 hypokalaemia; 11 (26%) had dose delays. Conclusions: CORAL represents the first trial of an AR targeted agent in ovarian cancer. While responses were rare, a subset of patients achieved sustained clinical benefit. Targeting AR in EOC including low-grade serous cancer warrants further investigation. Trial registration: CORAL is registered on the ISRCTN registry: ISRCTN63407050; http://www.isrctn.com/ISRCTN63407050

A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel, IP cisplatin, and IV bevacizumab as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5539-5539 ◽  
Author(s):  
J. A. Konner ◽  
D. Grabon ◽  
S. Pezzulli ◽  
A. Iasonos ◽  
P. Sabbatini ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Small Bowel ◽  
Fallopian Tube ◽  
Phase Ii ◽  
Anastomotic Dehiscence ◽  
Stage Ii ◽  
Phase Ii Trials ◽  
Fallopian Tube Cancer ◽  
Peritoneal Cancer ◽  
Grade 3

5539 Background: IP cisplatin (Cis) plus IV/IP paclitaxel (Tax) is a standard therapy for optimally debulked ovarian cancer. Bevacizumab (Bev) is a recombinant humanized IgG1 monoclonal antibody directed against vascular endothelial growth factor. Activity of Bev in recurrent ovarian cancer has been reported in phase II trials. In this study IP Cis and IV/IP Tax are combined with IV Bev as front-line therapy. Methods: Patients with optimal (<1 cm residual), FIGO stage II or III, epithelial ovarian, fallopian tube, or peritoneal cancer, acceptable organ function, and KPS ≥ 70% are eligible. Patients receive 6 cycles of chemotherapy plus Bev: Tax 135 mg/m2 IV over 3 hours on Day 1, Cis 75 mg/m2 IP on Day 2, Tax 60 mg/m2 IP on Day 8, Bev 15 mg/kg IV on Day 1 (starting cycle 2). Bev is continued every 3 weeks for 17 treatments after chemotherapy is complete. This study will enroll 41 patients. The primary endpoint is safety and tolerability, determined by whether at least 60% of patients complete the prescribed 6 cycles of cytotoxic chemotherapy without unacceptable toxicity. Results: Thirty-nine women [median age 56 (40–69)] have been treated on study: 26 (67%) completed 6 IV/IP cycles; 5 (13%) are receiving ongoing IV/IP treatment; 4 (10%) experienced IP port malfunction (3 finished 5 IV/IP cycles, 1 came off study for port revision); 3 (8%) switched from IP Cis to IV carboplatin due to grade 3 nephrotoxicity in cycle 1 (n = 2) or grade 3 hypertension in cycle 6 (n = 1); and 1 (2.5%) patient died following rectosigmoid anastomotic dehiscence during cycle 4. Grade 3/4 treatment-related toxicities include hypertension (10%), vasovagal events (10%), neutropenia (26%), nausea/vomiting (10%), and hypomagnesemia (8%). There were 3 occurrences of grade 3 abdominal pain (8%); and 3 adhesion-related grade 3 small bowel obstructions (8%), during cycles 3, 9, and 15, respectively. Conclusions: The addition of Bev to this IV/IP regimen appears to be feasible. Bev may increase the risk of small bowel obstruction/perforation in these patients. Enrollment continues and updated results will be presented. [Table: see text]

Phase II clinical trial of six mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS5615-TPS5615
Author(s):  
Shibani Nicum ◽  
Claire E Brooks ◽  
Rose Wharton ◽  
Lucy Boyle ◽  
Stanley B. Kaye ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Xenograft Model ◽  
Phase Iii ◽  
Tpmt Activity ◽  
Compromise Design

TPS5615 Background: BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumor cells with these mutations demonstrate increased sensitivity to cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor, AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin (Issaeva 2010). Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers. This multi-center phase II single arm trial was set up to investigate the activity and safety of 6MP with methotrexate in patients with breast or ovarian cancer who are known to have a BRCA mutation. Methods: Two-stage Simon compromise design (Jung 2001, Jung 2004) with α=0.20, power=90% to detect an increase in activity from 10 to 20%. 1st stage: if ≤ 3/30 evaluable patients respond at 8 weeks the trial will be stopped for futility; 2nd stage: if ≥9/65 evaluable patients respond at 8 weeks the treatment will be regarded as potentially effective and a phase III trial will be considered if the treatment appears safe and well-tolerated. 65 patients with BRCA defective cancer progressing after at least one prior chemotherapy or relapsed platinum resistant ovarian cancer, ECOG performance status 0-2 will be recruited and treated with daily 6MP (75mg/m2 ) and weekly methotrexate (20mg/m2) until progression. The starting dose was later reduced by 25% due to excess of expected toxicity. Patients with low TPMT activity or a low/low genotype are excluded due to the risk of increased toxicity. Prior treatment with a PARP inhibitor is permissible. Primary outcome: objective response at 8 weeks: complete, partial response or stable disease defined by RECIST 1.1. Secondary outcomes include safety, PFS, OS and quality of life. Of the 46 patients screened for TMPT activity between 15 Jun2009 and 05Dec 2012 from 12 UK sites, 31 patients were recruited. The pre-specified activity goal for the 1st stage was met and accrual into the 2nd stage continues. Clinical trial information: 2009-016846-16.

Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886 Hydrogen Sulfate) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3612-3612
Author(s):  
Geraldine Helen O'Sullivan Coyne ◽  
Andrea M. Gross ◽  
Eva Dombi ◽  
Cecilia Tibery ◽  
Amanda Carbonell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Rating Scale ◽  
Objective Response ◽  
Pancreatic Enzyme ◽  
Pain Interference ◽  
Medical Illness ◽  
Best Interest ◽  
Patient Reported ◽  
Grade 3

3612 Background: NF1-related PN are locally invasive tumors characterized by increased activation of the RAS pathway causing significant morbidity including disfigurement, pain and functional limitations. Selumetinib has received breakthrough designation for NF1 PN based on phase I / II trials in children. We present results for the ongoing phase II study of selumetinib in adults with NF1 PN, which includes pharmacodynamic (PD) evaluation of serial tumor biopsies as well as functional/patient-reported outcomes (PROs). Methods: Open-label Simon 2-stage design. Eligibility: NF1 patients (pts) ≥18 years old with inoperable/symptomatic/progressive PN. First 2 pts received selumetinib 75 mg BID; subsequent pts received selumetinib 50 mg BID. Primary objective: response rate by volumetric MRI analysis (partial response [PR]; ≥20% volume decrease). Secondary objectives: PD studies on pre/on-treatment biopsies of PN and cutaneous neurofibromas, assessment of clinical benefit using PROs (Numeric Rating Scale-11, Pain Interference Index), and PN-specific functional assessments. Validated, fit-for-purpose, isozyme-specific measurements of pERK/ERK/pMEK/MEK performed using SOPs designed for labile phosphoproteins (PMID 27001313). Results: As of February 2020, 27 pts have enrolled. Outcomes are reported for 23 pts (74% male; median age 33 years, range 18-60). Most common PN-related morbidity: pain (19 pts). Sixteen pts achieved PR (69%), with 13/16 confirmed; no disease progression. Time to response: 11 months (range 5-25); median change in PN volume at best response: -22% (range -41% to +5.5%); median duration of treatment: 28 months (range 2-50). Selumetinib suppressed tumor pERK1,2/ERK1,2 but not pMEK1,2/MEK1,2 ratios from 1-10 hours following oral dosing (one t½). Pt-reported target tumor pain intensity and pain interference scores significantly improved (both p < 0.03). Pts 1 and 2 were dose-reduced due to grade 3 intolerable rash (n = 2) and pain (n = 1). Grade ≥3 drug-related toxicities on 50 mg (21 pts) include transaminitis (5 pts), rash (1 pt) and pancreatic enzyme elevation (1 pt). Two pts were dose reduced (rash = 1 pt, transaminitis = 1 pt). Two pts discontinued by choice, 2 pts withdrawn by PI (best interest of patient), and 1 pt each removed for transaminitis, surgical resection, serious concurrent medical illness, and non-compliance. Conclusions: Selumetinib shrinks the majority of adult PN and results in molecular target suppression and clinical benefit. Clinical trial information: NCT02407405 .

Phase II trial of guadecitabine priming and pembrolizumab in platinum resistant recurrent ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6025-6025
Author(s):  
Daniela Matei ◽  
Alok Pant ◽  
John William Moroney ◽  
Gini F. Fleming ◽  
Edward Tanner ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Clinical Benefit Rate ◽  
Platinum Resistant ◽  
Grade 3 ◽  
Anti Tumor Activity

6025 Background: Platinum resistant ovarian cancer (PROC) remains a disease of high need. Immune checkpoint inhibitors (ICI) have modest activity. We hypothesized that priming with a hypomethylating agent (HMA) guadecitabine (G) will improve the anti-tumor activity of ICI in PROC by enhancing tumor cell recognition by CD8+ T cells. Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients (pts) had recurrent PROC; ECOG PS of 0-1; normal end organ function; and measurable disease. Up to 5 prior cytotoxic regimens were allowed. Treatment consisted of G 30mg/m2 sq D1-4 and pembrolizumab (P) 200mg iv D5. Each cycle was 21 days. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), and toxicity assessment. Translational endpoints were LINE1 methylation in PBMCs, global tumor methylation, and immune endpoints. Tumor biopsies were obtained at baseline and after 2 cycles. If 2 patients experienced clinical benefit in stage I [n = 16], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 6 responses in 35 evaluable patients. Results: 48 pts were enrolled, 43 were treated, and 33 were evaluable for response. Histology was serous (35), endometrioid (2), clear cell (3) and other (3). Median age was 63 (range 40-88) and median number of prior regimens was 4 [range 1-8]. Two PRs were recorded in the first stage, allowing second stage of enrollment. Overall, there were 2 PRs (RR = 6.6%) and 16 pts had stable disease (SD) [48%]. The clinical benefit rate (PR + SD > 3 months) was 27%. One patient continued treatment for > 2 yrs. Grade 3-4 related toxicities were neutropenia [20], lymphopenia, (9), anemia (2), neutropenic fever (1), rash (1), and others (8). There were 13 grade 3-4 SAEs and 4 grade 5 SAEs, assessed as being unrelated to treatment. LINE1 was hypomethylated in PBMCs D5 vs. D1 (n = 21, p = 0.001). Epic arrays measured global tumor methylation, with 39579 CpG sites (0.05%) being differentially methylated (C2D5 vs. C1D1, n = 11, paired t-test; p < 0.01). Main pathways affected included endosomal transport, K+ transport, cathecolamine secretion, etc. PDL1 staining in archival tissue showed tumor staining > 0 in 16 of 35 and tumor/stroma interface staining > 0 in 20 of 35 specimens. Antigen-specific cytotoxic T cell activity was increased in CD8+ cells from ascites (C2D5 vs. C1D1). Conclusions: G+P has modest anti-tumor activity in patients with PROC, but some patients experienced prolonged disease stabilization. Biomarkers of response are being investigated. Clinical trial information: NCT02901899.

Evolve: A post PARP inhibitor clinical translational phase II trial of cediranib-olaparib in ovarian cancer—A Princess Margaret Consortium – GCIG Phase II Trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5521-5521 ◽  
Author(s):  
Stephanie Lheureux ◽  
Ana Oaknin ◽  
Swati Garg ◽  
Jeffrey Bruce ◽  
Neesha C. Dhani ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Tumor Biopsy ◽  
Ps Ii

5521 Background: PARP inhibitors (PARPi) are approved therapies in high grade serous ovarian cancer (HGSOC). There are few studies after PARPi progression and correlation with dynamic changes in resistance. We hypothesized that PARPi resistance could be overcome by adding an anti-angiogenic. Methods: We report the first phase 2 trial assessing the combination of olaparib and cediranib after PARPi failure in HGSOC. This investigator initiated study included three cohorts of 10 evaluable patients (pts): i) platinum sensitive post PARPi (PS), ii) platinum resistant post PARPi (PR) and iii) exploratory cohort of pts re-challenged with chemotherapy post PARPi progression (PE) (NCT02681237). The primary objective was to determine objective response rate by RECIST v1.1 and progression free survival (PFS) at 16 weeks. Secondary objectives were to evaluate safety, PFS, overall survival (OS) and mechanisms of PARPi resistance. Pts who had radiographic progression on any PARPi were eligible. Archival tumor at initial diagnosis and baseline tumor biopsy at PARPi progression were mandatory. Pts received olaparib tablets 150mg BID with cediranib 20mg QD until progression or unacceptable toxicity. CT scans were performed every 8 weeks. Whole exome and RNA sequencing were performed on paired tumors tissues. Results: Thirty-four pts were enrolled. BRCA1/2 mutations were found in 9/11 PS, 8/10 PR and 7/13 PE pts. By RECIST1.1, four partial responses were observed (2 in PR and 2 in PE cohorts) and 18 stable disease. The 16−week PFS was 54.5% (31.8−93.6) in PS, 50% (26.9−92.9) in PR and 36% (15.6−82.8) in PE, respectively. OS at 1 year was 81.8% (61.9−100) in PS, 64.8% (39.3−100) in PR and 39.1% (14.7−100) in PE. Main related adverse events were anemia, hypertension, diarrhea and fatigue, grade 3 < 10%. Molecular analyses identified different mechanisms of PARPi resistance in ~77% of evaluable pts with matched pre-post PARPi progression biopsies such as reversion mutations in BRCA1/2 and other homologous repair (HR) genes; BRCA, HR and MDR upregulation, CCNE amplification and RIG-I like receptor downregulation. Conclusions: Treatment with olaparib-cediranib after PARPi failure was feasible and met the predefined bar for efficacy in each cohort. This is the largest clinical trial prospectively evaluating PARPi failure and correlating tissue genomic mechanisms of resistance. Clinical trial information: NCT02681237.

Phase II trial of nab-paclitaxel (nanoparticle albumin-bound paclitaxel (ABX)) + capecitabine (XEL) in first-line treatment of metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1053-1053 ◽  
Author(s):  
B. G. Somer ◽  
L. S. Schwartzberg ◽  
F. Arena ◽  
A. Epperson ◽  
D. Fu ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Metastatic Breast ◽  
Safety And Efficacy ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Dose Reductions

1053 Background: ABX and XEL both have substantial single agent activity in MBC. Taxane and anti-metabolite doublets improve response rate and TTP and longer survival. ABX administered weekly has an excellent safety and efficacy profile with maintenance of dose intensity. This study was designed to test the safety and efficacy of ABX + XEL given in a novel combination schedule. Methods: This phase II, multicenter open label study utilized ABX 125 mg/m2 IV on day 1, 8 and with no premeds and capecitabine 825 mg/m2 PO BID days 1–14 on a Q 3 week cycle. The primary endpoint is objective response rate, with evaluation performed after every 2 cycles. Entry criteria include measurable MBC by RECIST criteria, age >18, PS 0–2, no prior chemo for metastatic disease, > 6 months since adjuvant fluoropyrimidine and/or paclitaxel. Results: The full sample of 50 patients (pts) have been enrolled; data from 43 pts are available for analysis. Median age is 58 (range 23.7–90.6). 37% received prior adjuvant anthracycline and 33% prior adjuvant taxane. Median number of metastatic sites is 2 (range 1–7), with most common sites of disease liver, 53.5%; bone, 51.2%; and lung, 14%. 226 cycles of therapy have been delivered. 5 pts required a dose reduction in XEL (3 pts to 650 mg/m2; 2 to 550 mg/m2) and 4 pts had dose reduction in ABX to 100 mg/m2. XEL dose reductions occurred due to hand-foot syndrome (3), neutropenia (1), and fatigue (1). ABX dose reductions occurred due to mucositis, diarrhea, fatigue, and neuropathy (1 pt each). 10 pts had grade 3–4 non-hematologic AEs: 3 hand-foot syndrome, 4 fatigue, and 3 GI. Hematologic AEs included 4 with grade 3 and 1 with grade 4 neutropenia, and 2 with grade 4 febrile neutropenia. The most common AEs of any grade were GI (30), dermatological (23), fatigue (15), neuropathy (12), and hand-foot syndrome (11). The incidence of Grade 1–2 neuropathy was 25% (no grade 3–4). Of 38 pts available for analysis of response, the overall response rate is 47.5%: PR 39.5%, CR 8%. Total of 15 pts have stable disease, 20 pts have completed 6+ cycles. No significant financial relationships to disclose.

Phase I study of combination chemotherapy with irinotecan and gemcitabine for taxane/platinum resistant ovarian, fallopian tube, or primary peritoneal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5538-5538
Author(s):  
Kiyoshi Yoshino ◽  
Shoji Kamiura ◽  
Haruki Ogawa ◽  
Atsushi Tokuhira ◽  
Masahiko Takemura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fallopian Tube ◽  
Combination Chemotherapy ◽  
Ovarian Cancer Cell Line ◽  
Objective Response ◽  
Peritoneal Cancer ◽  
Platinum Resistant ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

5538 Background: Development of new regimen is required to overcome platinum resistant ovarian cancer. Irinotecan and gemcitabine have a synergistic effect to inhibit the growth of ovarian cancer cell line in vitro. The objective is to evaluate the feasibility of combination chemotherapy with irinotecan and gemcitabine for taxane/platinum resistant recurrent ovarian, fallopian tube or peritoneal cancer and to determine the recommended dose. Methods: Nine patients with measurable disease (age range 51-70 years) were enrolled. Patients were treated with irinotecan and gemcitabine on days 1 and 8 every 3 weeks with starting dose of level 1. Dose levels included irinotecan/gemcitabine: 65/650 (level 0), 80/800 (level 1), 100/1000 (level 2), mg/m2 respectively. Level 2 is defined as the maximum dose as used in other malignancies. Dose-limiting toxicity (DLT) was assessed during the first cycle; toxicities were monitored throughout the treatment according to the CTCAE v4.0. Treatment continued until disease progression or unacceptable toxicity. Results: In level 1 (n = 6), grade 3/4 neutropenia was observed in 5 patients. Grade 3 nausea and vomiting was observed in 1, grade 3 diarrhea in 1. One patient of level 1 experienced DLTs. In level 2 (n = 3), grade 3/4 neutropenia are observed in 3, anemia in 1, and thrombocytopenia in one patient. Other toxicities were mild. Three patients who received level 2 did not show DLT. The objective response was CR/PR/SD/PD, 0/2/5/2. Conclusions: The dose level of irinotecan 100 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and 8 every 3 weeks is recommended for a phase II study. Clinical trial information: UMIN000005926.

Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5500-5500 ◽  
Author(s):  
M. W. Audeh ◽  
R. T. Penson ◽  
M. Friedlander ◽  
B. Powell ◽  
K. M. Bell-McGuinn ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Advanced Ovarian Cancer ◽  
Maximum Tolerated Dose ◽  
Tolerability Profile ◽  
Eligibility Criteria ◽  
Highly Active

5500 Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced chemotherapy-refractory ovarian cancer. The secondary aim was to assess the safety and tolerability profile in ovarian cancer patients with BRCA1/2 deficiency. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two patient (pt) sequential cohorts received continuous oral olaparib in 28-day cycles, initially at the MTD, 400 mg bd (33 pts), and subsequently at 100 mg bd (24 pts), a previously shown clinically active and PARP inhibitory dose. Eligibility criteria included confirmed genetic BRCA1/2 mutation and recurrent, measurable, incurable disease (previous chemotherapy, median 3 lines). The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Change in CA125 was a secondary efficacy endpoint. All adverse events were reported using CTCAE v3. Results: At this interim analysis dated October 31, 2008, of 57 enrolled pts (39 BRCA1 deficient and 18 BRCA2 deficient), 33 were evaluable at 400 mg bd and 24 at 100 mg bd. The confirmed RECIST ORR was 33% at 400 mg bd and 12.5% at 100 mg bd. Clinical benefit rate (ORR and/or confirmed >50% decline in CA125) was 57.6% at 400 mg bd and 16.7% at 100 mg bd. Toxicity was mainly mild in severity, reflecting grade 1/2 nausea (44%); fatigue (35%); and anemia (14%). Grade 3 toxicity occurred infrequently, and comprised primarily nausea (7%) and leukopenia (5%). Conclusions: Oral olaparib is well tolerated and highly active in advanced, chemotherapy-refractory BRCA-deficient ovarian cancer, with greater activity seen at the higher dose. Toxicity in BRCA1/2 carriers was similar to that seen in non-carriers. This study provides positive proof of the concept of the activity and tolerability of genetically defined targeted therapy with olaparib in BRCA-deficient ovarian cancers. [Table: see text]

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