Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with standard neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 155-155
Author(s):  
Premal H. Thaker ◽  
William Hampton Bradley ◽  
Charles A. Leath ◽  
Camille Catherine Gunderson ◽  
Nicholas Borys ◽  
...  
Keyword(s):  
Complete Response ◽  
Primary Objective ◽  
Ca 125 ◽  
Newly Diagnosed ◽  
Peritoneal Cancer ◽  
Interval Debulking Surgery ◽  
Objective Clinical Response ◽  
Dose Dense ◽  
Dose Levels ◽  
Pathological Cr

155 Background: This study evaluated weekly intraperitoneal GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, in combination with dose-dense weekly taxane (T) and carboplatinum (C) every 3 weeks in newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective of this study was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives were objective clinical response and pathological complete response at interval debulking surgery (IDB). Methods: This protocol followed a standard 3+3 design. Patients received GEN-1 at escalating dose levels from 36 mg/m2, 47 mg/m2, 61 mg/m2, to 79 mg/m2 weekly for 8 treatments with concurrent T/C. After IDB, patients did not receive further GEN-1 but continued on T/C. Patients were assessed for dose limiting toxicities (DLT) and had tumor samples at a time of diagnostic laparoscopy and IDB. Translational endpoints are yet to be analyzed. Patients are being followed for every 3 months for 2 years. Results: Fifteen patients were enrolled and 9 patients received all 8 treatments with no DLTs. The 79 mg/m2GEN-1 cohort of patients are actively being treated. Two patients were screen failures; 1 patient discontinued prior to GEN-1 administration due to port site infection. Most common related toxicities were Gr 1 nausea, fatigue, abdominal pain, and vomiting. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. One patient did not undergo IDB due to pulmonary embolism and severe deconditioning due to underlying cancer. Of the other 8 patients undergoing IDB: 3/8 had stable disease, 4/8 had partial responses (PR), and 1/8 had complete response (CR). There was 1 pathological CR, 3 micro PR, and 3 macro PR. All patients had a ≥ 89% drop in CA-125 following GEN-1. Conclusions: Adding GEN-1 to T/C is safe and appears to be active in NAC patients with newly diagnosed EOC. Updated results to be presented at meeting. Clinical trial information: NCT02480374.

Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5568-5568
Author(s):  
Premal H. Thaker ◽  
William Hampton Bradley ◽  
Charles A. Leath ◽  
Camille Catherine Gunderson ◽  
Nicholas Borys ◽  
...  
Keyword(s):  
Primary Objective ◽  
Advanced Stage ◽  
Newly Diagnosed ◽  
Debulking Surgery ◽  
Peritoneal Cancer ◽  
Interval Debulking Surgery ◽  
Objective Clinical Response ◽  
Dose Levels ◽  
Dose Limiting Toxicity ◽  
Clinical Trial Information

5568 Background: This study evaluated weekly intraperitoneal (IP) GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, with intravenous (IV) weekly taxane (T) and carboplatinum (C) every 3 weeks in epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives included objective clinical response and pathological response at interval debulking surgery (IDB). Methods: Newly diagnosed advanced stage EOC patients being treated with NAC were eligible. The trial utilized a 3+3 design with GEN-1 IP dose levels of 36 mg/m2, 47 mg/m2, 61 mg/m2, and 79 mg/m2 weekly for 8 treatments with concurrent IV T/C. Dose-limiting toxicity (DLT) was based on the first 4 doses of GEN-1 administered. Results: To date, 13 patients have been treated on-study with 12 patients receiving all 8 treatments of IP GEN-1 with no DLTs. The most common related toxicities were Gr 1 nausea, vomiting, abdominal pain and fatigue. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. One patient did not undergo IDB while on-study due to a cancer related pulmonary embolism and severe deconditioning. This patient has since improved and will have IDB. Conclusions: Adding GEN-1 to neoadjuvant T/C is safe and appears to be active in EOC patients. We are reporting the interim findings; final results with translational data to be presented. Clinical trial information: NCT02480374. [Table: see text]

Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced-stage ovarian cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 2-2 ◽  
Author(s):  
Premal H. Thaker ◽  
William Hampton Bradley ◽  
Charles A. Leath ◽  
Camille Catherine Gunderson ◽  
Nicholas Borys ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Primary Objective ◽  
Newly Diagnosed ◽  
Peritoneal Cancer ◽  
Interval Debulking Surgery ◽  
Objective Clinical Response ◽  
Dose Levels ◽  
Dose Limiting Toxicity ◽  
Ongoing Phase

2 Background: This study evaluated weekly intraperitoneal (IP) GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine-cholesterol lipopolymer, with intravenous (IV) weekly taxane (T) and carboplatinum (C) every 3 weeks in epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives included objective clinical response and pathological response at interval debulking surgery (IDS). Methods: Newly diagnosed EOC patients with no prior therapies were eligible. The trial utilized a 3+3 design with dose escalation in ~30% increments at GEN-1 IP dose levels of 36 mg/m2, 47 mg/m2, 61 mg/m2, and 79 mg/m2 weekly for 8 treatments with concurrent IV T/C. Dose-limiting toxicity (DLT) was based on the first 4 doses of GEN-1 administered. Results: 18 patients were enrolled into the study and 12 of those patients received all 8 treatments with no DLTs. 14 patients underwent IDS. Most common related toxicities were Gr 1 nausea, abdominal pain and fatigue. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. Conclusions: Adding GEN-1 to T/C is safe and appears to be active in EOC patients receiving NAC. Dose limiting toxicity was not reached and further dose escalation and safety and activity is being evaluated in an ongoing phase I/II study. Clinical trial information: NCT02480374. [Table: see text]

The Impact of Relative Dose Intensity on Response and Survival in a Series of 180 Newly Diagnosed Patients with Hodgkin’s Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2671-2671
Author(s):  
Filippo Russo ◽  
Gino Svanera ◽  
Paola Della Cioppa ◽  
Gaetano Corazzelli ◽  
Ferdinando Frigeri ◽  
...  
Keyword(s):  
Survival Rates ◽  
Dose Intensity ◽  
Complete Response ◽  
Relative Dose Intensity ◽  
Rank Statistic ◽  
Cycle Period ◽  
Newly Diagnosed ◽  
Exact Test ◽  
Dose Dense ◽  
The Impact

Abstract To improve ABVD results we first developed a protocol which adds G-CSF to the standard ABVD treatment. From March 1997 to May 2004 69 patients with HL were treated with ABVD+G-CSF and 22 with a standard ABVD. Recently we designed a new dose-dense and dose-intensity ABVD scheme (escABVD-21) for advanced HL; in this new schedule the adriamycin was escalated from 25 to 35 mg/m2 (cycles 1,2,3,4) and the inter-cycle period was shortened from 28 to 21 days (for all 6 cycles); primary G-CSF was administered from d3 to d8 and drugs were delivered at d10 and d21 of every cycle. From June 2004, 19 patients were treated with this protocol. Relative dose-intensity (RDI) was calculated for any of these 110 newly diagnosed HL patients treated with ABVD. The results were also compared with a historical group of 70 patients who had undergone hybrid MOPP/ABVD. HL patients received from 4 to 8 cycles of CT +/− IF-RT. Patients were divided in 4 groups according to the RDI. The first group included 20 (11%) pts with RDI less than 0.80; the 2nd group, 64 (36%) pts with RDI values between 0.80 and 0.95, the 3rd group, 74 (42%) pts with RDI values between 0.96 and 1.10 and, finally, the 4th group included pts with RDI values of more than 1.10. In Tab 2 we report the CR, EFS and OS rates according to the 4 levels of RDI. Figures 1 shows EFS curve according to Kaplan-Meyer. Response and survival rates of groups 1,2,3 and 4 were: 50%vs91%vs97% vs 100%, for CR (p<0.0001); 20%vs78%vs92%vs100% for EFS (p< 0.0001); and 25%vs91%vs99%vs100% for OS (p< 0.0001). The best progression rates of CR, EFS and OS were seen in patients with RDI >1.10. In particular, the new dose-dense and dose-intensity escABVD-21 protocol seems very promising in terms of complete response and toxicity profile: 19/19 pts (100%) obtained an early CR; (PET negative at the end of the 2nd cycle), and, as on 8th August 2005, all these19 patients were disease-free. The dose-escalation of adriamycin and the dose-density of the schedule were well-tolerated; toxicity was mild. These results show that subptimal RDI may compromise outcomes proportionally to the level of RDI reduction. On the contrary, Primary G-CSF permits to deliver dose-dense and dose intense schedules such as escABVD-21 maintaining the same profile of toxicity of standard ABVD, higher RDI levels, and consequently, a significant impact on complete response and survival rates. tab1 Presentation features n. of pts male sex age>45 yrs advanced stage E sites>1 bulky B symptoms IPI score ≥ 3 180 92 43 148 23 80 83 56 % 51% 24% 82% 13% 44% 46% 31% tab.2 Response and Survival according to 4 RDI levels RDI level (range 0.5–1.5) N. of pts. (%) CR rate Fisher’s Exact test (2-sided) EFS rate log-rank statistic 0S rate log-rank statistic overall 180(100%) 90% 80% 88% <0.80 20 (11%) 50% 20% 25% 0.80–0.95 64 (36%) 91% 28.391 78% 74.99 91% 96.76 0.96–1.10 76 (42%) 97% 92% 99% >1.10 20 (11%) 100% 100% 100% significance <0.0001 <0.0001 <0.0001 Figure Figure

Safety and effectiveness of dose dense neoadjuvant chemotherapy in patients with stage II/III breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10622-10622
Author(s):  
S. A. McDaniel ◽  
H. Krontiras ◽  
J. T. Carpenter ◽  
L. M. Nabell ◽  
K. I. Bland ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Dose Dense ◽  
To Receive

10622 Background: NSABP B-18 randomized women with operable breast cancer to receive chemotherapy either pre- or postoperatively; OS and DSF rates at 9 years were identical. Importantly, pathologic complete response (pCR) was directly proportional to DFS and OS. Recently, dose dense adjuvant chemotherapy has shown a statistically significant improvement in DFS and OS. However, no data is available for the use of dose dense preoperative chemotherapy at this time. Methods: Women enrolled in the I-SPY correlative trial with newly diagnosed breast cancer, T ≥ 3cm, any N, M0 were evaluated to assess response rates and safety to dose dense neoadjuvant chemotherapy (doxorubicin 60 mg/m2 IV Q2 wks × 4, paclitaxel 175 mg/m2 IV Q2 wks × 4, and cyclophosphamide 600 mg/m2 IV Q2 wks × 4). Results: Since 02/2003, 43 pts have been treated with dose dense neoadjuvant chemotherapy on the I-SPY trial at UAB (mean age 47.9). 47% of the pts were ER+, 37% were PR+ and 5% were Her2+ by FISH. 2 pts dropped out for personal reasons and 9 pts are actively undergoing treatment. Overall, 32 pts received dose dense chemotherapy and proceeded to surgery. Of those, 31 received dose dense sequential ATC and 1 received dose dense concurrent AC followed by T. 34% had a pCR (breast & nodes) while an additional 10% had a pCR in the breast but residual disease in lymph nodes; 41% had a PR; 9% had SD; and 6% had PD. Hematologic toxicity consisted of grade 3 anemia in 2 pts, febrile neutropenia in 2 pts and no grade 4 thrombocytopenia. Non-hematologic grade 3–4 toxicity consisted of mediport-associated thrombosis in 2 pts, hyperglycemia in 2 pts, syncope in 1 pt, neuropathy in 1 pt, and disseminated varicella in 1 pt. Conclusion: Our results show that dose dense neoadjuvant chemotherapy achieves a pCR (breast & nodes) in about 1/3 of patients (34%) with tolerable toxicity. No significant financial relationships to disclose.

Phase II study of intraperitoneal submicron particle paclitaxel (SPP) plus IV carboplatin and paclitaxel in patients with epithelial ovarian cancer undergoing cytoreductive surgery.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18046-e18046
Author(s):  
Sally Anne Mullany ◽  
David S. Miller ◽  
Katina Robison ◽  
Kimberly Levinson ◽  
Yi-Chun Lee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cytoreductive Surgery ◽  
Study Drug ◽  
Complete Response ◽  
Submicron Particles ◽  
Ca 125 ◽  
Local Toxicity ◽  
Nonsurgical Patients ◽  
Dose Levels

e18046 Background: Although advances in chemotherapy, cytoreductive surgery, and maintenance therapy (SOC) improved PFS for high grade epithelial ovarian cancer, > 20% of patients relapse during the first 6 months and 60% relapse after 6 months. Submicron particles (~800 nm) of paclitaxel (SPP) contain 1-2 billion molecules of pure drug that release tumoricidal levels of paclitaxel over many weeks. In a previous trial, percutaneous instillations of SPP in nonsurgical patients with intraperitoneal cancer were associated with reduced systemic and local toxicity as compared to standard chemotherapy regimens. (Williamson et al Cancer Chemo Pharm (2015) 75:1075). Methods: This study compared two dose-levels of IP SPP instilled in 200 ml of saline post-cytoreductive surgery. Eligible patients with primary (n = 6) or recurrent (n = 4) epithelial ovarian cancer who underwent complete cytoreductive surgery were enrolled to receive a single instillation of IP SPP followed by standard IV carboplatin and paclitaxel. Endpoints were PFS and evaluation of treatment-emergent adverse events. Clinical response was determined by CT scans and serum CA-125 measurements. Results: Of the 24 subjects screened, 10 were enrolled and received treatment: seven patients received 100 mg/m2 and three received 200 mg/m2. For analysis purposes, 7 out of 10 subjects were evaluable (1 withdrew, 1 died unrelated to study drug during IV treatment and 1 was unevaluable). Upon completion of planned chemotherapy post-SPP instillation, the PFS at 6 months was 66% (4/6) and at 12-months 66% (4/6) using RECIST 1.1. One subject had a complete response at the end of IV treatment, but died (unrelated to study treatment) before PFS evaluation. There was one case of incision dehiscence and one case of vaginal cuff leakage after surgery. Conclusions: This pilot study supports further evaluation of IP SPP to treat peritoneal carcinomas. Clinical trial information: NCT03029585.

scholarly journals Retrospective analysis of surgical outcomes and survival in women with advanced ovarian cancer undergoing interval debulking surgery

2016 ◽  
Author(s):  
Neha Kumar ◽  
Amita Maheshwari ◽  
Sudeep Gupta ◽  
Jaya Ghosh ◽  
Jyoti Bajpai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Ca 125 ◽  
Optimal Cytoreduction ◽  
Stage Iiic ◽  
Free Survival ◽  
Peritoneal Cancer ◽  
Interval Debulking Surgery

Introduction: Both primary (PDS) and interval debulking surgery (IDS) have reported similar progression free survival (PFS) and overall survival (OS) rates in various studies. Complete resection of all macroscopic disease is the strongest independent variable in predicting survival in both groups. Objective: To evaluate the demographics, surgical outcomes and survival in women with advanced ovarian cancer undergoing IDS. Methods: All women with Stage IIIC or Stage IV epithelial ovarian or primary peritoneal cancer, registered at our institution from January 2010 to December 2010, who were treated with NACT followed by IDS, were included in the study. Demographic data, CA-125 levels (baseline and presurgery), chemotherapy and surgical details were collected. Progression free survival (PFS) and overall survival (OS) were calculated and Cox regression and Kaplan-Meier survival analysis were used to evaluate factors associated with survival. Results: One hundred fifty women with Stage IIIC or Stage IV epithelial ovarian or primary peritoneal cancer were included in the analysis. The mean age was 51.08 years (27 to 73 years) and 97.3% had serous histology. Eighty percent (n = 120) had Stage IIIC and 20% (n = 30) had Stage IV disease. Ninety five percent women received Carboplatin and Paclitaxel or single agent Carboplatin as NACT and the median number of NACT cycles was 3. The median baseline CA-125 was 1649.3 U/ml (Range 16.4–235,100 U/ml) and the median CA-125 post NACT was 42.75 U/ml (Range 4.4–5151 U/ml). Seventy four percent women (n = 111) underwent an optimal cytoreduction – 62.7% (n = 94) had R0 and 11.3% (n = 17) had R1 resection. Twenty six percent women (n = 39) had R2 resection. The median CA-125 post NACT was 27.3 U/ml, 36 U/ml and 99 U/ml in women with R0, R1 and R2 resection respectively and the difference was statistically significant (p < 0.0005). The CA125 response was respectively, 97.6%, 95.7% and 93.8% in R0, R1 and R2 resection (p < 0.0005). The median follow up was 42.48 months (Range 1.48–70.93 months). The median PFS was 12.06 months (95% CI 10.02-14.1) – 12.98 months (95% CI 9.7–16.2) in R0, 9.56 months (95% CI 1.7–17.4) in R1 and 6.64 months (95% CI 4.9–8.3) in women with R2 resection (p = 0.158). The median OS was 38.9 months (95% CI 31.7–46.1) – 43.3 months (95% CI 33–53.5) in R0, 46.1 months (95% CI 26.6–65.5) in R1 and 28 months (95% CI 25–30.9) in R2 resection (p = 0.121). The median PFS and OS in women undergoing optimal cytoreduction (R0 and R1) was 12.98 months (95% CI 9.86–16.1) and 43.7 months (95% CI 34.7–52.7) respectively as compared to 6.64 months (95% CI 4.95–8.32) and 28 months (95% CI 25–30.9) respectively in women with R2 resection (PFS p = 0.064, OS p = 0.04). Multivariate analysis discussing the factors affecting the probability of optimal cytoreduction and the survival will be discussed. Conclusion: In women with advanced ovarian cancer undergoing NACT followed by IDS, a high rate of optimal cytoreduction is achieved. Residual disease is a primary factor affecting the survival of these women.

Predictive value of serum CA125 levels in women with persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) treated with bevacizumab (Bev) on a Gynecologic Oncology Group (GOG) phase II trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16505-e16505
Author(s):  
L. Randall-Whitis ◽  
R. A. Burger ◽  
M. Sill ◽  
B. J. Monk ◽  
B. Buening CCRC ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Gynecologic Oncology ◽  
Complete Response ◽  
Primary Objective ◽  
Phase Ii Clinical Trial ◽  
Gynecologic Oncology Group ◽  
Peritoneal Cancer ◽  
Serum Ca125 ◽  
Receive Treatment

e16505 Background: The clinical utility of serum CA125 in patients (pts) with EOC/PPC treated with biologic agents is unknown. The primary objective of this study was to determine the proportion of pts treated with bevacizumab on a phase II clinical trial with stable disease by RECIST who demonstrated disease progression (pgrn) as assessed by modified GCIG CA125 criteria. Methods: Sixty-two pts with measurable recurrent or persistent EOC/PPC were treated with bevacizumab 15 mg/kg Q 21 days on a phase II clinical trial. Primary endpoints of the clinical trial were progression-free (PF) survival at 6 months and response assessed by RECIST criteria. Pts were removed from therapy/evaluation for disease prgn by RECIST, toxicity, or by subject request. Serum CA125 was collected at entry and prior to each cycle but levels were only used to define a complete response which required CA125 normalization (≤35). Modified GCIG criteria were retrospectively applied to these CA125 values to determine time to progression from date of entry to either the first time CA125>70 for pts whose CA125 normalized on treatment or was greater than 2X the nadir value for pts whose CA125 did not normalize. Censored cases provided time until the date of last CA125 measurement. Results: The median PFS by RECIST was 4.7 mos. Of those patients who had prgn by CA125, the median residual time to prgn by RECIST was 1.4 mos. In all, twenty-five (40.3%) pts survived PF for 6 mos. by RECIST and 16 (25.8%) by CA125. Ten pts who survived PF for at least 6 mos. by RECIST indicated treatment failure before 6 mos. by CA125, or 40% of the 25 positive outcomes. Eight pts continued to receive treatment for at least 4 mos. after prgn by CA125, with one continuing therapy for more than 3 years. Conclusions: Serum CA125 levels were a useful marker of progression in some pts treated on this trial; however, some pts received clinical benefit from continued therapy in spite of indications of disease prgn by CA125. Consideration should be given before discontinuing bevacizumab therapy based on CA125 progression alone. No significant financial relationships to disclose.

Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in patients with TKI-naïve, EGFRm NSCLC with CNS metastases.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2006-2006 ◽  
Author(s):  
Myung-Ju Ahn ◽  
Dong-Wan Kim ◽  
Byoung Chul Cho ◽  
Sang-We Kim ◽  
Jong-Seok Lee ◽  
...  
Keyword(s):  
Dose Escalation ◽  
De Novo ◽  
Objective Response ◽  
Complete Response ◽  
Primary Objective ◽  
Egfr Inhibitor ◽  
Cns Metastases ◽  
T790m Mutation ◽  
Dose Levels

2006 Background: The dose escalation phase is complete forAZD3759, the first EGFR inhibitor primarily designed to cross the blood brain barrier (BBB) to treat patients with EGFRm NSCLC with CNS metastases. AZD3759 is being further evaluated in patients with brain (BM) and leptomeningeal metastases (LM) in TKI-naïve and TKI pre-treated cohorts (data presented separately) (NCT02228369). Methods: The primary objective is safety and tolerability, and secondary objectives include anti-tumor efficacy. Dose levels of 200 and 300 mg BID AZD3759 were assessed based on safety and efficacy data in dose escalation cohorts. Results: As of24 September, 2016,38 patients with EGFRm NSCLC were recruited into the expansion cohorts of this study: 16 patients with TKI naïve BM and 4 patients with TKI naïve LM. 15 and 5 patients were treated with 200 and 300 mg BID of AZD3759, respectively. No DLTs were observed at either dose, while 200 mg BID AZD3759 was better tolerated than 300 mg BID during > 2 month treatment. The longest duration on treatment was > 9 months. Drug-related adverse events (AEs) seen are typically observed for EGFR TKIs. In BM cohort, 56% and 13% of patients had dose interruptions and reductions respectively due to drug-related AEs. The Ctrough free plasma and CSF exposure at both doses were above pEGFR IC90. By investigators’ assessment, the intracranial objective response rate (ORR) was 63% (12 out of 19 evaluable patients) and achieved confirmed/unconfirmed partial/complete response [PR/CR]), extracranial ORR was 50% (10 out of 20 evaluable patients), and the overall ORR was 60% (12 out of 20 evaluable patients). 4 patients have not reached the 6-week RECIST assessment at the data cut-off. 18 of 20 patients are still ongoing (median 4-month follow up). 2 patients have withdrawn, one due to disease progression (de novo T790M mutation in both plasma and CSF), and another due to a non-drug related SAE. Conclusions: AZD3759 was well tolerated at the selected doses, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor efficacy in both intracranial and extracranial tumors in TKI-naïve patients with CNS metastases. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.

Safety of MEDI4736 (anti-PD-L1 antibody) administered concomitant with weekly nab-paclitaxel and dose dense doxorubicin/cyclophosphamide (ddAC) as neoadjuvant chemotherapy for stage I-III triple negative breast cancer (TNBC): A Phase I/II trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 572-572 ◽  
Author(s):  
Lajos Pusztai ◽  
Andrea Silber ◽  
Erin Wysong Hofstatter ◽  
Gina G. Chung ◽  
Nina Ruth Horowitz ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Phase I ◽  
Dose Level ◽  
Pathologic Complete Response ◽  
Concomitant Administration ◽  
Complete Response ◽  
Additional Patient ◽  
Chest X Ray ◽  
Dose Dense ◽  
Dose Levels

572 Background: Pathologic complete response (pCR) rates to neoadjuvant chemotherapy in TNBC plateaued at 40% with existing regimens, the co-administration of an immune checkpoint inhibitor might increase pCR rate. The objective of the Phase I portion of this trial was to assess the safety of administering MEDI4736 concomitant with sequential taxane and anthracycline chemotherapy. Methods: The Phase I part followed the 3+3 design exploring two dose levels of MEDI4736 (3 and 10 mg/kg iv q2wk) in combination with weekly nab-paclitaxel (100 mg/m2) x 12 followed by ddAC x 4. Dose limiting toxicities (DLT) were evaluated during the entire 20 weeks of therapy and were defined as (1) gr 4 immune related adverse event (irAE), (2) gr 3 irAE that did not resolve to gr 2 within 3 days or to ≤ gr 1 within 14 days, (3) > gr 3 colitis or pneumonitis, (4) ≥ gr 3 non-irAE causally related to MEDI4736. Results: 3 patients completed therapy at the 3 mg/kg dose without any DLT, 1 additional patient refused further study medication because of recurrent gr 2 fatigue after 7 weeks of therapy. At the 10 mg/kg dose level, all 3 patients completed the nab-paclitaxel+MEDI4736 treatment without any DLT and 2 patients also completed 3 of the 4 planned treatments with ddAC without DLT. Among all 7 patients who started therapy, 1 at the 3 mg/kg group experienced gr 3 dehydration and dyspnea without chest X ray abnormalities which resolved within 48 hours with hydration. There were no other gr 3 AEs. Among the 3 patients who have completed therapy as per protocol (not including the patient who withdraw consent), 1 achieved pCR, 1 had minimal, and 1 had extensive residual cancer. No surgical AE were seen. All patients at the 10 mg/kg dose level will complete surgery by March 2017 and final Phase I toxicity and efficacy results will be presented. Conclusions: Concomitant administration of MEDI4736 10 mg/kg with weekly nab-paclitaxel and subsequently with ddAC neoadjuvant chemotherapy appears safe. The Phase II portion of the trial is open and will accrue a maximum of 50 patients to assess the efficacy of the combination. Clinical trial information: NCT02489448.

Sign in / Sign up

Export Citation Format

Share Document