Use of supportive measures to improve outcome and decrease toxicity in docetaxel-based antiangiogenesis combinations.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 128-128 ◽  
Author(s):  
Fatima H. Karzai ◽  
Bamidele Adesunloye ◽  
Yangmin M. Ning ◽  
Ravi Amrit Madan ◽  
James L. Gulley ◽  
...  
Keyword(s):  
Median Number ◽  
Phase Iii ◽  
Pulmonary Emboli ◽  
Toxicity Profile ◽  
Improve Outcome ◽  
Phase Iii Trials ◽  
Combination Studies ◽  
Deep Vein ◽  
Clinical Trial Information ◽  
Deep Vein Thromboses

128 Background: We have recently completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P). Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90410 trials we attempted to contrast and compare our studies with the failed phase III trials. Methods: Among the first 52 pts on the ART-P, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). We later enrolled 11 more pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. Patients on CALGB 90410 received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and on MAINSAIL received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90410 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: Median number of Cs in ART-P was 16 (3−38). PFS was 22 months and median OS has not been reached. Pts with measurable disease had 1 CR and 25 PR (86.7% RR). Two patients (3%) had deep vein thromboses. Of 1,219 cycles given, 14 cycles were complicated by febrile neutropenia (FN) (1.1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90410 trial, median OS was 22.6 months with median PFS of 9.9 months. Median number of Cs was 8, and 19 pts developed thromboses/emboli (3.6%). In addition, 7% of patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allows the ART-P combination to be given for more cycles than were given in MAINSAIL and CALGB 90401 potentiating a longer PFS, RR and possibly OS with an improved toxicity profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.

Use of supportive measures to improve outcome and decrease toxicity in docetaxel-based antiangiogenesis combinations in metastatic castrate resistant prostate cancer (mCRPC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16017-e16017
Author(s):  
Fatima H. Karzai ◽  
Ravi Amrit Madan ◽  
Andrea Borghese Apolo ◽  
Yangmin M. Ning ◽  
Howard L. Parnes ◽  
...  
Keyword(s):  
Median Number ◽  
Phase Iii ◽  
Pulmonary Emboli ◽  
Phase Iii Trials ◽  
Castrate Resistant Prostate Cancer ◽  
Combination Studies ◽  
Castrate Resistant ◽  
Deep Vein ◽  
Compare And Contrast ◽  
Clinical Trial Information

e16017 Background: We have completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P) in mCRPC. Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90401 trials, we attempted to compare and contrast our studies with these failed phase III trials. Methods: Among the first 52 pts on ART-P, 3 received L 15 mg daily, 3 received 20 mg daily, and the others received 25 mg daily for 14 days of every 21−day cycle (C). We then enrolled 11 pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily. Pegfilgrastim was given on day 2. Patients on CALGB 90401 received D 75 mg/m2 and B 15 mg/kg on day 1, with P 10 mg. On MAINSAIL, pts received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90401 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: The median number of Cs on ART-P is 18 (1-52). Median PFS is 19.1 months. Twenty-seven pts had a PR, and one pt with measurable disease had a CR. Two patients (3%) had deep vein thromboses. Of 1,334 Cs given, 14 cycles were complicated by febrile neutropenia (FN) (1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90401 trial, median OS was 22.6 months with median PFS of 9.9 months. The median number of Cs were 8 and 19 pts developed thrombosis/emboli (3.6%). In addition, 37 patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allowed longer treatment duration with the ART-P combination as compared to D+L (MAINSAIL) and D+B (CALGB 90401), potentiating a longer PFS, RR and possibly OS with an improved safety profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.

Diagnostic visualization

1979 ◽  
Vol 292 (1390) ◽  
pp. 177-185
Keyword(s):  
Nuclear Medicine ◽  
Population Screening ◽  
Cerebral Abscess ◽  
Pulmonary Emboli ◽  
Radiological Investigation ◽  
Diagnostic Modalities ◽  
Deep Vein ◽  
Medical Situation ◽  
Deep Vein Thromboses

The concept of total diagnostic visualization is based on the presumption that on the whole no single radiological investigation is self-sufficient and that it should be considered in relation to all other available diagnostic modalities. Although nuclear medicine techniques are expanding rapidly, especially for functional investigations, and have the advantage of non-invasiveness and sensitivity (which are ideal requisites for population screening), they remain relatively non-specific. This paper attempts to show how improved specificity may be effected by means of cross-modality techniques, and this is discussed in relation to the detection of cerebral abscess, focal hepatic defects, pulmonary emboli and deep-vein thromboses. An example of how the technique can be used in an engineering situation, namely to discover defects in concrete, is also considered and related to the philosophy outlined in the medical situation. ‘Prove all things; hold fast that which is good.’ (1 Thessalonians 5:21)

Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5505-5505 ◽  
Author(s):  
Jonathan A. Ledermann ◽  
Philipp Harter ◽  
Charlie Gourley ◽  
Michael Friedlander ◽  
Ignace Vergote ◽  
...  
Keyword(s):  
Maintenance Treatment ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Phase Iii ◽  
Double Blind ◽  
Platinum Sensitive ◽  
Trial Outcome Index ◽  
Phase Iii Trials ◽  
Outcome Index ◽  
Clinical Trial Information

5505 Background: Previously, we reported that maintenance treatment with the oral PARP inhibitor olaparib (400 mg bid) led to a significant PFS improvement vs placebo in patients (pts) with platinum-sensitive relapsed SOC (Ledermann et al NEJM2012). A preplanned subgroup analysis from this randomized, double-blind Phase II trial (NCT00753545) suggested that olaparib may lead to a greater PFS, and an OS, benefit in pts with a known germline BRCAm (gBRCAm). Since gBRCA wild-type (gBRCAwt) pts may develop somatic tumor (t)BRCAm, efficacy analyses were performed for all pts with BRCAm. Methods: gBRCAm status was determined retrospectively for all consenting pts (n = 166) using blood samples taken before randomization. tBRCAm status was determined from archival tumor samples of 196 pts. We analyzed PFS/OS by gBRCAm and total BRCAm status. Preliminary data are reported. Results: gBRCA status was known for 218/265 pts (gBRCAm, 96; gBRCAwt, 122). Including tBRCAm, 136 pts had a BRCAm (BRCAwt, 116). gBRCAm pts had the greatest PFS benefit with olaparib maintenance vs placebo (median: 11.2 vs 4.1 months [m]; HR, 0.17; 95% CI 0.09-0.32; P<0.001) and a significant QoL improvement, as measured with Trial Outcome Index (OR, 4.08; 95% CI 1.11-19.85; p = 0.03). The PFS benefit was consistent when tBRCAm pts were included (median: 11.2 vs 4.3 m; HR, 0.19; 95% CI 0.11-0.32; p <0.0001). In an interim analysis of OS (58% maturity), a comparison of olaparib vs placebo in the overall population led to a HR of 0.88 (95% CI 0.64-1.21) with medians of 29.8 vs 27.8 m, respectively. Although HRs from the gBRCAm and gBRCAwt subgroups were similar (0.85 and 0.84, respectively), 13/37 gBRCAm placebo pts received a subsequent PARP inhibitor, confounding the OS data in this subgroup. The analysis of all BRCAm pts was less confounded and resulted in an OS HR of 0.74 (95% CI 0.46-1.19; median: 34.9 vs 31.9 m). 19 pts have received olaparib for >3 years. Olaparib tolerability was similar in BRCAm pts and the overall population. Conclusions: Olaparib maintenance treatment led to the greatest clinical benefit in pts with a BRCAm. These compelling data warrant confirmation in phase III trials. Clinical trial information: NCT00753545.

scholarly journals Efficacy of Panobinostat for the Treatment of Multiple Myeloma

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Evangelos Eleutherakis-Papaiakovou ◽  
Nikolaos Kanellias ◽  
Efstathios Kastritis ◽  
Maria Gavriatopoulou ◽  
Evangelos Terpos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Proteasome Inhibitors ◽  
Phase Iii ◽  
Toxicity Profile ◽  
Therapeutic Landscape ◽  
Heavily Pretreated ◽  
Phase Iii Trials ◽  
Clinical Potential ◽  
Shed Light

Panobinostat represents a potent oral nonselective pan-histone deacetylase inhibitor (HDAC) with activity in myeloma patients. It has been approved by the FDA and EMA in combination with bortezomib and dexamethasone for the treatment of multiple myeloma, in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. In order to further explore its clinical potential, it is evaluated in different combinations in relapsed/refractory and newly diagnosed multiple myeloma. This review focuses on available data about panobinostat’s pharmacology and its role in clinical practice. This review will reveal panobinostat’s efficacy as antimyeloma treatment, describing drug evolution from preclinical experimental administration to administration in phase III trials, which established its role in current clinical practice. Based on the latest data, we will present its mechanism of action, its efficacy, and most important issues regarding its toxicity profile. We will further try to shed light on its role in current and future therapeutic landscape of myeloma patients. Panobinostat retains its role in therapy of multiple myeloma because of its manageable toxicity profile and its efficacy, mainly in heavily pretreated multiple myeloma patients. These characteristics make it valuable also for novel regimens in combination with second-generation proteasome inhibitors, IMiDs, and monoclonal antibodies. Results of ongoing trials are expected to shed light on drug introduction in different therapeutic combinations or even at an earlier level of disease course.

GEMOX as first-line chemotherapy in advanced pancreatic cancer (APC): A monoinstitutional experience

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15179-15179
Author(s):  
M. Di Marco ◽  
E. Nobili ◽  
R. Di Cicilia ◽  
G. Brandi ◽  
S. Bertolini ◽  
...  
Keyword(s):  
Advanced Pancreatic Cancer ◽  
Complete Response ◽  
Median Number ◽  
Phase Iii ◽  
First Line ◽  
Kaplan Meier ◽  
Phase Iii Trials ◽  
Number Of Cycles ◽  
The Impact ◽  
Line Chemotherapy

15179 Background: To date, gemcitabine (GEM) remains the cornerstone of chemotherapy (CHT) for APC. According to GERCOR and GISCAD phase III trials the combination of GEM and oxaliplatin (GEMOX) has proven superior to GEM alone in terms of response rate (RR), time to progression (TTP) and clinical benefit rate (CBR). Methods: We conducted a retrospective analysis on 19 patients (pts) affected with histologically-confirmed APC, in order to determine the impact of GEMOX as first-line chemotherapy in terms of objective responses (OR) and TTP, using the Kaplan-Meier method. Among the 19 pts considered there were 15 males and 4 females (median age at diagnosis of 60.84 yrs; ECOG 0–2). The staging, according to AJCC criteria, was: IIB in 1 case, III in 5 cases and IV in the 13 remaning cases. The only metastatic site was the liver (in 13/19 pts). Ten of the 19 pts underwent surgical treatment prior to CHT: 2 radically resected (R0) subsequently treated with GEMOX after recurrence, 4 with positive margins (R1) and 4 surgically palliated. All pts received GEM 1000 mg/m2/d1 + oxaliplatin 100 mg/m2/d2 every 2 weeks. The median number of cycles was 5.89. Results: Among the 19 pts, 3 had a partial response (PR, 15.69%), 6 had stable disease (SD, 31.57%); no complete response was observed and 10 pts had progressive disease (PD, 52.63%). The overall disease control rate (DCR: PR + SD) was 47.37% while the OR were 15.69%. The median survival observed was 9.03 months (95% C.I. 5.15–12.91) and the median TTP was 6.13 months (95% C.I. 2.81–9.46). The main toxicities were: leucopenia, piastrinopenia, diarrhoea, nausea, fever and peripheral neuropathy; 3 pts discontinued the treatment due to grade 3–4 neurotoxicity. Conclusions: In our experience GEMOX gives an improved control of APC in terms of OR and TTP, with acceptable toxicity. The OS is in accordance to literature as well as the other data. No significant financial relationships to disclose.

Comparing the outcomes of noninferiority (NI) and superiority phase III trials.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13055-e13055
Author(s):  
Everardo D. Saad ◽  
Marc E. Buyse
Keyword(s):  
Progression Free Survival ◽  
Median Number ◽  
Phase Iii ◽  
Experimental Therapy ◽  
Tumor Type ◽  
Margin Width ◽  
Number Of Patients ◽  
Significant Difference ◽  
Phase Iii Trials ◽  
Superiority Trials

e13055 Background: We compared the outcomes of NI and superiority trials on advanced breast cancer (BC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC). Methods: We searched PubMed for phase III trials on systemic antineoplastic treatments for advanced BC, NSCLC and CRC published between 1/1998 and 12/2009 in 11 leading journals. We categorized primary endpoints (PEP) as time-to-event (overall survival or any variant of progression-free survival), response rate, or other (quality of life or toxicity). We used the PEP (defined as the one stated explicitly, used for N calculation, or cited first) to ascertain trial positivity. Results: We retrieved a total of 262 trials (93 on BC, 102 on NSCLC, and 67 on CRC), 36 of which (13.7%) used a NI design (12 in each tumor type). There was no significant trend in the proportion of NI trials in the two 6-year periods compared (1998-2003 vs 2004-9). The median number of patients/arm for NI and superiority trials were 284 and 164, respectively (p<0.001). There was no significant difference in the distribution of the PEP categories between NI and superiority trials. We could ascertain trial positivity in all but six trials: 24 (66.7%, 95% confidence interval [CI], 49.1% to 81.2%) NI trials were positive, compared with 89 (39.4%, 95% CI, 33.0% to 46.1%) superiority trials (p<0.001). NI trial positivity could be determined by finding a CI for the estimated treatment effect that excluded the NI margin in 15 of 27 trials (otherwise, positivity was based on authors’ conclusions, or the experimental therapy was superior to control for the PEP). The overall rates of trial positivity varied across tumor types: 48.4% for BC, 31.4% for NSCLC, and 53.7% for CRC (p=0.002). When adjusted for trial size, NI design (vs. superiority; odds ratio [OR]=4.2; 95% CI, 1.7 to 10.3) and tumor type (BC [OR=2.2; 95% CI, 1.2 to 4.0] and CRC [OR=2.8; 95% CI, 1.4 to 5.5] vs. NSCLC as reference) remained significantly associated with trial positivity. Conclusions: NI trials are more likely than superiority trials to yield positive results. The influence of NI margin width on trial results should be investigated.

Rates of peripheral neuropathy (PN) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM) treated with carfilzomib vs comparators in pivotal phase III trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8041-8041 ◽  
Author(s):  
Ruben Niesvizky ◽  
Vania Hungria ◽  
Joy Ho ◽  
Aleksandr Suvorov ◽  
Darrell White ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Pivotal Phase ◽  
Free Survival ◽  
Pain Subscale ◽  
Patient Reported ◽  
Phase Iii Trials ◽  
History Of ◽  
Recent Phase ◽  
Clinical Trial Information

8041 Background: PN is a dose-limiting toxicity for some anti-MM agents, such as the proteasome inhibitor (PI) bortezomib (V). Carfilzomib (K), a novel irreversible PI associated with low PN, was evaluated in 2 recent phase 3 studies in RRMM pts. Methods: This analysis evaluated PN rates in ASPIRE (K [27 mg/m2]-lenalidomide [R]-dexamethasone[d] [KRd] vs Rd in relapsed MM; Stewart 2015) and ENDEAVOR (Kd [K 56 mg/m2] vs Vd in RRMM; Dimopoulos 2016). We evaluated grade ≥2 PN during treatment, patient-reported outcomes (PROs; QLQ-C30 pain, FACT/GOG-neurotoxicity subscales), and progression-free survival (PFS) in pts with BL history of PN. Results: In ASPIRE, grade ≥2 PN rate was low (8.9% [KRd] vs 8.0% [Rd]; Table). Pain subscale scores were similar between arms. Median PFS was longer with KRd vs Rd for pts with BL grade ≥2 PN. In ENDEAVOR, grade ≥2 PN rate during the study (prespecified key secondary endpoint) was significantly lower with Kd vs Vd (6.0% vs 32.0%; Table). Pts had significantly improved pain and neurotoxicity subscale scores with Kd vs Vd. PFS improved with Kd vs Vd in pts with BL history of grade ≥2 PN (Table). Conclusions: In ENDEAVOR, Kd resulted in less PN vs Vd; in ASPIRE, PN rate was similar for KRd vs Rd. PFS was longer with KRd and Kd vs Rd and Vd, respectively, including in pts with BL grade ≥2 PN. Improved pain and neurotoxicity outcomes with K may be attributed to better disease control and/or lower PN rates. Clinical trial information: NCT01568866, NCT01080391. [Table: see text]

scholarly journals Liposomal Doxorubicin in Breast Cancer

2007 ◽  
Vol 3 (5) ◽  
pp. 557-569 ◽  
Author(s):  
M Shehata ◽  
A Mukherjee ◽  
R Sharma ◽  
S Chan
Keyword(s):  
Breast Cancer ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
Toxicity Profile ◽  
Pivotal Phase ◽  
Liposomal Formulations ◽  
Phase Iii Trials ◽  
Relative Differences

Drug-delivery carriers represent an important step in the development of targeted therapy. Encapsulation of drug into liposomes represents such a carrier, and helps to minimize side effects of conventional doxorubicin by improving the tumor-specific biodistribution profile. We review the development of the two liposomal doxorubicin formulations, pegylated liposomal doxorubicin and liposomal-encapsulated doxorubicin citrate from reconstitution and comparative pharmacokinetics to pivotal Phase III trials, with special emphasis in breast cancer. The relative differences in the toxicity profile can be attributed to their differences in the liposomal formulations. Areas of special interest include the reduction in cardiac toxicities and the improved efficacy, such as in the treatment of ovarian cancer. These improvements have also increased the potential of these liposomal formulations of doxorubicin for combination and sequencing with other biological and cytotoxic agents for clinical benefit.

A randomized phase II trial of irinotecan plus oxaliplatin versus oxaliplatin, fluorouracil (5 FU), leukovorin (LV) as first-line treatment in advanced gastric cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4536-4536
Author(s):  
I. Boukovinas ◽  
N. Androulakis ◽  
A. Polyzos ◽  
N. Vardakis ◽  
K. Amarantidis ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Response Duration ◽  
Median Number ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Median Response ◽  
Phase Iii Trials ◽  
First Line Treatment

4536 Background: To compare the efficacy and tolerance of two oxaliplatin-based regimens as first-line treatment of advanced gastric cancer. Methods: Chemotherapy-naïve patients with measurable recurrent or metastatic gastric adenocarcinoma, PS (ECOG) 0–2 and adequate organ functions were randomly assigned to receive either irinotecan 200mg/m2 and oxaliplatin 80mg/m2 (IO), every 21 days or oxaliplatin 85mg/m2 on day 1, 5-FU 400 mg/m2 (over 1 hour infusion) + 600mg/m2 (over 22 hours infusion) on days 1 and 2, leucovorin (LV) 200mg/m2 on days 1 and 2 (FOLFOX4) every 2 weeks. Study endpoints: Overall Response Rate (ORR), Toxicity Time to Progression (TTP) and Survival (S). Results: 138 patients were enrolled and all were evaluable for response. Median number of cycles administered was 5.5 (range 1–10) for IO and 7 (range 1–18) for FOLFOX4. In an intent-to treat analysis the ORR (RR+CR) was 29.4% for IO arm and 34.3 % for FOLFOX4 arm (p= 0.587). The median response duration was 5.63 months (mo) for IO arm and 6,6mo for FOLFOX4 arm. Median TTP was 4.2mo and 6,1mo for IO and FOLFOX4 arm respectively (p= 0.012). Median OS was 9.4mo for IO and 11.97mo for FOLFOX4 (p= 0.456). Toxicity was acceptable, with one toxic death in each arm. Grade 3–4 vomiting (7.3%), diarrhea (11.8%), neutropenia (22%) and febrile neutropenia (5.9%) occurred more frequently in IO arm, while anaemia (4.3%) and grade II neurotoxicity (11.4%) was more frequent in FOLFOX4 arm. Conclusions: Both regimens are well tolerated and active in advanced gastric cancer. Based on the TTP and toxicity profile, the FOLFOX4 regimen merits to be further evaluated in prospective phase III trials. No significant financial relationships to disclose.

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