Response Rates Using International Working Group (IWG) Criteria in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2526-2526
Author(s):  
Lewis R. Silverman ◽  
David R. McKenzie ◽  
Bercedis L. Peterson ◽  
Carlos M. De Castro ◽  
John Ellerton ◽  
...  
Keyword(s):  
Median Duration ◽  
Initial Response ◽  
Response Rates ◽  
Median Number ◽  
Response Criteria ◽  
Best Response ◽  
Published Report ◽  
Males And Females ◽  
Number Of Cycles ◽  
New Treatments

Abstract The CALGB conducted a series of clinical trials with azacitidine (Vidaza®) administered subcutaneously or intravenously in patients with MDS using the FAB classification (JCO2002;20:2429). Since the publication of these CALGB studies (8421, 8921, 9221), new response criteria for evaluating new treatments for MDS have been published by the IWG (Blood2000;96:3671). Two general differences between the CALGB and IWG response criteria are the required duration of improvement (CALGB: ≥4 weeks; IWG: ≥8 weeks) and peripheral blood values (CALGB: different criteria for hemoglobin targets for males and females; IWG: same criteria for males and females). The results reported here are based on re-collected data from patients described in the published report. After applying the IWG response criteria, the overall response rate (CR+PR+HI) in the azacitidine groups were similar across studies 8421, 8921, and 9221: 44% (21/48), 40% (28/70), and 48% (47/99), respectively. Best Response using IWG Response Criteria for MDS in Studies 8421, 8921, and 9221 Median duration of any response (CR, PR or HI) in the 114 azacitidine-treated responders was 366 days (range: 56 to 4641+ days). The median duration of CR in the 32 azacitidine-treated responders was 379 days (range: 92 to 4412+ days). The median number of cycles from first treatment with azacitidine to any response (CR, PR or HI) was 3 cycles (range: 1 to 17 cycles). Although 75% of the responders achieved a response by cycle 4, the other 25% achieved a response as late as cycle 17. The majority (90%) of responders achieved a response by cycle 6. Best response was observed, on average, 2 cycles after the initial response. In summary, reanalysis of the response rates using IWG criteria demonstrate consistent results across three sequential studies and further validate the superiority of azacitidine over supportive care alone.

Response Rates of Phase 2 and Phase 3 Trials of Decitabine (DAC) in Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2515-2515 ◽  
Author(s):  
Hussain I. Saba ◽  
Michael Lübbert ◽  
P.W. Wijermans
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Median Duration ◽  
Response Rate ◽  
Response Rates ◽  
Median Number ◽  
Phase 2 ◽  
Phase 3 ◽  
Overall Response ◽  
Number Of Cycles

Abstract Background: MDS is characterized by ineffective hematopoiesis, resulting in cytopenias with dysplastic morphology of peripheral blood cells and bone marrow. Decitabine (Dacogen™ DAC) is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. Due to the requirement for DNA synthesis and subsequent demethylation, decitabine may require prolonged administration to achieve maximum benefit. Overall response rates (ORR) (CR+PR) from 1 pivotal Phase 3 (D-0007) and 3 supportive Phase 2 trials (91–01, 95–11 and 97–19) in patients with intermediate and high risk MDS receiving DAC are being presented. Methods: The Phase 2 trials were open-label and single-arm, with a minimum of 4 treatment cycles and a maximum of 8 cycles, while the D-0007 was a 1:1 randomized comparison of DAC plus supportive care (SC) vs. SC alone, with a maximum of 10 cycles of therapy. The D-0007 study design dictated that patients be removed from therapy following 8 cycles of decitabine if CR was not achieved, and 6 cycles in the absence of PR. Patients who maintained a CR for 2 cycles were removed from therapy. Results: A total of 271 unique patients were exposed to DAC in the studies (n= 89 in D-0007, n=29 in 91–01, n = 66 in 95–11, n = 87 in 97–19). Patients receiving DAC had similar demographics and disease characteristics in all trials. Responses were observed in all IPSS and FAB subgroups. The percent of patients classified as intermediate-2 and high risk (according to the International Prognostic Scoring System) in the Phase 3 trial was 69% vs. 72% in the Phase 2 trials. By intent-to-treat analysis, the ORRs were 45%, 26%, and 26% respectively, for the Phase 2 trials. These results were corroborated in the Phase 3 trial, where the response rates were evaluated according to the more robust International Working Group MDS criteria, following a blinded, centralized bone marrow review. The D-0007 overall response rate was 17% for DAC (9% CR, 8% PR) vs. 0% for SC (p<0.001). Responses were durable, lasting a median of 266 days. The 95–11 and 97–19 response rates were also centrally reviewed, while 91–01 responses were investigator-assessed. In the 91–01 trial, the ORR was 45% (28% CR, 17% PR) with a median duration of response of 217 days, the 95–11 ORR was 26% (21% CR, 5% PR) with a median duration of 250 days, and the 97–19 ORR was 26% (22% CR, 5% PR) with a median duration of 146 days. Hematologic improvement (HI) was also evaluated according to varied criteria in conjunction with the response rates in all 4 studies; 12 patients (13%) had HI in D-0007, 2 patients (7%) in 91–01, 8 patients (12%) in 95–11, and 13 patients (15%) in 97–19. The D-0007 trial design dictated that patients who maintained a CR for 2 cycles be removed from therapy. As a result, the median number of cycles delivered was 3, with only 48% of patients receiving ≥4 cycles. In the Phase 2 studies, the median number of cycles is clearly higher (median 4), with the majority of patients receiving at least 4 cycles and approximately one-third of patients receiving ≥6 cycles. Conclusion: While response rates of ≥17% were demonstrated in these trials, the optimization of hypomethylating agents for maximum efficacy is very likely to include prolonged therapy, which may correlate with increases in response rate and duration.

scholarly journals Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Jin Sun Lee ◽  
Susan E. Yost ◽  
Suzette Blanchard ◽  
Daniel Schmolze ◽  
Hongwei Holly Yin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. Methods The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). Results Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). Conclusion Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. Trial registration ClinicalTrials.gov, NCT02120469. Registered 18 April 2014

Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15111-15111 ◽  
Author(s):  
Y. Park ◽  
S. Yi ◽  
H. Kim ◽  
S. Lee ◽  
I. Hwang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stable Disease ◽  
Single Agent ◽  
Advanced Pancreatic Cancer ◽  
Median Number ◽  
Line Treatment ◽  
Second Line ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles

15111 Background: The aim of this phase II study was to determine whether second line therapy with single agent irinotecan could provide any clinical benefit in patients with gemcitabine- pretreated advanced pancreatic cancer. Methods: From January 2004 to October 2006, patients with advanced pancreatic cancer previously treated with gemcitabine alone or combination were treated with single agent irinotecan(150 mg/m2, biweekly), until unacceptable toxicity or disease progression. Primary endpoint was response rate with single stage design. Results: Twenty-eight patients were enrolled(22 male, 6 female, median age : 54.5 years (39–76)). Nine patients are still alive and 3 remain on therapy with stable disease. The median number of cycles was 3.5(1–12). Twenty-four patients were assessable for toxicity and 21 for response. The most common toxicities was diarrhea (grade 3, 12.5%). Grade 3 neutropenia in 1 patient was observed. Other hematological and non-hematological toxicities were mild and manageable. Partial responses were observed in 3 patients (3/21, 14%). An additional 9 patients (9/21, 43%) had stable disease as their best response. 12 patients have progressed with a median time-to-progression of 4.0 months. Conclusions: Single-agent irinotecan was tolerated with manageable toxicity, offering encouraging activity as second-line treatment of patients with advanced pancreatic cancer, refractory to gemcitabine. No significant financial relationships to disclose.

Phase II trial of sorafenib (bay 43–9006) in patients with advanced anaplastic carcinoma of the thyroid (ATC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6058-6058 ◽  
Author(s):  
G. Nagaiah ◽  
P. Fu ◽  
J. K. Wasman ◽  
M. M. Cooney ◽  
C. Mooney ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Median Duration ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Median Number ◽  
Anaplastic Carcinoma ◽  
Open Label ◽  
Open Label Phase ◽  
Number Of Cycles

6058 Background: Sorafenib (bay 43–9006) is an oral, small molecule tyrosine kinase inhibitor of the raf-1 protein kinase receptor, VEGFR2 and PDGFR-β with antiangiogenic properties. We are conducting an open label, phase II study of sorafenib in patients with biopsy-proven ATC to evaluate if its objective response rate is >20% and to further characterize its safety profile. Methods: Patients with progressive ATC, after cytotoxic chemotherapy with or without radiation were given sorafenib, on a fixed dosing schedule of 400 mg PO bid on 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or patient refusal. Response was evaluated every 8 weeks with body scans using RECIST criteria. We employed a 2-stage study design: if none of the first 18 patients respond the study is terminated, otherwise accrual is continued to a total of 36 patients at which point if ≤3 of the patients respond, the treatment option is rejected. Results: To date 16 patients (10 male) have enrolled in the study. Median age is 55 years; with (range 28–79). Median time on study is 2 months. Median number of cycles given is 2 (range 1–27). Two of 15 evaluable patients (13%) have partial response (PR) and 4 patients (27%) have stable disease (SD). Median duration of PR/SD is 5.1 months (range 1–24.7months). Median time to progression is 1.5 months. Median duration of survival is 3.5 months (range 1–26 months). All patients at time of reporting are deceased. Most common toxicities are lymphopenia (81%) and fatigue (62%). Grade 3 toxicities include lymphopenia (25%), rash with desquamation, weight loss, and chest pain (all 12%). Grade 4 toxicities include dyspnea (6%) and lymphopenia (6%). There has been no significant cardiovascular toxicity. One patient died on study with rapidly progressive disease. Conclusions: Sorafenib demonstrates objective tumor response in the first 15 evaluable and pretreated patients with advanced ATC. This trial is ongoing and supported in part by NIH grant nos. CA62502. [Table: see text]

Phase I trial of sunitinib (S) and temsirolimus (T) in metastatic renal cell carcinoma (mRCC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 433-433
Author(s):  
Matthew T. Campbell ◽  
Randall E. Millikan ◽  
Emre Altinmakas ◽  
Lianchun Xiao ◽  
Nizar M. Tannir
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mtor Inhibitors ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Mean Time

433 Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.

scholarly journals Weekly Cyclophosphamide, Subcutaneous Bortezomib and Dexamethathasone (CyBorD) for Initial Treatment of Transplant Eligible Patients with Multiple Myeloma: Experience of Two Transplant Centres

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Georgia J McCaughan ◽  
Anvita Verma ◽  
Silvia Ling ◽  
Orly Lavee ◽  
John Moore ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Progressive Disease ◽  
Response Rates ◽  
Median Number ◽  
Inadequate Response ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Regulatory Constraints ◽  
Best Response

Introduction: Induction regimens utilising cyclophosphamide, bortezomib and dexamethasone (CyBorD) prior to autologous stem cell transplant are utilised worldwide where access to a combination immunomodulatory agent/proteasome inhibitor approach is limited due to financial or regulatory constraints. Protocols utilising weekly subcutaneous bortezomib are favoured in order to reduce toxicity, but there is a lack of published data regarding response rates and survival using this approach. Methods: We identified all patients treated between August 2015 and August 2019 at St Vincent's Hospital and January 2012 and August 2019 at Liverpool Hospital in Sydney, Australia who were prescribed four 28 day cycles of CyBorD (subcutaneous bortezomib 1.3mg/m2, cyclophosphamide 300mg/m2 (or 500mg) and dexamethasone 40mg (day 1, 8, 15 and 22) for newly diagnosed MM with an intent to proceed to ASCT. Results: The baseline patient and disease characteristics of the 70 eligible patients are listed in Table 1. Most patients received therapy as planned (62/70) and all but one proceeded to ASCT. Seven patients had additional therapy after 4 cycles of CyBorD due to inadequate response. Best response to CyBorD induction included stable disease (SD) in 16 (23%) partial response (PR) in 30 (43%), and a VGPR or better in 24 (33%) (2 complete response (CR)). No patient had progressive disease. All but one patient had successful stem cell mobilisation. The median number of collection days was 2 (range 1-4) and median number of stem cells collected was 10.4 x 106/kg. 6 patients required plerixafor. The one patient who could not be mobilised received lenalidomide prior to mobilisation. Best response post ASCT (n = 69) prior to unplanned therapy included SD in 2 (3%), PR in 25 (35%), ≥ VGPR in 41 (59%) (4 patients with CR) and undetermined in 1. Of those who had SD following induction, 4 achieved a ≥ VGPR following ASCT, 9 had a PR, 2 had SD and 1 did not undergo ASCT. Five patients underwent a second ASCT due to inadequate response. 37 patients received maintenance. After a median of 3 years follow-up, 12 patients (17%) had died (10 from progressive disease) and 28 (40%) had progressed. Overall survival at 1 year was 100% and 3 years was 85% (95% CI 71-93%) (Figure 1). Progression free survival at 1 year was 92% (95% CI 88-97%) and 3 years was 46% (95% CI 31-60%) (Figure 1). There were no deaths during induction and no documented bortezomib dose reductions. 16 of 70 patients had unplanned hospital admissions during induction. There was no transplant related mortality. Conclusions: To our knowledge, this is the largest study evaluating use of a weekly induction protocol of subcutcutaneous bortezomib, oral cyclosphosphamide and oral dexamethasone in transplant eligible MM. It shows comparable response rates and survival outcomes to other retrospective studies and documented toxicity was low. This induction protocol remains standard of care in many countries, in particular where financial constraints limit use of combined IMID/PI induction and this study confirms the efficacy and tolerability of this commonly used protocol. Disclosures Ling: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene BMS: Membership on an entity's Board of Directors or advisory committees; Specialised Therapeutics: Honoraria.

Palliative ambulatory 14-day infusional ifosfamide in the outpatient setting for treatment of advanced soft tissue sarcomas (STS): “Old wine in a new bottle.”

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10039-10039
Author(s):  
Salma Moona Alam ◽  
Charlotte Benson ◽  
David Olmos ◽  
Robin Lewis Jones ◽  
Scott Mitchell ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Synovial Sarcoma ◽  
Central Venous Access ◽  
Soft Tissue Sarcomas ◽  
Venous Access ◽  
Median Number ◽  
Outpatient Setting ◽  
Response To Treatment ◽  
Best Response ◽  
Number Of Cycles

10039 Background: Ifosfamide (IFO) has recognised activity in soft tissue sarcomas. There is evidence for improved cytotoxicity and tolerability utilising a prolonged 14 day infusional outpatient regimen compared with the standard 3-day regimen (Loeffler et al 1990). We undertook a retrospective review of all patients treated with this regimen from September 2008 - December 2011 to determine toxicity and treatment response. Methods: Pts. were identified from our database and demographics, histological subtype, toxicity and survival outcomes were collected. IFO was given via central venous access using 2 x 7 day pumps at 1g/m2/day with mesna for 14 days q 4 weekly. Oral sodium bicarbonate was used to maintain alkaline urine with oral mesna for haematuria, and thiamine for symptoms of encephalopathy as required. Results: 29 patients (pts), with advanced sarcoma, median age 56 years (27-76 yrs), 14F 15 M, median number of cycles = 1 ( 1-9). At baseline: PS 0=1, 1=24, 2=4. 18 pts had de-differentiated liposarcoma (D-LPS), 6 synovial sarcoma, 5 had other subtypes. 12 pts received only 1 cycle, with 5 stopping due to encephalopathy. Ten patients developed encephalopathy, 9 occurring in cycle 1, other toxicity was tolerable, with Gr 2-3 nausea (15 pts) and vomiting (9pts) and only 2 Gr 3 episodes of myelotoxicity for all cycles. 4 patients achieved PR, (2 with D-LPS and 2 with Synovial sarcoma) 11 pts. had SD. Median PFS was 19 months and OS was 12.5 months. 2 pts. with D-LPS had a sustained prolonged response of 15 and 16 months. Conclusions: Infusional IFO is generally well tolerated; however a significant incidence of neurotoxicity was seen. Pts. with D-LPS demonstrated best response to treatment, a sarcoma subtype that has previously failed to respond to systemic therapy. This regime warrants further investigation.

Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8600-8600 ◽  
Author(s):  
Preet Paul Singh ◽  
Wilson I. Gonsalves ◽  
Vinay Gupta ◽  
Francis Buadi ◽  
Martha Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Duration ◽  
Median Overall Survival ◽  
Median Number ◽  
Infusion Therapy ◽  
P Value ◽  
Short Term Mortality ◽  
Number Of Cycles ◽  
Clinical Records ◽  
Count Recovery

8600 Background: The combination of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (VDTPACE) was developed as an intense regimen for disease control prior to tandem transplantation for multiple myeloma (MM) in total therapy protocols. The regimen is very effective in this setting, and since has also been used in the relapsed setting. We examined the outcomes of a set of patients undergoing VDTPACE therapy for relapsed MM at our institution. Methods: We identified 71 patients who received VDTPACE for relapsed MM, at Mayo Clinic from 7/2006 to 7/2012. Plasma cell leukemia was excluded. All data was extracted from clinical records. Results: The median age of patients was 59 years (range, 39-80); 48 (67.6%) were male. The median time from diagnosis to initiation of VDTPACE was 38.2 months (range, 2-125). The median number of cycles given was 1 (range, 1-9). The overall response rate after one cycle was 57.1% (14.3% VGPR, 22.2% PR and 20.6% MR) in the 63 patients in whom the response was evaluable. The median overall survival (OS) post-VDTPACE was 8.2 months (95% CI, 5.7-10.9). Eighteen (25.4%) patients went on to autologous stem cell transplantation (SCT), and 7 (9.9%) received matched allogeneic SCT following VDTPACE, and the median OS post-VDTPACE was significantly longer for these groups compared to those who were not transplanted (15.3 and 20.5 months, respectively vs 5 months, p-value <0.001). Thirty eight of 66 (57.6%) patients were rehospitalized after initial admission for infusion therapy for a median duration of 6 days (range, 1-26). The median platelet and red cell transfusions were 4 (range, 0-21) and 5 (range, 0-22) units, respectively. Renal toxicity was seen in 13/62 (21%) patients and 27/65 (41.5%) patients developed neutropenic fever. The median duration to absolute neutrophil and platelet count recovery was 18 (range 12-42) and 27 (range, 12-42) days, respectively. Three (4.2%) patients died within 30 days and 11 (15.5%) within 8 weeks of initiating VDTPACE. Conclusions: VDTPACE is an effective therapy in relapsed MM but is associated with significant morbidity and short-term mortality. It appears to be more effective when followed by an autologous or allogeneic SCT.

Second-line therapy of KRAS-mutated (KRASm) metastatic colorectal cancer (CRC) with the MEK inihibitor selumetinib ([SEL], AZ6244, ARRY-142886) in combination with irinotecan (IRI): An AGICC study.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 380-380 ◽  
Author(s):  
Howard S. Hochster ◽  
Wells A. Messersmith ◽  
Bert H. O'Neil ◽  
Susan G. Groshen ◽  
Deirdre Jill Cohen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mek Inhibitor ◽  
Median Number ◽  
Dose Finding ◽  
Line Therapy ◽  
Best Response ◽  
Grade 3 ◽  
Gi Bleed ◽  
Number Of Cycles ◽  
Clinical Trial Information

380 Background: 2nd-line therapy of KRASm CRC is limited; targeting downstream signal transduction enzymes is rational here. Use of the MEK inhibitor SEL is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI plus SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin-based chemo + bevacizumab regimen, PS 0-1, acceptable organ function. Patients were treated with IRI 180 mg/m2 iv q2w and SEL 50-75 mg po bid. First 3 patients of run-in portion were treated with SEL 50 mg and if no DLTs, next 3-6 patients at 75 mg po bid. If no DLTs, then phase II dose of SEL 75 mg po bid would be used. Primary endpoint was RECIST 1.0, investigator determined response rate (RR). As compared to the historical RR of 4% (and median PFS 2.5 mos) for 2nd-line FOLFIRI (Tournigand), with alpha 0.10 & beta 0.90, a sample size of 45 would have the power to detect improvement in RR to 15%, and 79% power to demonstrate improved med PFS to 4.0 mos. Early stopping would occur for responses of 0 of 20 patients. Results: 32 patients were entered and treated. Median age was 54 (40-71) yrs, 18 were male and 22 Caucasian, all KRASm. The first 3 tolerated SEL 50 mg bid without SAE and the remaining 29 were treated at 75 bid. Median number of cycles on study was 3.5 and median TTP approximately 4.0 months. Observed grade 3 AEs included: diarrhea 3, fatigue 2, neutropenia 2, and 1 each PLTS, enteritis, GI bleed, rash; one grade 4 ANC. Grade 2 AEs: diarrhea 12, rash 8 pts. Best response (investigator reported) included 3 (9%) confirmed PR and 15 (47%) SD [including 2 unconfirmed PR] of 32 entered. Six patients were on study for > 6 months (6, 6, 8, 9, 12.5, 14.5 months). The study was terminated early due to non-protocol considerations. These data are not yet verified. Conclusions: Despite early termination, the higher RR and PFS noted for 32 patients with KRASm CRC treated with IRI and SEL as 2nd-line therapy of CRC (and treated for up to 14.5 months), are promising compared with historical controls. The strategy of MEK inhibition in KRAS mutated CRC should be explored further. Clinical trial information: NCT01116271.

A phase I study of the oral administration of irinotecan in combination with the potent P-glycoprotein (P-gp) inhibitor HM30181A.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3032-3032
Author(s):  
Antonio Jimeno ◽  
Mateusz Opyrchal ◽  
Jennifer Robinson Diamond ◽  
Christos Fountzilas ◽  
Bradley Corr ◽  
...  
Keyword(s):  
Oral Administration ◽  
Dose Level ◽  
Phase 1 ◽  
Median Number ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Pharmacologically Active

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]

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