DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing): A phase III trial—ECOG-ACRIN EA6134.

2021 ◽  
Vol 39 (36_suppl) ◽  
pp. 356154-356154
Author(s):  
Michael B. Atkins ◽  
Sandra J. Lee ◽  
Bartosz Chmielowski ◽  
Antoni Ribas ◽  
Ahmad A. Tarhini ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Initial Therapy ◽  
Phase Iii ◽  
Treatment Sequence ◽  
Ecog Performance Status ◽  
Randomized Evaluation ◽  
Alternate Therapy ◽  
Treatment Naïve ◽  
Grade 3

356154 Background: Combinations of immune checkpoint inhibitors (CPI) blocking PD-1 and CTLA-4 or BRAF/MEK inhibitors have both shown significant antitumor efficacy and overall survival (OS) benefit in patients (pts) with BRAFV600-mutant metastatic melanoma (MM), leading to broad regulatory approval. Little prospective data exists to guide the choice of one over the other as initial therapy or the preferred treatment sequence in this population. The DREAMseq Trial was designed to compare the efficacy and toxicity of the sequence of nivolumab/ipilimumab (N/I) followed by dabrafenib/trametinib (D/T) to the converse sequence. Methods: Eligible pts with treatment-naive BRAFV600-mutant MM were stratified by ECOG Performance Status (PS) 0 or 1 and LDH level and randomized 1:1 to receive Step 1 with either N/I (Arm A) or D/T (Arm B) and at disease progression (PD) were enrolled in Step 2 receiving the alternate therapy, D/T (Arm C) or N/I (Arm D), respectively. Pts received N (1mg/kg)/I (3 mg/kg) q3 wks x 4 doses followed by N 240 IV q2 wks for up to 72 wks (Arms A and D) or D 150 mg po BID and T 2 mg po qD until PD (Arms B and C). In 2019, investigators were given the option to use alternate induction dosing of N (3mg/kg)/I (1 mg/kg) q3 wks x 4 doses for Arms A and D. Cycles were every 6 wks and imaging was obtained at baseline and q12 wks on each arm. Primary endpoint was 2-year OS. At the 4th Interim Analysis with 59% of pts being 2 yrs from enrollment, the DSMC and NCI CTEP recommended halting accrual and releasing the data. Results: Beginning 7/2015, 265 out of a proposed 300 pts were enrolled (133 Arm A and 132 Arm B). Median age was 61 (25-85) and 63% were male. Demographics for Arm A and B were balanced with 67% PS 0 and 60% with normal LDH. As of 7/16/21, at a median follow-up of 27.7 mos, 27 pts had switched to Arm C and 46 to Arm D. Overall Grade 3+ toxicity was 60% in Arm A and 52% in Arm B. Grade 5 treatment-related AEs included 2 on Arm A and 1 on Arm C. ORR to date is: Arm A 46% (52/113), Arm B 43% (49/114), Arm C 48% (11/23) and Arm D 30% (8/27). 37/42 assessed pts in Arm A and 19/37 in Arm B remain in response. Median DOR: Arm A- Not reached; Arm B-12.7 mos (95% CI: 8.2, -) (p <0.001). There were 100 deaths (Arm A to C- 38/Arm B to D- 62). 2-yr OS rate for those starting with Arm A was 72% (95% CI: 62-81%) and for Arm B 52% (95% CI: 42-62%) (log-rank p= 0.0095). PFS showed a trend in favor of Arm A (log-rank p=0.054). Both the PFS and OS curves show a biphasic pattern with Arm B being above Arm A until 6 and 10 mos, respectively. For the 115 pts with documented progression on Step 1 (Arm A-44/Arm B-71), 60 (52%) had registered for Step 2. The principal reason for not enrolling on Step 2 was death from PD within 6 mos (Arm A:15/23; Arm B: 25/32). Conclusions: For pts with advanced BRAFV600-mutant MM, the treatment sequence beginning with the CPI combination of N/I resulted in superior OS, which became evident at 10 mos, with longer Step 1 DOR and more ongoing responses than the treatment sequence beginning with D/T. Clinical trial information: NCT02224781.

scholarly journals Phase III Randomized, Placebo-Controlled Trial of Docetaxel With or Without Gefitinib in Recurrent or Metastatic Head and Neck Cancer: An Eastern Cooperative Oncology Group Trial

2013 ◽  
Vol 31 (11) ◽  
pp. 1405-1414 ◽  
Author(s):  
Athanassios Argiris ◽  
Musie Ghebremichael ◽  
Jill Gilbert ◽  
Ju-Whei Lee ◽  
Kamakshi Sachidanandam ◽  
...  
Keyword(s):  
Head And Neck ◽  
Disease Progression ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
Oncology Group ◽  
Ecog Performance Status ◽  
Grade 3

Purpose We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing. Results Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response. Conclusion The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.

A randomized comparison of carboplatin/vinorelbine versus carboplatin/gemcitabine in advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7033-7033
Author(s):  
N. Helbekkmo ◽  
S. H. Sundtroem ◽  
U. Aaseboe ◽  
P. F. Brunsvig ◽  
C. L. Von Plessen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Performance Status ◽  
Stage Iiib ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Intention To Treat ◽  
Primary Endpoints ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
One Year

7033 Background: Carboplatin/vinorelbine (CV) and carboplatin/gemcitabine (CG) are novel 2-drug combinations in the treatment of NSCLC. In a randomized national multicenter phase III study in stage IIIB and IV patients (pts), we compared these regimens with respect to efficacy, toxicity and quality of life (QoL). Methods: Chemonaive pts with histologically or cytologically proven NSCLC, stage IIIB or IV and ECOG performance status (PS) 0–2 were eligible. There was no upper age limit. Pts received vinorelbine 25 mg/m2 or gemcitabine 1000 mg/m2, both administered on day 1 and 8, in combination with carboplatin (Chatelut AUC 4) at day 1. Three courses were administered in 3-week cycles. QoL questionnaires were completed at baseline, before each cycle and then every 8 weeks up to one year. Primary endpoints were survival and QoL and secondary endpoints toxicity and time to progression (TTP). Stratification was done for age, stage and PS, and the planned sample size per arm was minimum 200. The analyses were performed on an intention-to-treat basis Results: From Oct 2003 through Dec 2004, 433 pts from 33 institutions were randomized to CV (n=218) or CG (n=215). Follow-up was minimum one year. There was no difference in overall survival between the two arms (p=0.89). Median survival was 7.3 vs. 6.5 months and 1-year survival 28% and 31% in the CV and CG arm respectively. TTP was significantly longer in the CG arm (p=0.006) with median TTP 4.2 vs. 3.9 months. There was significantly more grade 3–4 anemia and thrombocytopenia in the CG arm (p<0.001) and more grade 3–4 leucopenia in the CV arm (p= 0.001). More pts in the CG arm needed transfusions of blood (p=0.003) or platelets (p=0.001). There was no difference between the arms with respect to neutropenic infections (p=0.87). QoL data are still being analyzed and will be presented at ASCO. Conclusions: Overall survival was similar in the two treatment arms. In the CG arm, the median TTP was longer, but grade 3–4 toxicity requiring interventions, was more frequent when compared to the VC arm. No significant financial relationships to disclose.

Randomized phase II trial of carboplatin combined with weekly paclitaxel (CP) and docetaxel alone (D) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): NJLCG 0801.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7565-7565
Author(s):  
Shunichi Sugawara ◽  
Makoto Maemondo ◽  
Toshiyuki Harada ◽  
Akira Inoue ◽  
Nobumichi Matsubara ◽  
...  
Keyword(s):  
Performance Status ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Toxicity Profile ◽  
Ecog Performance Status ◽  
Loss To Follow Up ◽  
Lethal Arrhythmia ◽  
Grade 3

7565 Background: Standard first-line chemotherapy for elderly NSCLC pts has been considered as a monotherapy with vinorelbine or gemcitabine globally. However, we have demonstrated the high efficacy of CP for elderly pts in our previous trial (Ann Oncol 2010). Meanwhile, D has been considered as an alternative option for this population in Japan according to the result of WJTOG9904 (JCO 2006). Thus we compared the two regimens to select the proper candidate for future phase III trial. Methods: Eligible pts were aged 70 years or older with newly diagnosed stage IIIB/IV NSCLC; ECOG performance status 0-1; adequate organ function; written informed consent. Pts were randomized to receive carboplatin (AUC 6) on day 1 and paclitaxel (70mg/m2 on day 1, 8, and 15) every 4 weeks or D (60mg/m2 on day 1) every 3 weeks. The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival, and toxicity profile. Assuming that ORR of 40% would be potential usefulness while ORR of 20% would be the lower limit of interest, 40 pts in each arm were required if expect 10% loss to follow up. Results: Between July 2006 and September 2010, 84 pts were enrolled and 41 pts in CP arm and 42 pts in D arm were eligible (median age, 76 years; 75% male; 72% stage IV). Median treatment cycle was 4 in each arm (CP, range 1-6; D, range 1-8). ORRs were 51% (95%CI: 36-66%) and 26% (95%CI: 12-39%) in the CP and D arm, respectively. With a median follow-up of 18.4 months, median PFS were 6.5 and 3.9 months in the CP and D arm, respectively (Logrank, P=0.0027). Grade 3 or severer toxicities were as follows: neutropenia (CP, 56% and D, 79%), anemia (CP, 15% and D, 7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and D, 25%). One treatment-related death due to neutropenia, pneumonia, and lethal arrhythmia occurred in D arm but none in CP arm. Conclusions: The platinum doublet CP achieved higher activity with an acceptable toxicity profile for elderly pts with advanced NSCLC compared to monotherapy with D. The superiority of CP to the monotherapy in this trial is consistent with results of recent IFCT-0501 trial (Lancet 2011).

A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients (pts) with metastatic melanoma: Analysis of peripheral neuropathy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20025-e20025
Author(s):  
Michele Del Vecchio ◽  
Evan Hersh ◽  
Michael Paul Brown ◽  
Arthur Clements ◽  
Carmen Loquai ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Metastatic Melanoma ◽  
Median Time ◽  
Performance Status ◽  
Stage Iv ◽  
Phase Iii ◽  
Common Side Effect ◽  
Ecog Performance Status ◽  
Phase Iii Trial ◽  
Grade 3

e20025 Background: Peripheral neuropathy (PN) is a common side effect associated with taxane treatment. In a phase III trial, nab-paclitaxel vs dacarbazine demonstrated a significant improvement in progression-free survival (4.8 vs 2.5 months; P = 0.044) and at the interim survival analysis, a trend toward prolonged overall survival (12.8 vs 10.7 months; P = 0.094) for the treatment of chemotherapy-naive patients with metastatic melanoma. Here we report on the PN profile of nab-paclitaxel in this phase III trial. Methods: Pts (median age, 63 years) with chemotherapy-naive stage IV melanoma (M1c stage, 65%; elevated LDH, 28%) and an ECOG performance status 0-1 were randomized to nab-paclitaxel 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or dacarbazine 1000 mg/m2on day 1 of each 21-day cycle (n = 265). PN events were defined based on the Standardized MedDRA Query (V 12.1, broad scope). Results: As expected, a higher proportion of pts receiving nab-paclitaxel vs dacarbazine had ≥ 1 treatment-related PN event (68% vs 8%; P < 0.001). Treatment-related grade ≥ 3 PN was more frequent with nab-paclitaxel vs dacarbazine (25% vs 0%; P < 0.001); 2 grade 4 events were reported in the nab-paclitaxel arm. Treatment-related grade ≥ 3 PN was 15% in pts who received up to the median of 3 cycles of nab-paclitaxel. PN led to dose reduction in 13% or discontinuation in 15% of nab-paclitaxel–treated pts. The median time to onset of grade ≥ 3 PN was 101 days (95% CI, 85 - 113). Most early-onset PN events, occurring within the first 3 cycles, were grade 1. Grade ≥ 2 PN events peaked by cycle 4 and subsided by cycle 9. Forty-one of the 64 (64%) pts with a grade ≥ 3 PN event had an improvement of ≥ 1 grade, with a median time to improvement of 28 days (95% CI, 17 - 64), and 33 of 64 (52%) pts had improved to grade 1 or better by a median of 67 days from onset (95% CI, 22- upper limit not estimable); 30 of 64 (47%) pts resumed treatment with nab-paclitaxel. Conclusions: In this phase III trial, grade ≥ 3 PN was the main treatment-related toxicity with nab-paclitaxel as observed in other studies. However, PN was rapidly reversible; a majority of pts had improvement of PN symptoms within 1 month and resumed treatment. Clinical trial information: NCT00864253.

Real-world outcomes of underrepresented patient populations treated with immune checkpoint inhibitors (ICIs): African American descent, poor ECOG performance status, and chronic viral infections.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2587-2587 ◽  
Author(s):  
Neil J. Shah ◽  
Matthew Blackburn ◽  
Michael R Cook ◽  
Anas Belouali ◽  
Michael Serzan ◽  
...  
Keyword(s):  
African American ◽  
Viral Infections ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Outcome Data ◽  
Viral Reactivation ◽  
Ecog Performance Status ◽  
Chronic Viral Infections ◽  
Grade 3 ◽  
Ecog Ps

2587 Background: ICIs have now become standard of care treatment for multiple malignancies. However, patients (pts) who are African American decent (AA), have a poor ECOG performance status (PS) or chronic viral infections [human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV)] were underrepresented in early clinical trials with ICIs and outcome data in these pt populations is not well reported. Methods: We performed a retrospective analysis of pts treated with ICIs (anti-PD(L)-1, anti-CTLA-4, or combination ICIs) across five MedStar Health hospitals from January 2011 to April 2018. Investigator-assessed best responses were noted. CTCAE v4.03 was used to capture immune-related adverse events (irAEs). Results: We identified 765 pts treated with 829 unique ICIs therapies across different malignancies. A total of 203 AA pts, 178 pts with a pre-treatment ECOG PS ≥2, 21pts with HIV, and 50 pts with HBV/HCV were noted. Any grade and grade ≥ 3 irAEs in the HIV cohort were 24% and 10% with an ORR of 29%. Any grade and grade ≥ 3 irAEs in HBV/HCV were 50% and 26% with an ORR of 21%. No viral reactivation or changes in pts anti-viral medications were noted during ICIs treatment. The ORR in AA pts was 35%. Any grade and grade ≥ 3 irAEs in the AA cohort were 27% and 8%, respectively. The ORR in pts with ECOG PS ≥2 was 14%. Any grade and grade ≥ 3 irAEs in this cohort were 20% and 4%. Similar trends were seen in the subset of patients with NSCLC treated with anti-PD(L)1 monotherapy (Table). Outcomes of NSCLC pts treated with anti-PD(L)-1 monotherapy. Conclusions: ICI therapy was not associated with any new safety signal in the above underrepresented populations. Prospective studies are needed to validate this data.[Table: see text]

North American (NA) subgroup results from VELOUR: Ziv-aflibercept versus placebo (pbo) plus FOLFIRI in mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 465-465 ◽  
Author(s):  
Edith P. Mitchell ◽  
Michael J. Guarino ◽  
Carmen Joseph Allegra ◽  
Emmanuelle Boelle ◽  
Michael L. Andria ◽  
...  
Keyword(s):  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Angiogenic Inhibitor ◽  
Worldwide Population ◽  
Trade Name ◽  
Venous Thromboembolic Events ◽  
Venous Thromboembolic ◽  
Grade 3

465 Background: Ziv-aflibercept (trade name ZALTRAP; known outside the US as aflibercept) is a new multiple angiogenic inhibitor that prevents VEGF-A, VEGF-B and PLGF from binding their receptors. Ziv-aflibercept was recently approved by the FDA in combination with FOLFIRI for patients with mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen. Approval was based on the multinational phase III VELOUR trial (N=1226) which showed statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with aflibercept + FOLFIRI. Detailed analyses of the NA subgroup are presented here. Methods: Patients were randomized 1:1 to ziv-aflibercept (4 mg/kg) + FOLFIRI or pbo + FOLFIRI every 2 wk. Patients had ECOG performance status (PS) ≤2, 1 prior oxaliplatin-based regimen, and prior bevacizumab (bev) was allowed. Primary endpoint was OS. The NA analysis was pre-specified, but not powered, to compare within or between subgroups. Results: NA patients (N=138) were randomized to ziv-aflibercept + FOLFIRI (n=63) or pbo + FOLFIRI (n=75). Baseline characteristics were similar in both arms (ziv-aflibercept: median 61 yrs; 60% male; 96% PS 0-1; 56% >1 metastatic organ; 74% prior bev). Ziv-aflibercept vs pbo improved median OS (17.94 vs 12.88 mos; HR=0.691, 95% CI: 0.442-1.079), median PFS (6.01 vs 4.17 mos; HR=0.536, 99.9% CI: 0.222-1.296) and ORR (12% vs 9%). Patients on average received more cycles (median 8.5 vs 7.0) and had longer duration of exposure (median 20 vs 14 wk), but had more treatment modifications with ziv-aflibercept vs pbo. Most of the severe AEs (grade ≥3) with ziv-aflibercept were grade 3 including hypertension, venous thromboembolic events, proteinuria, diarrhea, fatigue/asthenia, infection, stomatitis/ulceration and neutropenia. There were few grade 4 AEs. Conclusions: Ziv-aflibercept + FOLFIRI in NA mCRC patients previously treated with an oxaliplatin-based regimen (with or without prior bev) resulted in improved OS, PFS, and ORR, with an acceptable safety profile. The NA results are consistent with the VELOUR worldwide population. Clinical trial information: NCT00561470.

Preliminary findings from part 1 of COMBI-i: A phase III study of anti–PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 189-189 ◽  
Author(s):  
Reinhard Dummer ◽  
Ana María Arance Fernández ◽  
Johan Hansson ◽  
James M. G. Larkin ◽  
Georgina V. Long ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Antigen Expression ◽  
Complete Response ◽  
Mek Inhibitor ◽  
Phase Iii ◽  
Double Blind ◽  
Treatment Naïve ◽  
New Treatment ◽  
Grade 3

189 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with advanced BRAF V600–mutant melanoma; however, many still progress and die from this disease. Thus, new treatment strategies are needed. BRAF and MEK inhibitor combinations (eg, D+T) may reverse immunosuppressive phenotypes induced by oncogenic BRAF and improve sensitivity to checkpoint inhibitors by enhancing HLA and melanocytic antigen expression and tumor antigen–specific T-lymphocyte recognition. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating the anti–PD-1 antibody PDR001 in combination with D+T in treatment-naive pts with BRAF V600–mutant unresectable or metastatic melanoma in 3 parts: 1, safety run-in; 2, biomarker cohort; and 3, randomized, double-blind, placebo-controlled part. Here we report preliminary findings for 9 pts in part 1 dosed with PDR001 400 mg Q4W + D 150 mg BID + T 2 mg QD. Response was assessed at wk 12 and Q8W thereafter. Results: At data cutoff (16 Jul 2017; median follow-up, 2.7 mo), all 9 pts completed the 8-wk dose-limiting toxicity (DLT) period, during which 1 DLT (transaminitis [AST and ALT > 8 × ULN]; n = 1) occurred. Adverse events (AEs) of any grade occurring in > 3 pts included pyrexia (n = 9), headache (n = 6), chills (n = 4), and vomiting (n = 4). Grade 3/4 AEs reported in > 1 pt included hepatitis (n = 3), increased lipase (n = 2), and increased transaminases (n = 2). AEs leading to discontinuation occurred in 2 pts (22%; transaminitis, n = 1; grade 3 hepatitis, n = 1) who permanently discontinued PDR001 but were still receiving D+T at the data cutoff. All 9 pts responded: 3 (33%) achieved a complete response (confirmed, n = 1), and 6 (67%) had partial responses (confirmed, n = 1). Additional safety and efficacy results for these 9 pts, all ongoing at the data cutoff, will be presented. Conclusions: These preliminary results indicate that PDR001 can be combined with D+T with a manageable safety profile and demonstrate promising activity in pts with BRAF V600–mutant melanoma. Clinical trial information: NCT02967692.

A multicenter phase II study of cisplatin (C), gemcitabine (G), and bevacizumab (B) as first-line chemotherapy for metastatic urothelial carcinoma (UC): Hoosier Oncology Group GU-0475

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5018-5018
Author(s):  
N. M. Hahn ◽  
W. M. Stadler ◽  
R. T. Zon ◽  
D. M. Waterhouse ◽  
J. Picus ◽  
...  
Keyword(s):  
Performance Status ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
First Line ◽  
Ecog Performance Status ◽  
Angiogenic Therapy ◽  
Grade 3

5018 Background: Despite CG therapy, most metastatic UC patients die from their disease. Novel approaches are needed. Combining anti-angiogenic therapy with chemotherapy has improved outcomes in other malignancies, offering hope for similar improvements in UC patients. Methods: Metastatic or unresectable chemonaive UC patients (pts) with an ECOG performance status of 0–1 received C 70 mg/m2 iv d1, G 1,000–1,250 mg/m2 iv d1, 8, and B 15 mg/kg iv d1 on a q21d cycle for up to 8 cycles. Gemcitabine was reduced to 1,000 mg/m2 iv d1, 8 for all subsequent pts after 7 thromboembolic events were noted in the first 17 pts. The primary endpoint was progression free survival (PFS). The trial was designed to detect a 33% improvement in PFS from 7.5 months with traditional CG therapy to 11.25 months with CGB. Results: By December 2008, 45 pts were enrolled, with 43 evaluable for toxicity, 36 for response. Demographics include: 33 (77%) male, 10 (23%) female; median age 66 (Range: 41 - 78); 26 (60%) and 17 (40%) ECOG 0/1; 19 (44%) and 24 (56%) lymph node only / visceral metastases. PFS will be evaluated in May 2009 when all pts will have more than 6 month follow-up data. 14 (33%) and 6 (14%) pts experienced grade 3 or 4 hematologic toxicity (4 pts - thrombocytopenia, 2 pts - neutropenic fever). Grade 3 or 4 nonhematologic toxicity was observed in 24 (56%) and 9 (21%) pts (DVT/PE - 9 pts, CNS hemorrhage/proteinuria/hypertension - 1 pt each) Best RECIST response was: complete response 6 pts (17%, 95% CI 6–33%), partial response 18 pts (50%, 95% CI 33–67%); with overall response rate of 67% (95% CI 51–82%). Stable disease lasting at least 12 weeks was observed in 10 pts (28%, 95% CI 14–45%) and progressive disease in 2 pts (5%, 95% CI 1–19%). Conclusions: CGB demonstrates significant clinical activity in the first-line treatment of metastatic UC patients at the expense of considerable toxicity. The durability of disease control will be determined by assessment of PFS. A phase III trial to further define the toxicity risk vs. clinical benefit of bevacizumab addition to platinum-based doublets is planned in this population. [Table: see text]

Randomized, multicenter, open-label, phase III study of the BTK inhibitor ibrutinib versus chlorambucil in patients 65 years or older with treatment-naive CLL/SLL (RESONATE-2, PCYC-1115-CA).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS7130-TPS7130 ◽  
Author(s):  
Jan Andreas Burger ◽  
Paolo Ghia ◽  
Aaron Polliack ◽  
Constantine Tam ◽  
Deepali Suri ◽  
...  
Keyword(s):  
Performance Status ◽  
Single Agent ◽  
Unmet Need ◽  
Previous Treatment ◽  
Phase Iii ◽  
Open Label ◽  
Ecog Performance Status ◽  
Treatment Naïve ◽  
Phase Iii Study ◽  
Ecog Ps

TPS7130 Background: There is an unmet need for safer and more effective therapies for CLL patients who are older/have comorbidites. Ibrutinib, a small molecule inhibitor of BTK, has demonstrated single-agent activity in CLL in the Ph 1b/2 study, PCYC-1102-CA. Treatment-naïve (TN) patients aged >= 65 yrs (n=31) experienced an estimated PFS and OS of 96% at 26 months; ORRs per iwCLL were: 10% CR, 58% PR, and 13% PR with lymphocytosis (Byrd, ASH 2012). AEs were generally Grade 1/2, most commonly diarrhea. Incidence of Grade 3/4 hematologic toxicities was low. These findings support a phase III study of ibrutinib in older patients with treatment-naïve CLL/SLL. Methods: The ongoing study is a randomized, multicenter, open label Ph 3 study comparing safety and efficacy of ibrutinib vs. chlorambucil in TN patients aged >= 65 yrs with CLL/SLL. Approximately 272 patients will be randomized in 1:1 ratio to receive either chlorambucil or ibrutinib, stratified for ECOG PS and Rai stage. Oral chlorambucil will be administered at 0.5 mg/kg on Days 1 and 15 of each 28-day cycle, for up to 12 cycles. Ibrutinib 420 mg q.d. will continue until PD or unacceptable toxicity. Key incl. criteria include age >= 65 yrs, active disease requiring treatment per iwCLL, measurable nodal disease by CT, ECOG performance status 0-2, and adequate organ function (ANC ≥1,000/μL, platelets ≥50,000/μL, creatinine clearance ≥30 mL/min). Key excl. criteria include Richter’s transformation, del(17p13.1) or previous treatment for CLL/SLL. The primary endpoint of the study is PFS, assessed by Independent Review Committee (IRC). Secondary endpoints include ORR, MRD-negative CRs, fatigue by FACIT-F, hematological improvement, safety, and tolerability. Subjects who relapse on PCYC-1115 will be enrolled on PCYC-1116 for long term follow up. Second line therapy is investigator choice; ibrutinib will be made available for patients who experience IRC-confirmed PD ≤12 months of completing chlorambucil therapy, if they meet the treatment criteria. Approximately 85 sites will enroll patients in North America, Europe, Israel, Australia/New Zealand and China. Enrollment began in Q1 2013. Clinical trial information: NCT01722487.

Real-world outcomes with immuno-oncology (IO) therapies: A prospective, observational cohort study in patients (pts) with advanced melanoma (OPTIMIzE).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14144-e14144
Author(s):  
John M. Kirkwood ◽  
Lisa A. Kottschade ◽  
Robert R. McWilliams ◽  
Nikhil I. Khushalani ◽  
Sekwon Jang ◽  
...  
Keyword(s):  
Real World ◽  
Cox Model ◽  
Performance Status ◽  
Objective Response ◽  
Advanced Melanoma ◽  
Ecog Performance Status ◽  
Treatment Naïve ◽  
The Difference ◽  
Grade 3

e14144 Background: There is little real-world evidence evaluating treatment patterns and outcomes with IO therapies for pts with advanced melanoma (aMEL). We present results from the OPTIMIzE (NCT02780089) study in pts with aMEL receiving IO therapies. Methods: OPTIMIzE is a US-based multisite (150 sites), community-based study of adult pts with aMEL. Pts receiving first-line (1L) nivolumab (NIVO)+ipilimumab (IPI), anti-PD-1 (NIVO/pembrolizumab), or IPI between 2011-2018 with a minimum 1 y of follow-up were included. Baseline characteristics, objective response rate (ORR), overall survival (OS), treatment-related adverse events (TRAEs), and quality of life (QoL) were analyzed. QoL assessments included the Functional Assessment of Cancer Therapy–Melanoma (FACT-M), EQ-5D index, and visual analog scale (VAS). Results: Cohort size: 81 NIVO+IPI, 147 anti-PD-1, and 16 IPI (IPI arm not included in the analysis). Overall, mean age was 64.5 y; 42% had BRAF mutation. Mean follow-up was 14.1 mo. Pts in the NIVO+IPI group were younger, had better ECOG performance status, and a higher likelihood of M1c disease and elevated LDH vs the anti-PD-1 group. ORR was higher for pts treated with NIVO+IPI vs anti-PD-1 (48% vs 33%, P= 0.08). Unadjusted 1-y OS was 78.4% for NIVO+IPI and 73.1% for anti-PD-1. In multivariate Cox model analysis, the hazard ratio for OS for NIVO+IPI vs anti-PD-1 was 0.78 (95% CI, 0.46–1.33; P= 0.36). Grade 3/4 TRAEs occurred in 53% and 22% of pts in the NIVO+IPI and anti-PD-1 groups, respectively ( P˂0.001). QoL changes from baseline were clinically meaningful for EQ-5D VAS and FACT-M in the NIVO+IPI group at 12 mo (Table). After adjusting for baseline covariates, the difference at 12 mo between NIVO+IPI vs anti-PD-1 was 6.7 ( P= 0.04) for EQ-5D VAS and 8.8 ( P= 0.02) for FACT-M. Conclusions: Safety and efficacy outcomes from this prospective real-world study are consistent with those reported in prior clinical trials in treatment-naive aMEL pts. No clinically meaningful deterioration in QoL measures was observed in either group. Clinical trial information: NCT02780089. [Table: see text]

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