Randomized Phase II Study of Combined Epigenetic Therapy: Decitabine Vs. Decitabine and Valproic Acid in MDS and AML

Abstract Introduction: Inhibition of DNA methylation (DNMTi) by decitabine (DAC) or azacitidine is a form of epigenetic therapy that is clinically effective in the treatment of MDS and AML. In-vitro, histone deacetylase inhibition (HDACi) following DNA hypomethylation induction results in synergistic enhancement of gene expression activation, but the effects of HDACi on the cell cycle can also interfere with DNTMi activity, resulting in schedule dependent antagonism. Phase I/II studies of the combination of DNMTi and HDACi have shown some promise, triggering randomized studies. Methods: We conducted a randomized phase II study of DAC at 20 mg/m2 IV/1 hour daily ×5 q4 weeks vs. DAC at a similar dose + Valproic acid (VPA) 50 mg/kg PO daily ×7 starting on day 1 of DAC. Eligibility included MDS (FAB), IPSS>0 or AML, age >60 (excluding APL and CBF AML). An adaptive randomization design based on a composite score of CR, response and survival was used after the 40th patient to assign patients to the superior arm. DNA methylation was measured by bisulfite pyrosequencing on peripheral blood mononuclear cells prior to and during treatment. Results: 76 patients were enrolled on the study, 2 of whom received no therapy and are excluded from analysis. These included 8 patients with CMML (median age 72), 23 patients with AML (median age 71 (63–81), median BM blasts 40% (30–87), median WBCs 5.4 (1.1–97)) and 43 patients with MDS (median age 66 (36–89), IPSS Int1 (10), Int2 (19) and high (14)). Cytogenetics were abnormal in 40 patients (54%), most with complex or poor risk karyotypes. 42 patients (57%) were randomized to DAC alone. Overall, the median number of courses given so far is 4 (1–17) and 27 patients (36%) remain on therapy, at a median follow-up of 14 months. Response data are available for 67 patients (7 are too early). Overall, responses were seen in 31 patients (46%), with CR in 23 (34%) and other responses in 8 (12%). Overall response rate was 39% in AML, 71% in CMML and 46% in MDS. In patients receiving decitabine alone, the overall response rate was 17/40 (43%), compared to 14/27 (52%) in those randomized to DAC+VPA (p=NS). Median time to first response was 64 days (18–194) with DAC alone compared to 57 days (23–123) with DAC+VPA (p=NS). VPA added significant neurotoxicity to the regimen, with several patients discontinuing the drug due to somnolence or confusion. Median survival was 8.7 months in AML and 14.9 months in MDS (p=0.04). Kaplan-Meier analysis showed no difference in survival between DAC and DAC+VPA in the first year after therapy. DNA methylation analysis showed a similar degree of LINE demethylation in both arms, Conclusions: Preliminary analysis of this randomized study suggests that adding VPA to DAC only marginally improves response rate and time to first response and has no impact on survival in MDS and AML. It remains to be seen (in randomized studies) whether more potent HDACi will show greater evidence of clinical synergy with DNMTi.

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Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Blood ◽

10.1182/blood.v124.21.303.303 ◽

2014 ◽

Vol 124 (21) ◽

pp. 303-303 ◽

Cited By ~ 6

Author(s):

Rachid Baz ◽

Thomas G. Martin ◽

Melissa Alsina ◽

Kenneth H. Shain ◽

Hearn J. Cho ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Advisory Committees ◽

Overall Response ◽

Best Response ◽

Randomized Phase Ii ◽

Grade 3

Abstract Background: Pomalidomide-dexamethasone results in an overall response rate of 33% and median PFS of 4.2 months in patients with prior lenalidomide and bortezomib (Richardson et al. Blood 2014). In this randomized phase II trial, we compared pomalidomide-dexamethasone (arm B) versus the addition of oral weekly cyclophosphamide to pomalidomide-dexamethasone (arm C) in patients with lenalidomide-refractory multiple myeloma (MM). We have previously reported that the recommended phase II dose of cyclophosphamide with standard-dose pomalidomide + dexamethasone was 400 mg PO D1, 8, 15. Patients and Methods: Eligible patients had relapsed and refractory MM after at least 2 prior therapies and were lenalidomide refractory. Patients had a platelet count ≥ 50,000/mm3 and ANC ≥ 1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count was ≥ 30,000/mm3and ANC could be supported with GCSF during screening and therapy). Patients were randomized (1:1) to receive pomalidomide 4 mg PO D1-21 and dexamethasone 40 mg PO D1, 8, 15, 22 (20 mg if older than 75 years) (arm B) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28-day cycle (arm C). Patients randomized to arm B were allowed to cross over to arm C in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin, or LMWH. The primary endpoint was overall response rate using IMWG criteria. Secondary endpoints included an evaluation of PFS, OS and safety of the two arms. Results: Between 7/2012 and 3/2014, 36 patients were randomized to arm B and 34 to arm C. Patients characteristics were not different between the 2 arms (table below). The median number of prior therapies was 4 (2-12). All patients were lenalidomide refractory and none received prior pomalidomide. After a median follow up of 15 months, the overall response rate (partial response or better) was 39% and 65% (p=0.03) for arm B and C, respectively. The clinical benefit rate (minimal response or better) was 64% and 79% (p=0.2) for arm B and C, respectively. The median PFS was 4.4 months (95% CI 2.3-5.9) for arm B and 9.2 months (95% CI 4.6-16) for arm C (log rank p=0.04). As of July 2014, 28 patients had died (16 arm B, 12 arm C) with median overall survival of 10.5 versus 16.4 months (p=0.08) for arm B and C, respectively. Hematologic grade 3/4 adverse events were more frequent in arm C, although this was not statistically significant (see table). Thirteen patients crossed over and oral weekly cyclophosphamide was added to their tolerated dose of pomalidomide dexamethasone. For those patients, the best response was as follows: 2 PR, 2 MR, and 6 SD, 3 PD. Conclusions: Pomalidomide-dexamethasone in combination with oral weekly cyclophosphamide resulted in a superior response rate and PFS compared to pomalidomide-dexamethasone alone in patients with relapsed and refractory MM. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. Table Arm B (N=36) Arm C (N=34) P value Age, years, median (range) 63 (50-78) 64 (47-80) 0.7 Male, n (%) 23 (64) 18 (53) 0.3 Number of prior therapies, median (range) 4 (2-12) 4 (2-9) 0.5 Bortezomib refractory, n (%) 28 (78) 24 (71) 0.3 Carfilzomib refractory, n (%) 16 (44) 13 (38) 0.5 Prior high-dose therapy, n (%) 27 (75) 28 (82) 0.6 Prior alkylating agent, n (%) 32 (89) 32 (94) 1 B2-microglobulin, median (range) 3.2 (1.6-10) 3.6 (1.5-13.9) 0.5 Serum creatinine, median (range) 1 (0.5-2.3) 0.9 (0.6-2.1) 0.6 High-risk cytogenetics, n (%) 5 (24) 6 (28) 0.8 Deletion 17p, n (%) 3 (14) 4 (20) 0.8 t(4;14), n (%) 3 (14) 3 (14) 0.9 Trisomy or tetrasomy 1q, n (%) 11 (55) 6 (33) 0.4 Best response (partial response or better), n (%) 14 (39) 22 (65) 0.03 Clinical benefit rate (MR or better), n (%) 23 (64) 27 (79) 0.2 Grade 3/4 neutropenia, n (%) 12 (33) 17 (50) 0.2 Grade 3/4 febrile neutropenia, n (%) 4 (11) 6 (18) 0.5 Grade 3/4 thrombocytopenia, n (%) 2 (5) 5 (15) 0.2 Grade 3/4 anemia, n (%) 3 (8) 7 (20) 0.2 Grade 3/4 pneumonia, n (%) 4 (11) 3 (9) 1 Grade 3/4 fatigue, n (%) 2 (5) 4 (12) 0.4 Number of serious adverse events 17 20 Disclosures Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Karypharm: Research Funding; Sanofi: Research Funding. Off Label Use: Pomalidomide cyclophosphamide dexamethasone in relapsed refractory myeloma. Martin:Sanofi: Research Funding; Novartis: Speakers Bureau. Alsina:Triphase: Research Funding; Millenium: Research Funding. Shain:Onyx / Amgen: Research Funding; Treshold: Research Funding. Chari:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

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Phase II study of PX-866 in recurrent glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2053 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2053-2053 ◽

Cited By ~ 3

Author(s):

Marshall W. Pitz ◽

Elizabeth A. Eisenhauer ◽

Mary Valeria MacNeil ◽

Brian Thiessen ◽

David R. Macdonald ◽

...

Keyword(s):

Phase Ii ◽

Stable Disease ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Performance Status ◽

Recurrent Glioblastoma ◽

Pik3ca Mutations ◽

Overall Response ◽

Grade 3

2053 Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: A multinomial design of response and early progression (< 8 weeks on study) was used. In stage 1 (15 pts), 0 responses and ≥ 10 early progressions would stop accrual; after full accrual, ≥ 4 responses OR ≤ 13 early progressions was prespecified as of interest. Pts with histologically confirmed GBM, at first recurrence after chemoradiation and adjuvant temozolomide were given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam were done every cycle (8 weeks). Tumour tissue was collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRviii, PIK3CA mutations). Results: A total of 33 pts were enrolled, eligible and evaluable. Median age was 56 (range 35-78), 12 were female; 29 had performance status (PS) 0-1 and 4 had PS 2. Median time from initial diagnosis to enrolment was 308 days (range 141-1256). Median number of cycles was 1 (range 1-7). Thirty-two pts have discontinued therapy, 26 due to disease/symptomatic progression and 6 due to toxicity (5 LFT elevation and 1 allergic reaction). Other adverse effects (AE): fatigue (16 pts/2 grade 3), diarrhea (11 pts/5 grade 3), nausea (19 pts/1 grade 3), vomiting (11 pts/1 grade 3) and lymphopenia (29 pts/7 grade 3/4). Five pts had related serious AEs (1 LFTs, 1 GI and 3 venous thromboembolism) All pts were evaluable for response; 25 had a best response of progression, 1 had partial response (overall response rate 3%) and seven (21%) had stable disease (SD, median 7.3 months; range 3.1-13.6). Six month PFS was 17%. In preliminary analyses, no statistical association was found between SD and PTEN or EGFRviii status (results pending in 16 pts). Conclusions: PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of pts obtained durable stable disease. Further correlative work is required to identify the predictor of this effect. Clinical trial information: NCT01259869.

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Cetuximab plus docetaxel-cisplatin (DC) as first-line treatment for locally advanced or metastatic gastric cancer: Preliminary results of a phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15592 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15592-e15592

Author(s):

J. Fahlke ◽

K. Ridwelski ◽

A. Florschuetz ◽

E. Kettner ◽

M. Leithaeuser ◽

...

Keyword(s):

Gastric Cancer ◽

Disease Progression ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Published Data ◽

First Line ◽

Overall Response ◽

Grade 3

e15592 Background: Based on promising published data, this multicenter, phase II study was initiated to investigate a combined treatment using DC and cetuximab in the first-line setting for patients with gastric cancer. Methods: Patients aged 18–75 years with stage III (T4, nonresectable) or stage IV gastric cancer, ECOG performance status (PS) ≤2, and life expectancy ≥3 months were recruited to receive cetuximab (400 mg/m2 on day 1 then 250 mg/m2 q1w) and DC (D 75 mg/m2 and C 75 mg/m2; both as 1-h infusions on day 1 and then q3w). Treatment was stopped in the event of disease progression, intolerable toxicity, or consent withdrawal. Tumor staging was performed after cycle 3 and then every 12 weeks. The primary endpoint was overall response rate and secondary endpoints included time to progression, overall survival and toxicity. Planned accrual was 79 patients. A per-protocol interim response analysis was planned for the initial 20 evaluable patients. Results: Preliminary data are available for 30 patients; median age 64 [range: 40–73] years; median ECOG PS 1 [range: 0–2]; adenocarcinoma 87%. Median cycles administered were 3 [range: 1–14] and the median follow-up was 1.63 months. The overall response rate was 27.3% (complete response, n=1; partial response, n=5). Stable disease was observed in 10 patients, and disease progression in 6 patients. The most relevant NCI-CTC grade 3–4 hematologic events per patient were leukopenia and neutropenia (73%), anemia (13%), and febrile neutropenia (10%). Major grade 3–4 nonhematologic toxicities were nausea (30%), vomiting (20%), diarrhea (13%), acne (13%), and fatigue (13%). Conclusions: DC and cetuximab were well tolerated and resulted in promising response rates and a predictable toxicity profile. The study is ongoing. No significant financial relationships to disclose.

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Phase II Study of Denileukin Diftitox (Ontak) for Relapsed/Refractory T-Cell Non-Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v106.11.3350.3350 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3350-3350

Author(s):

Nam H. Dang ◽

Barbara Pro ◽

Fredrick Hagemeister ◽

Felipe Samaniego ◽

Dan Jones ◽

...

Keyword(s):

T Cell ◽

Tumor Cells ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Interleukin 2 ◽

Cancer Center ◽

Overall Response ◽

Denileukin Diftitox

Abstract Denileukin diftitox (ONTAK) is a fusion protein combining interleukin-2 (IL-2) and the enzymatically active domain of diphtheria toxin that targets tumor cells expressing the IL-2 receptor. We initiated a phase II study at MD Anderson Cancer Center to evaluate its efficacy in relapsed/refractory T-cell lymphoma excluding CTCL. Denileukin diftitox was administered at 18 mcg/kg/day by IV infusion daily for 5 days every three weeks for up to 8 cycles. Corticosteroid was given before every infusion to reduce the incidence and severity of acute hypersensitivity reaction. Twenty-five patients are currently evaluable for response. Median age was 55 years (range 26–80) and mean number of prior treatments was 2 (range 1–6). Tumor CD25 status was determined by flow cytometry and/or immunohistochemistry, with CD25 positivity being defined as 10% or more tumor cells expressing detectable CD25. Of the 13 patients with CD25+ T-cell lymphomas, there were 4 CR (30.8%) and 4 PR (30.8%) for an overall response rate of 61.6%. Of the 10 patients with CD25- tumors, there were 1 CR (10%) and 3 PR (30%) for an overall response rate of 40%. Two patients had a tumor CD25 of undetermined status. The overall response rate was 48% with 5 CR (20%) and 7 PR (28%). The median progression-free survival for responding patients was 6 months (range, 1–24+ months), with 1 patient with CD25+ ALK-1 negative ALCL having an ongoing CR at 24+ months. Of note is the fact that one patient who experienced a CR and another who had a PR went on to receive allogeneic transplantations while in remission induced by denileukin diftitox. Treatment was well tolerated, with the majority of toxicity being grade 1or 2 and transient. Most common toxicities seen were transient transaminase elevation, hypoalbuminemia and edema. Denileukin diftitox has activity in relapsed/refractory T-cell NHL, and is well tolerated at the dosing scheduled tested. While response to denileukin diftitox is seen in both CD25+ and CD25− T-NHL, drug activity in CD25 expressing tumors is particularly striking.

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Final Results of the Phase I/II Trial of Weekly Bortezomib In Combination with Temsirolimus (CCI-779) In Relapsed or Relapsed/Refractory Multiple Myeloma Specifically In Patients Refractory to Bortezomib

Blood ◽

10.1182/blood.v116.21.990.990 ◽

2010 ◽

Vol 116 (21) ◽

pp. 990-990 ◽

Cited By ~ 5

Author(s):

Irene M. Ghobrial ◽

Edie Weller ◽

Ravi Vij ◽

Nikhil C. Munshi ◽

Ranjit Banwait ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Phase I Study ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Advisory Committees ◽

Overall Response ◽

Phase I And Ii

Abstract Abstract 990 Introduction: This study aimed to determine activity and safety of weekly bortezomib (Takeda Inc) and temsirolimus (Pfizer Inc) in patients with relapsed/refractory Multiple Myeloma (MM). Methods: Eligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with any prior lines of therapy including bortezomib, 2) no chemotherapy within 3 weeks, or biological/novel therapy within 2 weeks. Primary endpoint was the percent of patients with at least a minimal response (MR). Results: Twenty patients were enrolled on the phase I study and 43 on the phase II study. The MTD was determined at 1.6 mg/m2 bortezomib Days 1, 8, 15, and 22 every 35 days in combination with 25 mg IV temsirolimus Days 1, 8, 15, 22, and 29 every 35 days. Twenty % were stage III by ISS staging system in the phase I, and 21% in the phase II. The overall response rate of MR or better in the Phase II study was 20/43 (47%, 95%CI: 33,60), with 5% CR, 9% VGPR, 19% PR and 14% MR. Progression without any response occurred in just 1 patient (3%). One patient had an unconfirmed PR, but was included in the stable disease category. An additional 3 (6%) patients were unevaluable in the phase II trial because they did not complete their first cycle of therapy and had no follow up laboratory results for response. If these patients are excluded, the ORR including MR improves to 50% (95% CI: 36,64). The overall response rate in the phase I study was 20% with responses occurring in all the stages of the dose escalation. If three patients who were unevaluable in the phase I trial are excluded, then the response rate of evaluable phase I patients is 24% (95% CI: 9,46). Response was also evaluated by whether patients were bortezomib-refractory or not. These were defined as progressing while on therapy or progressing within 60 days of completing bortezomib therapy. Fifty-one patients had received bortezomib as part of prior treatment. Of these patients, 32 were refractory to bortezomib therapy immediately prior to study entry, and an additional 2 pts were refractory at prior time points. Responses observed among the 32 patients refractory to their most recent bortezomib therapy include 3 PR and 3 MR (ORR: 19%, 95% CI: 9,34). Another 21 patients had SD, 2 PD and 3 patients were unevaluable. Of the evaluable patients, the ORR was 6/29 (21%). Responses observed among the 19 patients who were not refractory to their last bortezomib treatment include 2 VGPR, 5 PR and 3 MR with 6 patients with SD, 0 PD and 3 unevaluable. The ORR among the evaluable patients who received bortezomib but were not refractory was 62%. Median time to response of MR or better (min, max) among all patients was 1.7 months (0.5,14.2) and among phase II patients 1.3 months (0.5,8.0). Median duration of MR or better (min, max) among all patients is 5.2 months (0.5,15.8) and among phase II patients is 4.6 months (0.5,10.8). Median duration of PR or better response (min, max) among all patients is 6.0 months (1.8,15.8) and among phase II patients is 5.2 months (1.8,10.8). The median time to progression for all patients in the phase I and II studies was 7.3 months (95% CI: 5.7 –17.2) and the median progression free survival was 6.4 months (95% CI: 4.8–7.4). The median overall survival in all phase I and II patients was 11.4 months (95%CI: 8.6-undetermined). Three deaths occurred during therapy in the phase I and II studies, 1 of septic shock, 1 with H1N1 infection, and 1 with cardiac amyloid and ventricular arrhythmia. The most common G1-4 toxicities that occurred in > 25% of patients included cytopenias, hypertrigyceridemia and diarrhea. Grade 3 and 4 thrombocytopenia occurred in 48% of patients in the phase I and II studies, G3 and 4 neutropenia occurred in 36%, and anemia in 26% of phase I and II patients. G3 and 4 hypertriglyceridemia occurred in 5% and diarrhea in 9%. Peripheral neuropathy (PN) was rare with no G3 or 4 neuropathy reported. Overall, there was 34% grade 1 and 2 PN seen. Conclusions: The combination of weekly bortezomib and temsirolimus showed an encouraging response rate in heavily pretreated patients with relapsed or refractory MM, with an overall response rate in evaluable patients as part of the phase II portion of the trial of 50%, and a 21% ORR including MR or better in evaluable bortezomib refractory patients. Cytopenias were the most common toxicities, specifically thrombocytopenia, as well as GI toxicity, with side effects proving manageable. Significant PN was rare in this study. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vij:Novartis: Honoraria; Eisai: Speakers Bureau. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.

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Brentuximab Vedotin Followed By ABVD in Patients with Previously Untreated Hodgkin Lymphoma. a Pilot Phase II Study

Blood ◽

10.1182/blood.v124.21.3088.3088 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3088-3088 ◽

Cited By ~ 3

Author(s):

Pier Luigi Zinzani ◽

Stefano Luminari ◽

Francesco Merli ◽

Emanuela Anna Pesce ◽

Stephane Chauvie ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Complete Response ◽

Pilot Phase ◽

First Line ◽

Overall Response

Abstract active and well tolerated single agent in the treatment of heavily pretreated Hodgkin lymphoma patients. In this pilot phase II study patients with previously untreated HL underwent sequential regimen consisting in 2 cycles of BV before doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) +/- radiotherapy (RT). The primary endpoint of the study was the response to BV assessed by positron emission tomography (PET) after the 2 cycles (PET2), defined as reduction of Deauville score or, in case of no change in Deauville score, as any reduction in standard uptake value (SUV) intensity compared to basal SUV. Between April and October 2013, 12 patients with a median age at diagnosis of 36 years (range, 19-70), 11 stage I-IIA and 1 stage IIIA, were enrolled. BV was administered as scheduled and at the full dose of 1.8 mg/kg in all patients. After the 2 cycles of BV, the overall response rate was 91%, comprising of ten (83%) complete responses and one (8%) partial metabolic response. The non responding patient had stage III and showed a new lesion at PET2. After ABVD +/- RT, the overall response rate was 100% with 11 complete responses and 1 partial response (converting from progression disease). At a median follow up of 8 months, all 11 patients are still in complete response, while the remaining one relapsed. During BV therapy, the only grade 3 adverse events were transient and asymptomatic increase in liver transaminases (n=3, 25%) and gamma glutamyl transpeptidase (n=2, 17%). During ABVD +/- RT grade III-IV neutropenia occurred in 9 (75%) patients. All toxicities were transient and resolved with growth factor support. Two cycles of BV as first line-treatment in limited stage HL induced an outstanding complete response rate with limited toxicity and reducing the need of chemotherapy. Waiting for a longer follow up to assess the duration of response, our data (sequential administration of immunotherapy and chemotherapy) should be considered the starting point for further studies in first line therapy for limited stage HL patients. Disclosures No relevant conflicts of interest to declare.

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Pyrotinib or Lapatinib Combined With Capecitabine in HER2–Positive Metastatic Breast Cancer With Prior Taxanes, Anthracyclines, and/or Trastuzumab: A Randomized, Phase II Study

Journal of Clinical Oncology ◽

10.1200/jco.19.00108 ◽

2019 ◽

Vol 37 (29) ◽

pp. 2610-2619 ◽

Cited By ~ 43

Author(s):

Fei Ma ◽

Quchang Ouyang ◽

Wei Li ◽

Zefei Jiang ◽

Zhongsheng Tong ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Metastatic Breast ◽

Progression Free Survival ◽

Her2 Positive ◽

Overall Response ◽

Randomized Phase Ii

PURPOSE Pyrotinib, an irreversible pan-ErbB inhibitor, showed promising antitumor activity and acceptable tolerability in a phase I trial. We assessed the efficacy and tolerability of pyrotinib versus lapatinib, both in combination with capecitabine, in women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in an open-label, multicenter, randomized phase II study. PATIENTS AND METHODS Chinese patients with HER2-positive relapsed or metastatic breast cancer previously treated with taxanes, anthracyclines, and/or trastuzumab were assigned (1:1) to receive 400 mg pyrotinib or lapatinib 1,250 mg orally once per day for 21-day cycles in combination with capecitabine (1,000 mg/m2 orally twice per day on days 1 to 14). The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS Between May 29, 2015, and March 15, 2016, 128 eligible patients were randomly assigned to the pyrotinib (n = 65) or lapatinib (n = 63) treatment groups. The overall response rate was 78.5% (95% CI, 68.5% to 88.5%) with pyrotinib and 57.1% (95% CI, 44.9% to 69.4%) with lapatinib (treatment difference, 21.3%; 95% CI, 4.0% to 38.7%; P = .01). The median progression-free survival was 18.1 months (95% CI, 13.9 months to not reached) with pyrotinib and 7.0 months (95% CI, 5.6 to 9.8 months) with lapatinib (adjusted hazard ratio, 0.36; 95% CI, 0.23 to 0.58; P < .001). The most frequent grade 3 to 4 adverse events were hand-foot syndrome in 16 of 65 patients (24.6%) in the pyrotinib group versus 13 of 63 (20.6%) in the lapatinib group; diarrhea in 10 patients (15.4%) versus three patients (4.8%), respectively; and decreased neutrophil count in six patients (9.2%) versus two patients (3.2%), respectively. CONCLUSION In women with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines, and/or trastuzumab, pyrotinib plus capecitabine yielded statistically significant better overall response rate and progression-free survival than lapatinib plus capecitabine in this randomized phase II trial.

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A phase II study of pemetrexed and doxorubicin in patients with advanced or metastatic breast cancer (MBC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.1047 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 1047-1047

Author(s):

M. Blasinska-Morawiec ◽

M. Martin ◽

F. Salas ◽

S. Falcon ◽

J. Rolski ◽

...

Keyword(s):

Breast Cancer ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Single Agent ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Overall Response

1047 Background: Pemetrexed has a single-agent activity in MBC while doxorubicin is an established agent in breast cancer chemotherapy. This phase II study investigated the combination in patients with advanced or MBC who had not been previously treated with anthracyclines. Primary objective was to evaluate the overall response rate. Methods: Patients received pemetrexed 500 mg/m2 (10-min intravenous infusion) followed by doxorubicin 50 mg/m2 on day 1 of six 21-day cycles. Additional cycles were permitted based upon: absence of progressive disease, adequate cardiac function, and a maximum cumulative limit of doxorubicin 450 mg/m2. Routine folic acid and vitamin B12 supplementation was given to all patients. Results: A total of 79 women with advanced or MBC were enrolled at 15 centers in 7 countries. Major racial groups were Caucasians (50.6%) and Hispanics (24.1%). Median age was 55 years (range, 26–79) and most (91.1%) had performance status of 0 or 1. Patients had either metastatic (72.2 %) or locally advanced disease (27.9%). Sixteen (20.3%) patients had received prior adjuvant chemotherapy. A median of 6 cycles (range, 1–9) was delivered. During the 438 cycles, no doses were omitted, and 7 doses were reduced (3 for pemetrexed, 4 for doxorubicin). A total of 129 doses (29.5%) were delayed, primarily due to scheduling conflicts (84 doses) and neutropenia (19 doses). The relative dose intensity for both drugs was 93%. Overall response rate was 60.8% (95% CI, 49.1–71.6) with complete response in 8 patients (10.1%), partial response in 40 patients (50.6%), and stable disease in 20 patients (25.3%). Maximum CTC grade 3 and 4 toxicities observed in >5% patients were neutropenia (19 patients, 24.1%), leukopenia (8 patients, 10.1%), and vomiting (5 patients, 6.3%). Five deaths occurred during study treatment, 2 of which had causes (diarrhea, pneumonia) possibly related to the study drugs. One patient had resting left ventricular ejection fraction decreased to <50% after 6 cycles and did not receive further treatment. Conclusions: The combination of pemetrexed and doxorubicin was well tolerated and had promising response in patients with advanced or MBC. Survival and time-to-event results are forthcoming. No significant financial relationships to disclose.

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Gemcitabine, paclitaxel, and doxorubicin for patients (pts) with urothelial carcinoma (UC) and renal insufficiency: Preliminary results of a multicenter phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.246 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 246-246 ◽

Cited By ~ 3

Author(s):

L. C. Pagliaro ◽

M. Munsell ◽

D. Harris ◽

R. L. Carolla ◽

A. O. Siefker-Radtke

Keyword(s):

Renal Insufficiency ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Locally Advanced ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Overall Response

246 Background: The role of cisplatin-based chemotherapy for the treatment of locally advanced or metastatic UC is well established. Pts with impaired renal function cannot receive cisplatin, however, and substitution with carboplatin yielded inferior results. We initiated a phase II study to assess the efficacy of gemcitabine, paclitaxel, and doxorubicin (GTA) treatment for UC in pts with renal insufficiency. Methods: Eligible pts had metastatic or unresectable UC of bladder, urethra, or upper tract, no prior chemotherapy, glomerular filtration rate < 60 ml/min, ECOG performance status ≤ 2, left ventricular ejection fraction > 40%, and adequate hematopoietic and hepatic function. Pts were excluded if they had brain metastasis, peripheral neuropathy ≥ grade 2, significant heart disease within 6 months of enrollment, or required hemodialysis. Outpatient treatment consisted of 900 mg/m2 gemcitabine, 135 mg/m2 paclitaxel, and 40 mg/m2 doxorubicin on day 1 every 2 weeks. Pegfilgrastim 6 mg sc was given immediately after GTA on day 1, or on day 2 if requested by the pt. Tumor evaluation was repeated every 3 cycles (6 weeks); treatment duration was limited to 9 cycles. A Simon 2-stage design was chosen to detect a target overall response rate of 40% and to reject a response rate of 25% or less. Results: Twenty-five pts enrolled and 21 could be assessed for response. Median (range) age was 72.8 years (53.4, 89.3) and 8 pts (32.0%) were female. RECIST responses occurred in 12 pts (4 complete; 8 partial), for an overall response rate of 57.1% (95% CI 34.0-78.2). Notable grade 3 and 4 toxicities were anemia (9 pts), thrombocytopenia (3 pts), neutropenia (2 pts), dyspnea (1 pt), mucositis (1 pt), and sepsis (1 pt). No adverse events were attributed to same-day pegfilgrastim and there were no treatment-related deaths. Eleven pts (44.0%) died of progressive disease; the median (range) follow-up time for 14 surviving pts was 5.5 months (2.3, 17.5). Conclusions: GTA has been well-tolerated in the setting of renal insufficiency, with an observed response rate in advanced UC exceeding the targeted response. The study will continue to a maximum of 72 pts. [Table: see text]

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Prospective randomized phase II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4035 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4035-4035 ◽

Cited By ~ 4

Author(s):

Heike Richly ◽

Luise Maute ◽

Gerhard Heil ◽

Jörn Rüssel ◽

Elke Jäger ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Trial ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Time To Progression ◽

Overall Response ◽

Randomized Phase Ii

4035 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours, but PDAC is still associated with a poor prognosis in advanced disease with an overall 5-year survival of only about 15%. Therefore there is a need for new treatment strategies. To improve the standard therapy with gemcitabine we initiated a prospective randomized phase-II trial with gemcitabine (GEM) vs. gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. Methods: Patients (N=113) with locally advanced or metastatic PDAC were prospectively randomized to receive gemcitabine alone (GEM) at a dosage of 1000 mg/m² day 1, 8, 15 q28 or to a combination of gemcitabine and sunitinib (SUNGEM) at a dosage of GEM 1000 mg/m² d1+8 and sunitinib 50mg p.o. d1-14, qd21 (based on a phase-I trial). The primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), time to progression (TTP), overall response rate (ORR) and toxicity. Results: The confirmatory analysis of PFS was based on the ITT population (N=106). The median PFS was 13.3 weeks (95 %-Cl: 10.4-18.1 weeks) in the GEM group and 11.6 weeks in the SUNGEM arm (95 %-Cl: 7.0-18.0 weeks) (one-sided logrank: p=0.74). The 6-month PFS rate was 26.8 % (95 %-Cl: 15.4-39.5 %) in GEM arm and 25.0 % in SUNGEM arm (95 %-Cl: 14.0-37.8 %). The overall response rate was 6.1 % (95 %-Cl: 0.7-20.2 %) in the GEM arm and was a slightly but not significantly higher for the SUNGEM arm with 7.1% (95%-Cl: 0.9 – 23.5%).The median time to progression (TTP) was 14.0 weeks (95 %-Cl: 12.4-22.3 weeks) for the GEM arm and 18.0 weeks (95 %-Cl: 11.3-19.3 weeks) for the SUNGEM arm (two-sided logrank: p=0.60). The median OS was 30.4 weeks (95 %-Cl: 18.1-37.6 weeks) for the SUNGEM and 36.7 weeks (95 %-Cl: 20.6-49.0 weeks) for the GEM arm (two-sided logrank: p=0.44). With regard to toxicities, at least one AE of grade 3 or 4 was reported in 78.8% in the SUNGEM arm and 72.2% in the GEM arm. Conclusions: The combination of gemcitabine plus sunitinib (SUNGEM) did not improve the PFS in locally advanced or metastatic PDAC compared to gemcitabine alone. Clinical trial information: NCT00673504.

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