Phase II trial of the oral mTOR inhibitor everolimus (RAD001) for patients with relapsed or refractory lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8055-8055 ◽  
Author(s):  
P. B. Johnston ◽  
S. M. Ansell ◽  
J. P. Colgan ◽  
T. M. Habermann ◽  
D. J. Inwards ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mtor Inhibitor ◽  
Mtor Inhibitors ◽  
Cell Transplant ◽  
Mtor Inhibition ◽  
Treatment Regimens ◽  
Common Grade ◽  
Group 3 ◽  
Grade 3 ◽  
Group 1

8055 Background: mTOR inhibition with intravenous temsirolimus (Wyeth Pharmaceuticals) has been associated with responses in mantle cell lymphoma (J Clin Oncol 23;5347, 2005) as well as other lymphomas (Blood 108 (11) 2483; 2006). This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in three simultaneous two-stage phase II lymphoma studies - aggressive (group 1), indolent (group 2), or uncommon (group 3). The goals were to learn the toxicity profile and to assess the anti-tumor response. Planned interim analysis for groups 1 and 3 have been completed and are the subject of this report. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. 12 pts were enrolled in stage 1 of each study. At least 1 success in 12 is required to proceed to stage 2, to a total of 37 pts. Overall, the treatment will be considered promising if 4 or more successes are observed in all 37 pts in each group. Results: The median age of the 12 pts in group 1 was 68.5 yrs (range: 53–80), with a median of 3 (range, 1–15) prior therapies. Four pts had a prior stem cell transplant (SCT). Pts completed a median of 7 (range, 1–12) cycles of therapy. 6 confirmed responses have been achieved (1 CR, 5 PR), meeting the overall criteria for promising results in this study. Common grade 3 adverse events (AEs) include thrombocytopenia (3 pts) and anemia (2 pts). For group 3, the median age was 49 yrs (range, 27–78), with a median of 7 (range, 1–13) prior therapies and 6 pts had a prior SCT. Pts have completed a median of 6.5 cycles (range, 1–11). 5 confirmed responses have been achieved (5 PR), meeting the criteria for this regimen to be considered promising. Of these 5 patients, 3 had HD, 1 T-cell NHL, and 1 had macroglobulinemia. Common grade 3 AEs include anemia (3 pts) and thrombocytopenia (2 pts). No grade 4 AEs were reported. Conclusions: Oral everolimus has activity in a spectrum of lymphomas with acceptable toxicity. The responses observed in both group 1 and group 3 met the criteria to continue accrual. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens. No significant financial relationships to disclose.

mTOR Inhibition for Relapsed or Refractory Hodgkin Lymphoma: Promising Single Agent Activity with Everolimus (RAD001).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Patrick B. Johnston ◽  
Steven M. Ansell ◽  
Joseph P. Colgan ◽  
Thomas M. Habermann ◽  
David J. Inwards ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Mtor Inhibitors ◽  
Cell Transplant ◽  
Mtor Inhibition ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Background: mTOR inhibition has produced responses in mantle cell lymphoma as well as other non-Hodgkin lymphomas. This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in simultaneous two-stage phase II lymphoma studies, including one arm involving Hodgkin lymphoma. The goals were to learn the toxicity profile and to assess the anti-tumor response. A total of 17 patients with Hodgkin lymphoma were enrolled in the uncommon arm at completion of enrollment. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12, with a possible extension in responders) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. Results: The median age of the 17 pts with Hodgkin lymphoma was 37 yrs (range: 27–68), with a median of 6 (range, 4–14) prior therapies. Fourteen pts (82.4%) had a prior stem cell transplant (SCT). Pts completed a median of 6 (range, 1–13) cycles of therapy. Fifteen of 17 patients were evaluable for response as of this analysis. The overall response rate was 47% (7/15), all partial responses. Ten patients are continuing on study while 6 have gone off due to disease progression and 1 due to other reasons. Common grade 3 adverse events (AEs) include thrombocytopenia (5 pts), anemia (5 pts) and alkaline phosphatase elevation (1 pts). 1 patient was reported to have grade 4 neutropenia. Conclusions: Oral everolimus has promising activity with acceptable toxicity in Hodgkin lymphoma. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens for Hodgkin lymphoma.

Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 435-435
Author(s):  
Andrew J. Armstrong ◽  
James D. Turnbull ◽  
Julien Cobert ◽  
Tracy Jaffe ◽  
Michael Roger Harrison ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Mtor Inhibition ◽  
Grade 3

435 Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting. Methods: We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized. Results: 21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2). Conclusions: Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.

Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle-cell lymphoma: Results from an international study (NHL-003)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8569-8569 ◽  
Author(s):  
C. B. Reeder ◽  
T. E. Witzig ◽  
P. L. Zinzani ◽  
J. M. Vose ◽  
R. Buckstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Single Agent ◽  
International Study ◽  
Response Assessment ◽  
Cell Transplant ◽  
Mantle Cell ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3

8569 Introduction: Relapsed or refractory MCL patients demonstrated a promising overall response rate (ORR) of 53% with a median duration of response (DR) of 13.7 months to single-agent lenalidomide when analyzed as a subset in a recent a phase II study (NHL-002). A supporting international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed or refractory aggressive NHL. In this report, we analyze the current results from the MCL patients enrolled in this trial. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Patients continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression. Results: Fifty-four MCL patients were enrolled and were evaluable for response assessment. Median age was 69 years (33–82) and 40 patients (74%) were male. Median time from diagnosis was 3.2 years (0.4–10.4), patients had received a median of 3 prior treatments (1–8), 17 of the patients (32%) had received prior bortezomib therapy (MCL-bortezomib), and 14 (26%) had received a prior stem cell transplant (MCL-stem cell). Response rates are shown in the Table. The most common grade 3 or 4 adverse events were neutropenia (43%), thrombocytopenia (22%) and anemia (11%). Conclusions: This is the second study to demonstrate that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects. [Table: see text] [Table: see text]

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Once Daily ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

Romidepsin (HDACi) plus cisplatin and nivolumab triplet combination in patients with metastatic triple negative breast cancer (mTNBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1076-1076
Author(s):  
Priyanka Sharma ◽  
Vandana G Abramson ◽  
Anne O'Dea ◽  
Lauren Elizabeth Nye ◽  
Ingrid A. Mayer ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Phase I ◽  
Phase Ii ◽  
Histone Deacetylase Inhibitors ◽  
Objective Response ◽  
Common Grade ◽  
Group 2 ◽  
Grade 3 ◽  
Recognition And Response ◽  
Minimax Design

1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m2, D2, 9) plus cisplatin 75mg/m2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m2 D2,9 + cisplatin 75mg/m2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]

scholarly journals Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

2013 ◽  
Vol 31 (5) ◽  
pp. 584-591 ◽  
Author(s):  
Xavier C. Badoux ◽  
Michael J. Keating ◽  
Sijin Wen ◽  
William G. Wierda ◽  
Susan M. O'Brien ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Salvage Therapy ◽  
Phase Ii Study ◽  
Venous Thromboembolic Event ◽  
Febrile Episode ◽  
Lymphocytic Leukemia ◽  
Common Grade ◽  
Venous Thromboembolic ◽  
Grade 3

Purpose Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL. Patients and Methods Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m2 intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically. Results The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study. Conclusion The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation.

Phase II Trial of the mTOR Inhibitor RAD001 in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: The Dana Farber Cancer Institute Experience.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1011-1011
Author(s):  
Irene M. Ghobrial ◽  
Stacey Chuma ◽  
Amy Sam ◽  
Renee Leduc ◽  
Marybeth Nelson ◽  
...  
Keyword(s):  
Phase Ii ◽  
Overall Response Rate ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Significant Activity ◽  
Waldenström Macroglobulinemia ◽  
Overall Response ◽  
Dana Farber Cancer Institute ◽  
Waldenstrom Macroglobulinemia ◽  
Grade 3

Abstract INTRODUCTION: Previous studies have demonstrated the clinical activity of the mTOR inhibitor RAD001 in low- grade lymphomas. Our preclinical studies demonstrated activity of mTOR inhibitors in Waldenstrom Macroglobulinemia (WM) cell lines and patient samples. This phase II study aimed to determine safety and activity of the oral mTOR inhibitor RAD001 (Novartis Pharmaceutical, MA) in patients with relapsed or refractory WM. METHODS: Patients who had at least one previous therapy for WM, and who had symptomatic relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received daily RAD001 at 10 mg. A cycle was considered 28 days. Patients were allowed to stay on therapy until progression of disease or excessive toxicity. This study was conducted in a collaborative effort between Dana Farber Cancer Institute (DFCI) and Mayo Clinic College of Medicine. Here, we report the data on the patients accrued at DFCI. RESULTS: 19 pts (15 men and 4 women) have been treated to date. All patients had symptomatic disease and required therapy. The median number of lines of prior treatment was 3 (range 1 – 5) including included rituximab, nucleoside analogues (fludarabine or 2-CDA), combination chemotherapy (e.g. CHOP, CVP), chloramucil, and bortezomib. The median IgM at baseline was 3330 mg/dL (range 1010– 7410). The median follow on RAD001 was 8 months (range 3 – 22 months). Eighteen pts are currently evaluable for response. Best responses to RAD001 after 2 cycles using IgM monoclonal protein were as follows: partial remission in 8 (44%), minimal response in 5 (28%). Progressive disease occurred in 4 (22%) and stable disease occurred in 1 (6%). The overall response rate (PR+MR) was 72%. The median duration of response has not been reached (3–22+ months). Patients tolerated therapy well without significant toxicities. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 1 patient, grade 3 pneumonia in 1 patient, grade 3 hyperglycemia in 1 patient and grade 3 mucositis in 1 patient. Other adverse events of grade 2 or lower included nail cracking, mucositis, diarrhea, and fatigue. Attributable toxicities otherwise proved manageable with appropriate supportive care, and RAD001 was generally well tolerated. One patient enrolled on the study withdrew consent and changed to hospice care within 3 weeks of therapy, and passed away due to disease progression. CONCLUSIONS: The use of the oral RAD001 single agent RAD001 in patients with relapsed or refractory WM was welltolerated and demonstrated significant activity achieving an overall response rate in 72% of patients. Future studies of combination of this agent with rituximab and bortezomib are currently being planned.

Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 445-445 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Craig B. Reeder ◽  
Edward N. Libby ◽  
Luciano J. Costa ◽  
P. Leif Bergsagel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Initial Phase ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

Final Results of ECOG1100: A phase I/II study of combined blockade of the ErbB receptor network in patients with HER2- overexpressing metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1033-1033 ◽  
Author(s):  
S. L. Moulder ◽  
A. O’Neill ◽  
C. Arteaga ◽  
M. Pins ◽  
J. Sparano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Cell Lines ◽  
Dose Level ◽  
Phase Ii ◽  
Prior Exposure ◽  
Prior Chemotherapy ◽  
Group 2 ◽  
Grade 3 ◽  
Group 1

1033 Background: Activation of EGF receptor has been associated with resistance to trastuzumab in breast cancer cell lines. EGFR tyrosine kinase inhibitors inhibit HER2 phosphorylation and synergize with trastuzumab in HER2+ cell lines that co-express EGFR. Methods: Pts with MBC and HER2 overexpression by immunohistochemistry (3+) and/or HER2 gene-amplification by FISH, 0–2 prior chemotherapy regimens for met disease, LVEF 50%, and no prior trastuzumab were treated with trastuzumab 2 mg/kg/wk and gefitinib 250- 500 mg/day until disease progression, unacceptable toxicity or withdrawal of consent. The phase I portion of the trial used a 3+3 design to determine MTD. In the phase II portion of the trial, patients were stratified based upon prior chemotherapy exposure (Group 1= no prior exposure to chemotherapy, Group 2= prior exposure to 1–2 chemotherapy regimens). Response measured using RECIST criteria. The primary endpoint was to increase proportion progression free from 50 to 65% at 6 months in Group 1 and from 50 to 70% at 3 months in Group 2. Results: Phase I: DLT (Grade 3 diarrhea) occurred in 2/3 patients treated at the 500 mg/day dose level of gefitinib in combination with weekly trastuzumab. 0/3 patients treated at the 250 mg/day dose level experienced DLT. This was considered MTD and was the dose selected for the Phase II portion of the trial. Phase II: 36 eligible pts were enrolled. Most patients were ECOG PS of 0 and had visceral organ involvement. Of the patients enrolled in Group 1, one pt achieved a CR, one PR and 7 had SD (≥ 24 weeks). Median time to progression (TTP) was 2.9 months (95% CI, 2.5–4). In Group 2 no responses were observed with a median TTP of 2.5 months (95% CI, 1.5- 2.7). Most common severe toxicities were rash (grade 3, 14%) and diarrhea (grade 3, 30%). No grade 3 cardiac toxicity was encountered. Conclusions: Trastuzumab in combination with gefitinib at doses of 250 mg/day demonstrated an acceptable toxicity profile; however, during planned interim analysis, the TTP did not meet predetermined statistical endpoints required for study continuation. These results do not support the further use of this combination and have implications for other trials using trastuzumab and EGFR TK inhibitors simultaneously. [Table: see text]

International randomized phase III study of capecitabine (Cap), bevacizumab (Bev), and mitomycin C (MMC) in first-line metastatic colorectal cancer (mCRC): Final results of the AGITG MAX trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4023-4023
Author(s):  
N. C. Tebbutt ◽  
V. Gebski ◽  
K. Wilson ◽  
M. Cummins ◽  
Y. Chua ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Phase Iii ◽  
First Line ◽  
Treatment Regimens ◽  
Intention To Treat ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Low Toxicity ◽  
Grade 3

4023 Background: The addition of Bev to oxaliplatin or irinotecan based doublet chemotherapy has shown benefit in mCRC. Cap± MMC are alternate chemotherapy regimens suitable for patients (pts) who are either unfit for or who do not require initial oxaliplatin/irinotecan. This phase III study compared Cap with Cap Bev and Cap Bev MMC. The aim was to develop a low toxicity regimen suitable for a broad population of pts with mCRC. Methods: Previously untreated pts with unresectable mCRC considered suitable for Cap monotherapy were randomised to arm A Cap (Cap 2000mg/m2/d or 2500mg/m2 d1–14 q21d), arm B Cap Bev (Bev 7.5mg/kg q3w) or arm C Cap Bev MMC (MMC 7mg/m2 q6w). Primary endpoint: PFS, secondary endpoints: RR, toxicity, OS, QoL . Randomisation was stratified by age, PS, centre and Cap dose. Response was assessed every 6w. The study was designed to detect an increase in the median PFS from 5.5m (arm A) to 8m (arm B or C) at p<0.025 with 80% power. Results: A total of 471 pts were randomised from July 2005-June 2007. Outcomes were evaluated on an intention to treat basis and included 15 ineligible pts. Baseline demographics were well balanced between arms with median age 67y (range 31–86y). Toxicity was reported: ASCO 2008 abstr 4029. The most common grade 3/4 toxicities were PPE (16%, 26%, 28%) and diarrhoea (11%, 17%, 16%) for arms (A,B,C). However, adjusted rates per cycle were similar as arms B & C received more cycles of Cap (A8.3, B10.8, C10.5). Other toxicity rates were generally <10%. The study achieved its primary endpoint with a highly significant improvement in PFS for arms B & C. RR and OS are summarized ( Table ). Conclusions: All treatment regimens were well tolerated in a relatively elderly patient cohort. The addition of Bev±MMC to Cap significantly improved PFS without significant additional toxicity. OS was similar for all arms. Cap Bev±MMC is an active, low toxicity regimen that may be considered as a treatment option for pts with mCRC. [Table: see text] [Table: see text]

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