Safety and Efficacy of Bortezomib (Velcade) for the Treatment of Relapsed Classical Hodgkin’s Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2638-2638 ◽  
Author(s):  
Anas Younes ◽  
Barbara Pro ◽  
Jorge Romaguera ◽  
Nam Dang
Keyword(s):  
Platelet Count ◽  
Treatment Response ◽  
Cell Lines ◽  
Single Agent ◽  
Prior Treatment ◽  
Clinical Activity ◽  
Treatment Regimens ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3

Abstract The proteasome inhibitor bortezomib has demonstrated clinical activity in patients with multiple myeloma and different types of non-Hodgkin’s lymphoma. Its activity in patients with Hodgkin’s disease (HD) is unknown. We have recently reported that bortezomib had a significant activity against HD-derived cell lines in vitro (Zheng et al, Clin Cancer Res 2004), In four HD-derived cell lines, bortezomib induced cell cycle arrest and apoptosis in a dose and time dependent manner, irrespective of IkB gene mutations. Furthermore, bortezomib enhanced the activity of chemotherapy and TRAIL in these cell lines. Based on these encouraging preclinical results, we initiated a pilot study of single agent bortezomib in patients with relapsed classical HD. Eligibility: (1) relapsed classical HD with a measurable disease (2) At least 2 prior treatment regimens; (3) Patients with prior autologous stem cell transplant (ASCT) are eligible (4) platelet counts > 50,000/uL and ANC counts of > 1,500/uL (5) no HIV infection, or CNS involvement with HD, (6) bilirubin < 2mg/dL and creatinine < 2.5 mg/dL. Patients were treated with 1.3 mg/m2 bortezomib intravenously on days 1, 4, 8, 11 of 21-day cycles in an outpatient setting. Treatment was delayed if the Platelet counts on the day of therapy was < 30,000/mm3. After 3 cycles of bortezomib therapy patients were evaluated for treatment response. If there was no evidence of disease progression after 3 cycles of therapy, patients were allowed to receive a maximum of 6 cycles. To date, 11 patients are enrolled (6 men and 5 women), with a median age of 28 years (range: 21 to 68 years). All patients were heavily pretreated, with a median number of 5 prior treatment regimens (range 2 to 7 regimens), and all patients have previously failed ASCT. The median pretreatment platelet count was 126, 000/uL (range 66,000 – 339,000/uL). All patients received at least one dose of bortezomib and are evaluable for treatment toxicity. Treatment was reasonably well tolerated with the majority of toxic effects were of grade 1 and 2. Two patients had grade 3 dyspnea and one patient had grade 3 neutropenic fever. Progressive thrombocytopenia was the most common hematologic toxicity, which frequently caused delays in therapy. Nadir platelet count below 30,000/uL was observed in 3/11 patients during the first cycle, in 4/10 during the second cycle, and in 4/6 during the third cycle. Nadir ANC below 1000/uL was observed in 1/11 pts during cycle 1, in 2/10 during cycle 2, and in 1/6 during cycle 3. Eight patients completed the planned 3 cycles and are evaluable for treatment response. One patient achieved a partial remission and one had a minimal response. Our preliminary data demonstrate encouraging clinical activity of bortezomib in this heavily pretreated patients with classical HD, and warrants studying bortezomib in less heavily pretreated patients either as a single agent or in combination with chemotherapy.

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.

Phase II Trial of Combination of the Histone Deacetylase Inhibitor ITF2357 and Meclorethamine Demonstrates Clinical Activity and Safety in Heavily Pretreated Patients with Relapsed/Refractory Hodgkin Lymphoma (HL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2586-2586 ◽  
Author(s):  
Carmelo Carlo-Stella ◽  
Anna Guidetti ◽  
Simonetta Viviani ◽  
Valeria Bonfante ◽  
Pinuccia Valagussa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Response To Therapy ◽  
Prior Treatment ◽  
Study Entry ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Heavily Pretreated ◽  
Ongoing Phase

Abstract Introduction: HL patients with refractory disease or relapsing after autologous stem cell transplantation (SCT) have very poor prognosis with currently available salvage chemotherapy. ITF2357 (Italfarmaco S.p.A., Milano, Italy) is an orally bioavailable hydroxamate inhibitor of class I and II histone deacetylases (HDACs) with preclinical and clinical activity as single agent in hematopoietic cancers. Our preclinical data demonstrating a synergistic activity of ITF2357 with the alkylating agent Meclorethamine in HL cell lines, established the rationale for this currently ongoing phase II study aimed to determine activity and safety of the sequential ITF2357 and Meclorethamine treatment. Methods: Patients with relapsed/refractory HL who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled. Eligibility criteria included prior treatment with autologous and/or allogeneic SCT, prior treatment with single agent Meclorethamine, at least one target lesion ≥2 cm, ECOG performance status of 0–1, and platelet ≥75,000/μL. ITF2357 (50 mg QID, per os, days 1–3) followed by Meclorethamine (6 mg/sqm, intravenously, day 4) was dosed in 3-week cycles until disease progression or appearance of clinical significant toxicity, but for a maximum of 12 cycles. Tumor responses were determined after cycles 2, 6, 9 and 12 by computed tomography (CT) and positron emission tomography (PET) scan. Serum levels of thymus- and activation-regulated chemokine (TARC) were assessed by ELISA prior to each cycle of therapy. Results: To date, 19 patients have been enrolled (16 males and 3 females; median age, 33 years; range, 21–61 years), including 8 patients enrolled in a preliminary compassionate use trial, and 11 patients of a planned 23 enrolled in this ongoing phase II trial. Prior to study entry, patients received a median of 5 (range 2–7) lines of treatment with autologous SCT performed in 15 (79%) and an additional allogeneic SCT in 5 (26%) patients. At study entry, 6 patients had relapsed and 13 refractory HL. Seventeen of 19 patients received a median of 3 cycles (range, 1–10) of ITF2357/Meclorethamine and are evaluable for response by CT and PET scans. Best response to therapy included 2 (12%) complete remissions (CR) and 3 (18%) partial remissions (PR), for an overall response rate (ORR) of 30%. In addition, 5 (29%) patients had stable disease (SD) with 4 (23%) patients achieving SD for ≥4 months, while 7 (41%) patients progressed. After the first cycle of therapy, serum TARC levels were decreased by 70±16% (mean±SEM, P ≤0.05) in 5 patients who achieved major clinical responses (PR+CR), and by 16±14% (P = ns) in patients who achieved SD. Overall, therapy was well tolerated without significant adverse events, and no patient required dose reductions for management of toxicities. The most common drug-related non-hematological toxicities were grade 1–2 nausea (12/17) and fatigue (14/17). Four patients experienced infections [pneumonia (n = 1), oral herpes simplex (n = 2), oral candidiasis (n = 1)]. No prolongation of QT/QTc interval has been detected over 70 therapy cycles. Hematological toxicities included grade 1–2 anemia (13/17), neutropenia (7/17), and thrombocytopenia (12/17). Grade 3–4 neutropenia and thrombocytopenia were observed in 7 and 8 patients, respectively. RBC and platelet transfusions were required by 4 and 5 patients, respectively. Conclusions: Preliminary results from this ongoing trial suggest that ITF2357, in combination with Meclorethamine, demonstrates significant anti-tumor activity in heavily pretreated relapsed/refractory HL and is well tolerated. Preliminary data also suggest that early decrease in serum TARC levels may predict response to therapy.

Nanoparticle albumin-bound (Nab) paclitaxel (P) in combination with bevacizumab (B) with and without gemcitabine (G): Early experience at the Braman Family Breast Cancer Institute

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10748-10748
Author(s):  
C. F. Lobo ◽  
G. Lopes ◽  
O. Silva ◽  
S. Gluck
Keyword(s):  
Breast Cancer ◽  
Single Agent ◽  
Metastatic Breast ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Hemorrhagic Complication ◽  
Breast Cancer Patients ◽  
Hormone Receptor Positive ◽  
Heavily Pretreated ◽  
Grade 3

10748 Background: Nab-P improves outcomes when compared against single agent cremophor-based P, as does the addition of bevacizumab or gemcitabine to the same agent. There are no available data regarding combinations of Nab-P with B and/or G. Ongoing investigational efforts are evaluating various doublets with these agents, but, to the best of our knowledge, not all 3 of them in the same regimen. All drugs are currently FDA-approved in the treatment of breast cancer. Methods: Review of single-institution experience, evaluating safety and preliminary evidence of activity with the use of Nab-P and B with and without G in heavily pretreated her2neu negative metastatic breast cancer patients. Assessment of response was undertaken by the investigators independently of treating physician. RECIST criteria were used. Three patients received Nab-P and B at the following doses: Nab-P 100 mg/m2, B 10 mg/kg every 2 weeks, and 2 patients received all 3 drugs as follows: Nab-P 100 mg/m2, G 1,000 mg/m2, B 10 mg/kg every 2 weeks. Results: Five women have been evaluated. Median age was 51 (range 34–69). Two patients had hormone-receptor positive disease and 3 had ER/PR/Her2neu-negative cancer. Prior number of regimens was 3 (range 2–7). Four patients had been treated with a taxane. One received both paclitaxel and docetaxel, and 3 docetaxel only. A median of 5 cycles have been administered (range 3–9). First-cycle grade 3/4 toxicity was seen in only one patient who had a baseline grade 2 thrombocytopenia that progressed to grade 3. The thrombocytopenia resolved without requiring transfusion and without any hemorrhagic complication. Another patient developed grade 2 peripheral neuropathy. Two patients are not yet assessable for response. At time of first evaluation 1 patient had progressive disease (Nab-P, B; 7 prior lines of treatment), one had stable disease (Nab-P, B, G; 3 prior lines of therapy, including docetaxel), and 1 had a partial response (Nab-P, B, G; 2 prior therapies, including docetaxel). Conclusions: These very preliminary data suggest that Nab-P in combination with B with and without G is a safe regimen and formal Phase I/II trials are being developed to confirm its clinical activity. [Table: see text]

Results of a phase Ib trial evaluating the safety and clinical activity of sapanisertib (TAK 228) in combination with serabelisib (TAK 117) and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3604-3604
Author(s):  
Casey B. Williams ◽  
Kirstin Anne Williams ◽  
Amy K. Krie ◽  
Pradip De ◽  
Nandini Dey ◽  
...  
Keyword(s):  
Clinical Results ◽  
Clinical Activity ◽  
Open Label ◽  
Effective Treatment Option ◽  
Taxane Resistance ◽  
Phase 2 Study ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Dose Reductions

3604 Background: The link between taxane resistance and activation of PI3K/AKT/mTOR signaling suggests that by inhibiting this pathway in combination with anti-microtubule agents like paclitaxel may improve treatment outcomes in many malignancies. To investigate this further we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial to determine the safety, efficacy, and RP2D. Methods: Open label, cohort study using a traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts. A dose expansion of cohort 4, the recommended RP2D, is planned for February 2020. Results: Enrollment to the DLT evaluation has been completed and the clinical results are summarized in Table. Sixteen patients have been enrolled; a majority were heavily pretreated and resistant to paclitaxel. Overall, the combination was safe and tolerable. One DLT occurred due to renal dysfunction in cohort 5. 360 adverse events have been reported, but only 28 (8%) grade 3 or 4 events. The most common events were leukopenia and non-febrile neutropenia. Two patients required dose reductions as a result of pneumonitis. The ORR is currently 46% in 13 evaluable patients. CBR is 69% and PFS is currently at 10 months. Two patients achieved a CR and three patients remain on treatment. Conclusions: The combination proved to be well tolerated in the doses and schedules used in cohorts 1-4 and exhibited very promising clinical activity in heavily pretreated patients. This regimen could prove to be a highly effective treatment option and a phase 2 study is warranted at the RP2D. Clinical trial information: NCT03154294 . [Table: see text]

Motexafin Gadolinium (MGd) Has Clinical Activity in Relapsed/Refractory Low Grade Lymphomas (LG) and Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4758-4758
Author(s):  
Brad S. Kahl ◽  
Ranjana Advani ◽  
Neil Kay ◽  
Izidore S. Lossos ◽  
Andrew Evens ◽  
...  
Keyword(s):  
Adverse Events ◽  
Single Agent ◽  
Marrow Transplant ◽  
Lymphocytic Leukemia ◽  
Prior Treatment ◽  
Cancer Drug ◽  
Clinical Activity ◽  
Low Grade ◽  
Motexafin Gadolinium ◽  
Treatment Regimens

Motexafin gadolinium (MGd, Xcytrin®) is a novel anti-cancer drug that selectively concentrates in cancer cells and disrupts redox dependent pathways by targeting oxidative stress related proteins such as thioredoxin reductase and metallothioneins. MGd has been shown to generate reactive oxygen species and induce apoptosis in tumor cells. We initiated a study to evaluate the safety and efficacy of MGd in two B-cell malignancies, relapsed/refractory LG and relapsed/refractory CLL or CLL/small lymphocytic lymphoma (CLL/SLL). MGd was given intravenously (IV) at 6mg/kg/day for 3 days q 2 weeks for LG and 5mg/kg/day for 10 days q 3 weeks for CLL/SLL. Ten patients (pts) with LG (2 grade 1, 5 grade 2, 1 grade 3 follicular, 2 marginal zone), 2 pts with CLL/SLL and 1 pt with CLL have been enrolled. Median age was 64.5 yrs (range 44–77), median prior treatment regimens was 3.5 (range 1–6) and median time from diagnosis to treatment was 52 mo. Many LG pts had failed prior aggressive treatment regimens including: CHOP (4), ICE (1), HyperCVAD(1), auto-bone marrow transplant (1); all failed rituxamab and 6 failed Zevalin. CLL/SLL and CLL pts had failed rituxamab (3), fludarabine (2), and R-CHOP (1). MGd related adverse events included skin and urine discoloration (6 and 4 pts), diarrhea, nausea, vesiculobullous rash, peripheral neuropathy (3 pts each). MGd related ≥gr 3 adverse events included skin rash (3 pts), fatigue, neuropathy, photosensitivity (1 pt each). Importantly, no MGd-related myelosuppression was observed. In 12 evaluable pts, there have been three PRs of 2+, 5+ and 8 months duration (2 follicular, 1 CLL). Two pts had SD (follicular, SLL) one of these had resolution of lymphoma related autoimmune hemolytic anemia. Responses occurred after ≤2 cycles of therapy and were seen in patients after extensive prior treatment (mean 4.3 prior regimens, range 3–7). MGd is a non-myelosuppressive drug with single agent activity in LG and CLL/SLL.

scholarly journals Prolonged Treatment Response to Pembrolizumab in a Patient with Pretreated Metastatic Colon Cancer and Lynch Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Matthew Keating ◽  
Lisa Giscombe ◽  
Toufic Tannous ◽  
Kevan Hartshorn
Keyword(s):  
Colon Cancer ◽  
Treatment Response ◽  
Treatment Duration ◽  
Single Agent ◽  
Prolonged Treatment ◽  
Close Monitoring ◽  
Metastatic Colon Cancer ◽  
Strong Response ◽  
Heavily Pretreated ◽  
Pretreated Patients

Pembrolizumab and other immunotherapies now play a prominent role in the treatment of metastatic colon cancer. Clinicians have achieved significant response rates even in heavily pretreated patients, particularly those with mismatched repair deficiencies. The endpoint of pembrolizumab treatment for patients who enjoy a strong response remains unclear. Herein, we present the case of a 33-year-old man with pretreated metastatic colon cancer and a prolonged treatment response of over three years to single-agent pembrolizumab even after treatment discontinuation in July 2018. Prior to pembrolizumab, he was found to have lung and liver metastases despite multiple lines of chemotherapy. With pembrolizumab, there was a persistent downtrend in CEA level and uptrend in weight. After nearly three years of pembrolizumab treatment from October 2015 through July 2018, PET scan showed no FDG-avid disease, and further treatment was placed on hold. He remains under surveillance, with CT scan in February 2019 again showing no evidence of local or metastatic disease. In patients whose treatment duration and disease course are not defined by toxicities/progressive disease but rather by sustained treatment responses, we propose that immunotherapy treatment duration be guided by close monitoring of CEA levels, weight, and clinical exams in addition to traditional imaging.

Sirtuin Inhibition in Combination with Histone Deacetylase (HDAC) Inhibition Is Effective Therapy for Aggressive B-Cell Lymphomas in Both Pre-Clinical and Clinical Studies of Disease.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2725-2725
Author(s):  
Jennifer E Amengual ◽  
Sean Clark-Garvey ◽  
Matko Kalac ◽  
Luigi Scotto ◽  
Enrica Marchi ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Hdac Inhibitors ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3

Abstract Abstract 2725 There is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III HDACs, or sirtuins, are inhibited by agents such as niacinamide. One therapeutic strategy for lymphomas addicted to Bcl6 overexpression is the pharmacologic modification of Bcl6 and p53 using HDAC inhibitors. Here we report on the combination of sirtuin inhibitor, niacinamide (NIA), plus HDAC inhibitors in preclinical models, and a phase Iclinical trial in patients with relapsed or refractory lymphoma. Cytotoxicity was measured in 8 diffuse large B-cell lymphoma (DLBCL) cell lines (4 ABC and 4 GC) with 4 HDAC inhibitors (romidepsin, vorinostat, panobinostat and belinostat) in combination with NIA. Synergy was achieved predominantly in GC vs ABC cell lines, with romidepsin plus NIA having the greatest synergy. Acetylation of Bcl6 was observed in cells treated with HDAC inhibitors, or the combination, compared with control as measured by immunoprecipitation. Cells treated with the combination had increased acetylated-p53, p21 and BLIMP-1 content. In vivo effects of the drug combination were studied in a double transgenic mouse model of aggressive spontaneous B-cell lymphoma (l-myc overexpressing crossed with CD19-tagged mCherry luciferase). These mice express equal basal levels of Bcl6 and p53 as GC cell lines. Mice treated with NIA and romidepsin for 5 hrsachieved increased acetylation of Bcl6 and p53, and accumulation of p21 and BLIMP1. Mice treated with the combination exhibited decreased tumor burden achieving complete responses (CR=30%) compared to single agents and control (CR=0) after 3 weeks of treatment. The combination was well tolerated. Based on this rationale, a phase I clinical trial of vorinostat plus NIA was conducted in patients with relapsed or refractory lymphoid malignancies. Twenty-five patients enrolled between 3/2009 and 3/2011. Median age was 43 (range:25–75), 44% female, and 84% white. This was a group of heavily pretreated patients, median number of therapies was 4; with 16 auto- and 4 allo-transplants. Patients were treated on a 14/21 day cycle. Vorinostatwas given orally as a fixed dose of 400 mg daily. NIA was given orally, daily, in escalating doses from 20–100 mg/kg. A range of 1–18 cycles were given. The most common toxicities included fatigue (84%), nausea (80%), diarrhea (72%), and anorexia (56%). There was a DLT in cohort 4 (vorinostat 400 mg/NIA 80 mg/kg) of grade 3 infection. Two DLTs occurred at dose level 5 (vorinostat 400mg/NIA 100 mg/kg), a grade 4 transaminitis, not otherwise explained; and grade 4 hypotension. These events led to the determination of dose cohort 4 as the MTD. In total, there were 12 different grade 3–4 toxicities including neutropenia, infection, and transaminitis that occurred in 11 patients. There were two deaths that occurred within safety follow-up period in patients who had fulminant disease progression (POD); none of these events were related to the study drugs. Overall this was a very well tolerated treatment regimen and the responses seen were with the weakest HDAC and sirtuininhibitors available given to extremely heavily pretreated patients. The overall response rate was 24%, with 2 CRs and 3 partial responses (PR). CRs were maintained for 13 to 18 weeks. All PRs were in HL patients with 6–10 prior regimens including auto- and allo-transplants, and maintained for 4–13 weeks. Twelve patients achieved stable disease (SD) (57%), 2 of whom achieved near-PR. Of the 7 patients with germinal center derived lymphomas (4 DLBCL + 3 FL), there was 1 CR, 3 SD, and 3 POD. The preclinical and clinical data establish proof-of-principle that the Bcl6: p53 axis may be therapeutic targets, and that acetylation of these transcription factors could potentially serve as biomarkers for activity. Currently we are exploring new, more potent sirtuin inhibitors with second generation HDAC inhibitors, and working to further define mechanism of action. By targeting discrete molecular subtypes of DLBCL it may be possible to increase complete response rates in this challenging disease. Disclosures: Amengual: Acetylon Pharmaceuticals, Inc: Research Funding. Off Label Use: Vorinostat is not FDA approved for the treatment of B-cell and Hodgkins lymphoma. Niacinamide is not FDA approved for the treatment of lymphoma. Neylon:Seattle Genetics, Inc: Consultancy, Speakers Bureau; Allos Therapeutics, Inc: Speakers Bureau. Zain:Allos Therapeutics, Inc: Speakers Bureau; Seattle Genetics, Inc: Speakers Bureau. O'Connor:Allos Therapeutics, Inc: Consultancy; Seattle Genetics, Inc: Membership on an entity's Board of Directors or advisory committees; Millenium Pharaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc: Consultancy.

Phase I study of oral irinotecan and temozolomide in children with relapsed high-risk neuroblastoma: A New Approach to Neuroblastoma Therapy (NANT) Consortium study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9567-9567
Author(s):  
L. M. Wagner ◽  
J. G. Villablanca ◽  
C. F. Stewart ◽  
K. R. Crews ◽  
M. A. O'Shaughnessy ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Stable Disease ◽  
Single Agent ◽  
Previous Treatment ◽  
Maximum Tolerated Dose ◽  
New Approach ◽  
Treatment Regimens ◽  
Heavily Pretreated ◽  
Grade 3

9567 Background: Irinotecan (IRN) and temozolomide (TEM) have single-agent activity and schedule-dependent synergy against neuroblastoma. Because intravenous IRN is costly and inconvenient, especially with protracted scheduling common in pediatric trials, we sought to determine the maximum tolerated dose (MTD) of oral IRN combined with TEM in children with recurrent/resistant high-risk neuroblastoma, using the antibiotic cefixime to reduce IRN-associated diarrhea. Methods: Patients received oral TEM on days 1–5 and oral IRN on days 1–5 and 8–12, with courses repeated every 21 days. Oral cefixime 8 mg/kg (max 400 mg/day) was started on day -5 and continued daily. Results: Fifteen patients (median age 7 years, range 2–22) with a median of 3.5 previous treatment regimens were evaluable for toxicity and have to date received 71 courses (median 2, range 1–19+). Neutropenia and thrombocytopenia were dose-limiting in the first 6 patients, and TEM was reduced from 100 to 75 mg/m2/day for all subsequent patients. IRN was then escalated from 30 to 60 mg/m2/day. First-course grade 3 diarrhea was dose-limiting in 1 of 6 patients treated at the IRN MTD of 60 mg/m2/day. Other toxicities were mild and reversible. No grade 4 therapy-related toxicity occurred in 27 courses administered at the MTD. The median SN-38 lactone AUC at this dose was 72 ng*hr/ml, similar to that reported with protracted intravenous IRN at the single-agent MTD. Of 14 patients evaluable for response, one with measurable nodal disease had a very good partial response through 6 courses. Six additional patients had stable disease for a median of 7.5 courses (range 6–19+). Two patients remain on study after 10 and 19 courses. Conclusions: This combination was well tolerated in heavily-pretreated children with resistant neuroblastoma, and 7 (50%) of 14 evaluable patients had response/stable disease for 6 or more courses in this Phase I trial. This all-oral regimen was feasible and resulted in favorable SN-38-lactone exposures. The dose recommended for further study in this patient population is TEM 75 mg/m2/day plus IRN 60 mg/m2/day when given with cefixime. No significant financial relationships to disclose.

Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer

2005 ◽  
Vol 23 (23) ◽  
pp. 5314-5322 ◽  
Author(s):  
Stephen Chan ◽  
Max E. Scheulen ◽  
Stephen Johnston ◽  
Klaus Mross ◽  
Fatima Cardoso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adverse Events ◽  
Dose Level ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Time To Tumor Progression

Purpose In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. Patients and Methods Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. Results Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). Conclusion In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4519-4519
Author(s):  
Arjun Vasant Balar ◽  
Victor Moreno ◽  
Eric Angevin ◽  
Hui Kong Gan ◽  
Maria Vieito ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Tumor Types

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

Sign in / Sign up

Export Citation Format

Share Document