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.

Identification of predictive markers of clinical activity from a phase II trial of single agent pertuzumab (rhuMab 2C4), a HER dimerization inhibitor, in advanced ovarian cancer (OC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3001-3001 ◽  
Author(s):  
L. Amler ◽  
M. S. Gordon ◽  
A. Strauss ◽  
N. Rabbee ◽  
M. K. Derynck ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Ca 125 ◽  
Clinical Activity ◽  
Fresh Tissue ◽  
Formalin Fixed Paraffin ◽  
Heavily Pretreated ◽  
Dimerization Inhibitor

3001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Interim data from a phase II trial suggested that P has activity in OC, especially in a subset of tumors with activated HER2 (Abstract #5051 ASCO 2005). Methods: 123 pts with relapsed OC were treated with P. Cohort 1 was treated with 840mg followed by 420mg and cohort 2 with 1050mg every 3 weeks. Fresh tissue biopsies were mandated from Cohort 1, and archival formalin fixed paraffin tissue (FFPET ) were obtained from both cohorts. Molecular expression studies from FFPET and fresh tissue were conducted. Results: From final data of 117 evaluable pts, 5 pts had objective partial responses (RR = 4.3%). Eight pts (6.8%) had SD for ≥ 6 months, and an additional 4 pts (3.4%) had SD with CA-125 reduction of ≥50%. Overall rate of activity = 14.5%. Of the 65 fresh tumor biopsies, 28 were evaluable and 8 (28.6%) were positive for phosphorylated HER2 (pHER2) by ELISA. Among pts who had pHER2 status determined, TTP was 20.9 weeks for pHER2+ pts (n=8), compared to 5.8 weeks for pHER2- (n = 20). Data from microarray expression profiling were analyzed with respect to pHER2 status from the same tumors. The expression levels of HER2, EGFR and HER3 in combination with the expression of certain HER ligands may be predictive of pHER2 status. We have extended these analyses to qRT-PCR from macrodissected FFPET of HER receptors and ligands. This was analyzed with respect to clinical outcome. Preliminary analyses of expression data suggest that HER receptors and ligands may be promising candidates for diagnostic markers. Updated data in 78 OC pts will be presented. Conclusions: Clinical activity was observed in 14.5% of pts with heavily pretreated OC (PRs, SD ≥ 6 months, and SD with CA-125 reductions of ≥50%). This study suggests that P may be active in OC, and that specific HER receptors and ligands may be promising diagnostics for identifying tumors responsive to P. [Table: see text]

A phase II trial of temozolomide and vinorelbine for patients with recurrent brain metastases

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2050-2050
Author(s):  
F. M. Iwamoto ◽  
A. M. Omuro ◽  
J. J. Raizer ◽  
C. P. Nolan ◽  
A. Hormigo ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Minor Response ◽  
Radiographic Response ◽  
Whole Brain Radiation ◽  
Heavily Pretreated ◽  
Grade 3

2050 Background: Temozolomide has shown modest efficacy in the treatment of recurrent brain metastases. We designed a regimen combining temozolomide with vinorelbine, a lipophilic agent that crosses the blood-brain barrier, trying to improve efficacy. Methods: This is a phase II trial with 28-day cycles using temozolomide (150 mg/m2, days 1–7 and 15–21) and vinorelbine on days 1 and 8. We previously reported a phase I trial that established an MTD of 30 mg/m2 of vinorelbine in this combination, but the dose was decreased to 25 mg/m2 in this phase II trial. The phase II component was planned as a two-stage clinical trial. Since two or more responses were observed after the 20 initial patients, 15 more assessable patients were required. This design had a 91% probability to detect a true response rate of 20% or more. The primary endpoint was objective radiographic response. Secondary endpoints include OS, PFS and toxicity. Patients = 18 years old with KPS = 60, adequate organ function and progressive or recurrent brain metastases were eligible. Results: Thirty-six patients (13 men, 23 women) with a median age of 56 years (range, 38–76) and median KPS of 80 were enrolled. The primary tumor sites were lung (n=19), breast (n=11), colon (n=2), bladder (n=1), endometrium (n=1), head/neck (n=1) and kidney (n=1). Prior therapies included whole-brain radiation therapy (81%), chemotherapy (97%), radiosurgery (42%) and brain metastasis resection (47%). Objective radiographic response was 7% (1 CR and 1 minor response); 4 patients had SD and 23 PD. Three patients withdrew consent and did not undergo follow-up scans, 2 patients did not receive the planned treatment and 2 patients recently began treatment and have not been assessed. The median follow-up was 12.3 weeks and 72% of patients have died. Median PFS and OS were 8.3 weeks and 5 months, respectively. Grade 3/4 toxicities were mainly hematological and 3 patients were removed from the study due to myelosuppression. Conclusions: In this heavily pretreated population of patients with brain metastases, adding vinorelbine to temozolomide does not seem to improve response rates as compared to temozolomide alone. Single-agent temozolomide also has a more favorable toxicity profile. [Table: see text]

Phase II trial of temsirolimus (CCI-779) in patients with relapsed or refractory multiple myeloma (MM): Preliminary results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7616-7616 ◽  
Author(s):  
S. S. Farag ◽  
S. Zhang ◽  
M. Miller ◽  
M. Buckner ◽  
E. Kraut ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mononuclear Cells ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Single Agent ◽  
M Protein ◽  
Blood Levels ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Median Proportion

7616 Background: Temsirolimus (TEM) is a novel inhibitor of mTOR, a critical molecule in the PI3K/Akt pathway, which is known to play an important role in transducing mitogenic signals induced by the action of cytokines on MM cells. Methods: We performed a phase II trial to investigate the clinical activity and toxicity of TEM in relapsed/refractory MM patients. Patients had Salmon-Durie stage I-IIIA, failed at least one prior therapy, were ≥18 years, had ANC ≥1.2x109/l, platelets ≥75x109/l, serum Cr ≤1.5 mg/dl, fasting cholesterol ≤350 mg/dl, triglycerides ≤400 mg/dl, and ECOG performance status 0–2. TEM was dosed at 25 mg IV on days 1, 8, 15 and 22 of each 28-day cycle. Treatment was continued until progression. Results: 14 patients are evaluable for response and toxicity. Median age was 62.5 (range, 41–75) years; 8 patients were male. 12 patients had stage IIIA and 1 patient had stage IIA and IA each, respectively. Median β2-mg was 3.3 (range, 2.5–7.9) and CRP was 2.2 (range, 0.5–139). Patients had failed a median of 2 (range, 1–5) prior regimens, and 6 had failed autologous stem cell transplant. Overall, 6 (43%) of 14 patients responded, with 5 achieving minor (26–49% decrease in M-protein) responses, and 1 a partial (>50% decrease in M-protein) response using Bladé criteria. 11 patients progressed on treatment. Overall, median time-to-progression was 4.6 months from start of treatment. Grade 3/4 toxicity included neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), nausea (n=1), stomatitis (n=1) and diarrhea (n=1). Response was associated with a maximal reduction in phosphorylated p70S6K (p-p70S6K) and 4EBP1 (p-4EBP1) in peripheral blood mononuclear cells at 48 hours after TEM dosing. The median proportion of p-p70S6K relative to baseline following treatment was 0.38 (range, 0.26–0.84) in responding patients versus 1.65 (range, 0.74–1.66) in non-responders (P=0.0001). Similarly, the median proportion of p-4EBP1 following treatment in responders was 0.49 (range, 0.12–1.25) versus 1.12 (range, 0.73–2.09) in non-responders (P=0.025). Correlation with blood levels of TEM is ongoing. Conclusions: TEM has anti-myeloma activity, and further investigation of TEM as a single agent and in combination therapy is warranted. No significant financial relationships to disclose.

Irinotecan with 5-FU/FA in advanced biliary tract adenocarcinomas—A two-center phase II trial (GBFiri)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14088-14088
Author(s):  
J. Feisthammel ◽  
K. Schoppmeyer ◽  
M. Wiedmann ◽  
J. Mossner ◽  
M. Schulze ◽  
...  
Keyword(s):  
Overall Survival ◽  
Folinic Acid ◽  
Biliary Tract ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Synergistic Activity ◽  
Biliary Cancer ◽  
Free Survival

14088 Background: The majority of patients with biliary tract cancer present with advanced, unresectable tumors. Irinotecan and 5-Fluorouracil/folinic acid (FOLFIRI) have synergistic activity in gastrointestinal cancers. The aim of this study was to determine the tolerability and activity of systemic chemotherapy with FOLFIRI in patients with intrahepatic cholangiocarcinoma (CCC) or gallbladder cancer (GBC). Methods: This was a prospective, multicenter, non-randomised, open-label, phase II trial. Eligibility criteria: Inoperable adenocarcinoma of the biliary tract, measurable disease, age 18–80 years, ECOG PS 0–2. Patients received irinotecan 80 mg/m2 as a 30 min infusion, followed by folinic acid 500 mg/m2 over 2 h and 5-FU 2000 mg/m2 over 24h weekly × 6 followed by a 2 week rest. Treatment was continued until progression or limiting toxicity. Response to therapy was assessed after every other cycle according to RECIST criteria. Primary end point was response rate, secondary end points were overall survival, progression free survival and toxicity. Results: 30 pts (CCC 17, GBC 13) were enrolled. A total of 387 doses (Median 12.9; 1 to 36) were administered with an overall relative dose intensity of 98%. 30 patients are evaluable for safety. WHO grade 3/4 drug related adverse events occured in 7 patients (23%): Leukopenias in 2, anemia in 1, and diarrhea in 4 patients. 14 patients completed 2 cycles and were evaluable for response. Response rates: CR 0/30, PR 3/30 (10%) and SD 3/30 (10%). 8 patients presented with disease progression at restaging. Median overall survival: CCC 166 days, GBC 327 days. Progression-free-survival: CCC 84 days, GBC 159 days. Conclusions: FOLFIRI is a well tolerated regimen in patients with biliary cancer that can be safely administered on an outpatient basis. FOLFIRI has no substantial activity in CCC and moderate activity in GBC. Further studies are required to define a standard palliative chemotherapy for treatment of biliary cancer. No significant financial relationships to disclose.

Mocetinostat (MGCD0103), An Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, Produces Clinical Responses In Relapsed/Refractory Hodgkin Lymphoma (HL): Update From a Phase II Clinical Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1763-1763 ◽  
Author(s):  
Anas Younes ◽  
R. Gregory Bociek ◽  
John Kuruvilla ◽  
Pierre Laneuville ◽  
Henry C. Fung ◽  
...  
Keyword(s):  
Success Rate ◽  
Phase Ii ◽  
Research Funding ◽  
Treatment Success ◽  
Single Agent ◽  
Hematological Toxicity ◽  
Clinical Activity ◽  
Open Label ◽  
Heavily Pretreated ◽  
Equity Ownership

Abstract Abstract 1763 Background: HL patients with relapsed or refractory disease are incurable with standard therapies and new options are needed. Deregulation of HDAC activity can cause malignant diseases in humans. Mocetinostat inhibits Class I and IV HDACs and was shown to have preclinical and clinical activity. Methods: This was an open-label, Phase II trial in adults (≥18 years old) with relapsed/refractory HL. Patients initially received MGCD0103 at a starting dose of 110 mg (110 mg cohort) or 85 mg (85 mg cohort) 3x per week in 4-week cycles. Eligibility criteria included ≥1 target lesion (≥2 cm), no limit of prior therapies, ECOG status of 0–1, and platelet counts ≥25,000/μL. Tumor responses were determined every 8 weeks. The primary objective of this study was to estimate the treatment success rate defined as complete response (CR) + partial response (PR) + durable stable disease (SD for at least 6 cycles). Results: A total of 51 patients (23 patients in the 110 mg cohort and 28 patients in the 85 mg cohort) were enrolled (median age: 33 years old, range: 19–68 years old; gender: 29 male, 22 female; 84% caucasians; ECOG: 0: 49%, 1: 51%). Two patients experienced CR (110 mg cohort), 12 patients experienced PR (6 patients in each cohort) and 1 patient experienced durable SD (in the 85 mg cohort). The success rate was found to be 35% in the efficacy evaluable population (n=43) and 29% in the intent-to-treat population (n=51). Treatment-related adverse events of grade 3 or higher in ≥ 5% of patients included: thrombocytopenia (22%), fatigue (16%), neutropenia (14%), pneumonia (12%), anemia (10%), pericardial effusion (6%) and abnormal liver function tests (6%). Conclusions: Mocetinostat demonstrated single agent activity in heavily pretreated relapsed/refractory HL patients. The response rate reported in this study is among the best single agent activity described in HL with HDAC inhibitors, especially in the context of the minimal hematological toxicity observed. Despite the modest increased incidence of non-fatal pericardial effusions, the benefits of Mocetinostat outweigh the risks in this heavily pretreated patient population for which no curative options are available. Further development of Mocetinostat in HL is warranted, especially in less heavily treated patients and with prospective cardiac evaluations. Disclosures: Younes: Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Kuruvilla:Hoffman Laroche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Genzyme: Honoraria. Drouin:Methylgene: Employment. Patterson:Methylgene: Employment. Besterman:Methylgene: Employment, Equity Ownership. Martell:Methylgene: Equity Ownership.

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.

Phase II Trial of Combination of Bortezomib and Rituximab in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: Preliminary Results.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4494-4494
Author(s):  
Irene M. Ghobrial ◽  
Swaminathan Padmanabhan ◽  
Ashraf Badros ◽  
Marybeth Nelson ◽  
Renee Leduc ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase Ii ◽  
Single Agent ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Similar Treatment ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Best Response ◽  
Grade 3

Abstract INTRODUCTION: Previous studies have demonstrated the clinical activity of bortezomib as a single agent in patients with Waldenstrom Macroglobulinemia (WM). We performed preclinical studies that demonstrated synergistic activity of bortezomib with the anti-CD20 antibody rituximab in WM cell lines. This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory WM. METHODS: Patients who had at least one previous therapy for WM, symptomatic, and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15 q 28 days x 6 cycles and rituximab 375 mg/m2 at days 1, 8, 15, 22 on cycles 1 and 4. RESULTS: 17 pts (10 men and 7 women, median age 62 years, range 43 – 81) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5) including prior bortezomib and prior rituximab in some of those patients. The median IgM at baseline was 4070 mg/dL (range 1370– 10,800); median M-spike at baseline was 2.48 g/dL (range 1.5 – 4.87); and median hemoglobin was 11.0 g/dL (6.3–15.2). The median follow up was 5 months (range 1 – 11 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil, and bortezomib. 13 pts are currently evaluable for response, best response to bortezomib and rituximab after 2 cycles are presented in Table 1. Median duration of response has not been reached. None of the patients progressed while on therapy with bortezomib and rituximab. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 1 patient at cycle 6 and improved to grade 1 within 2 weeks of holding therapy. Other grade 3 and 4 toxicities included neutropenia in 3 patients, and anemia and hyponatremia in 1 patient. One patient discontinued therapy on study after 1 cycle because of inability to travel to study site and completed similar treatment off study and was unevaluable on this study. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. CONCLUSIONS: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates exciting activity achieving CR+ PR + MR in 85%, and/or stabilization of disease in 15% of evaluable patients with relapsed WM. No significant peripheral neuropathy was observed with this regimen. Updated data will be presented at the meeting. Response N=13; ORR (CR+PR+MR)= 85% Median time to best response (months) Complete Response 1 (8%) 6 Partial Response 3 (23%) 3.5 (3–4) Minimal Response 7 (54%) 4 (2–6) Stable Disease 2 (15%) NA Progressive Disease 0

Confirmation of the Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Relapsed or Refractory Mantle-Cell Lymphoma: Results of An International Study (NHL-003)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 262-262 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Thomas E. Witzig ◽  
Julie M. Vose ◽  
Craig B. Reeder ◽  
Rena Buckstein ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Efficacy And Safety ◽  
Mantle Cell ◽  
Measurable Disease

Abstract Introduction: Mantle-cell lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma (NHL) that typically responds to initial chemo-immunotherapy, but with a relatively short duration of response (DR) and progression-free survival (PFS) when treated with conventional chemotherapy agents. Although the overall survival (OS) of MCL has improved, most patients are not cured and new agents are needed. A sub-analysis of a recent phase II trial (NHL-002) investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL, demonstrated a promising overall response rate (ORR) of 53% with a median DR of 11.9 months. A confirmatory international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed/refractory aggressive NHL that had received at least one prior treatment and had measurable disease. 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: This report focuses on the 39 MCL patients that were enrolled and evaluable for response assessment. Median age was 66 (33–82) years and 29 (74%) patients were male. Median time from diagnosis to lenalidomide treatment was 3.4 (0.4–9) years. Patients had received a median of 3 (1–8) prior treatments, and 23% (9/39) of patients had received prior bortezomib treatment. The ORR with lenalidomide was 41% (16/39), including 13% (5/39) complete response (CR)/unconfirmed CR, and 28% (11/39) partial responses. Ten (26%) patients had stable disease. The most common grade 3 or 4 adverse events were neutropenia (51%) and thrombocytopenia (25%), anemia (13%), fatigue (10%) and febrile neutropenia (10%). Conclusion: These results confirm that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects.

Clinical Activity and Safety of the Combined Therapy with the AKT Inhibitor Perifosine and the Multikinase Inhibitor Sorafenib In Heavily Pretreated Patients with Relapsed/Refractory Lymphomas: Preliminary Results of a Phase II Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2861-2861
Author(s):  
Carmelo Carlo-Stella ◽  
Anna Guidetti ◽  
Simonetta Viviani ◽  
Liliana Devizzi ◽  
Paola Matteucci ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Akt Inhibitor ◽  
Multikinase Inhibitor ◽  
Significant Toxicity ◽  
Heavily Pretreated

Abstract Abstract 2861 Introduction: The AKT inhibitor Perifosine (Æterna Zentaris GmBH, Germany) has been shown in phase II studies to induce partial responses in a variety of solid tumors. Sorafenib (Nexavar, Bayer) is an oral multikinase inhibitor exerting in vitro and in vivo antiproliferative, antiangiogenic, and proapoptotic effects in a variety of hematological and nonhematological tumors. Our preclinical data demonstrating that the combination of Perifosine and Sorafenib induces gene expression profiling and signaling changes associated with a synergistic cytotoxic activity against lymphoma cell lines in vitro and in vivo, established the rationale for this ongoing phase II study aimed to determine safety and activity of Perifosine/Sorafenib combination therapy in relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Methods: Between July 2008 and July 2010, 26 out of 36 planned patients (18 males and 8 females; median age, 42 years; range, 19–73 years) with relapsed/refractory diffuse large B cell lymphoma (DLBCL, n = 3), follicular lymphoma (FL, n = 3), Waldenstrom macroglobulinemia (WM, n = 1), chronic lymphocytic leukemia (CLL, n = 4), and HL (n = 15) who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled in this trial. Prior to study entry, patients received a median of 5 (range 2 – 11) lines of treatment with autologous SCT performed in 19 (73%) and an additional allogeneic SCT in 10 (38%) patients. At study entry, 7 patients had relapsed and 19 refractory lymphoma. Perifosine (50 mg BID, per os) was initially administered as single agent for 4 weeks to assess tolerability and tumor response. Patients achieving less than partial remission (PR) were given the combination therapy, i.e., Perifosine (50 mg BID, per os) plus Sorafenib (400 mg BID, per os) until disease progression or clinical significant toxicity. Patients achieving ≥PR went off-study and continued with Perifosine (50 mg BID, per os) alone until disease progression or clinical significant toxicity. Tumor responses were assessed according to the revised response criteria for malignant lymphoma of the International Working Group. NCI CTCAE v3.0 was used for toxicity assessment. The study was approved by the Institutional Ethical Committee. Results: After a 4-week treatment with Perifosine alone, 22 out of 26 patients achieved <PR and were started on Perifosine/Sorafenib combination therapy. As of July 2010, a median of 5 months (range, 2 – 18) combination therapy have been administered, and 22 patients are evaluable for toxicity and response. In contrast, 4 patients who achieved ≥PR went off-study and continued therapy with Perifosine single agent. Combination therapy was well tolerated without significant adverse events. No patients interrupted the treatment due to toxicity. The most common drug-related hematological toxicities included grade 1–2 anemia (5%), neutropenia (5%), and thrombocytopenia (18%). Non-hematological toxicities included grade 1–2 diarrhea (27%) and hand-foot syndrome (27%). Three patients (14%) experienced grade 3 infections [pneumonia (n = 2), skin infection (n = 1)]. Best response to Perifosine/Sorafenib therapy included 5 (23%) PR with median response duration of 9 months (range, 1– 12) with 2 of 5 patients having received an allogeneic SCT. Eleven patients (50%) achieved stable disease (SD) with 7 patients (32%) achieving SD for ≥4 months, while 6 patients (27%) progressed. Interestingly, all responding patients had a diagnosis of HL, thus raising to 33% the PR rate in this histological subgroup. At a median follow-up of 11 months (range, 5 – 25), study patients (n = 22) have a median overall survival (OS) of 15 months and a projected 2-year OS of 42% (95% CI: 20% - 66%), with a median time to progression (TTP) for patients achieving PR or SD (n = 16) of 7 months. The subgroup of HL patients (n =15) has a median OS of 16 months and a projected 2-year OS of 42% (95% CI: 12% - 72%), with a median TTP for patients achieving PR or SD (n = 11) of 10 months. Conclusions: Perifosine/Sorafenib combination therapy has a good toxicity profile and is well tolerated by heavily pretreated, refractory/relapsed lymphoma patients. Preliminary results from this phase II trial suggest that Perifosine/Sorafenib combination therapy exerts significant anti-lymphoma activity in at least one third of relapsed/refractory HL patients, whereas no response other than SD was observed in NHL patients. Disclosures: Off Label Use: Sorafenib for lymphoma.

A phase II trial of cabozantinib (Cabo) in patients (pts) with castrate-resistant prostate cancer (CRPC) metastatic to bone (NCT01428219).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS5094-TPS5094
Author(s):  
Petros Grivas ◽  
Stephanie Daignault ◽  
Kathleen A. Cooney ◽  
Jon Jacobson ◽  
Corrie Yablon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Bone Metabolism ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Bone Lesions ◽  
Clinical Activity ◽  
Type I ◽  
Synergistic Activity ◽  
Ct Guided

TPS5094 Background: MET overexpression predicts prostate cancer invasion and bone metastasis; inhibition of MET/VEGF pathways has synergistic activity in CRPC (Knudsen et al. Adv Cancer Res 2004; Aftab et al. Clin Transl Oncol 2011). Cabo is a small molecule that inhibits multiple receptor tyrosine kinases, including MET and VEGFR2. A phase II randomized discontinuation trial of Cabo showed clinical activity in CRPC, including reduction of soft tissue lesions, prolongation of progression-free survival (PFS), resolution of bone scans, and reductions in bone turnover markers, pain and narcotic use (Smith et al, JCO 2013). To further define the activity of Cabo in pts with CRPC and bone metastases, we launched a phase II trial to characterize the effects of Cabo on bone metabolism and tumor activity in prostate cancer bone lesions. We hypothesize that the clinical activity of Cabo correlates with measurable pharmacodynamic effects on bone micro-environment. Methods: After informed consent, chemotherapy-naive pts with progressive CRPC and bone metastases accessible to CT-guided biopsy, adequate performance status/organ function, are treated with Cabo 60 mg once daily. Primary endpoint: proportion of pts progression-free (PF) at 12 weeks. Secondary endpoints: safety, PFS, response proportion/duration, PSA response, PSA time-to-progression. A Simon's two-stage mini-max design permits early termination after the first 27 evaluable pts in case of unfavorable results. Alternatively, up to 46 evaluable pts will be accrued. Cabo would not be of interest if the 12-week PF proportion is <0.45; it would be of definite clinical interest if the 12-week PF proportion is >0.65 (5% type I error, 85% power). Perfusion/diffusion-weighted MRI (parametric response maps) and bone lesion biopsies are required at baseline and 6 weeks after starting Cabo. Doxycycline is administered prior to bone biopsy for bone labeling. Bone cores are sent for dynamic histomorphometry and immunohistochemistry (phospho-MET/MET, phospho-VEGFR2/VEGFR2, phospho-Akt/Akt). Serum is collected at several time-points to measure markers of bone metabolism. 13 of 27 first-stage pts have been enrolled and started Cabo. Clinical trial information: NCT01428219.

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