GAIN-(L): Efficacy and biomarker findings of RG7160 (GA201), a novel, dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with first-line cisplatin and pemetrexed in metastatic nonsquamous NSCLC.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7544-7544
Author(s):  
James F. Spicer ◽  
Enriqueta Felip ◽  
Lionel Bosquée ◽  
Vanesa Gregorc ◽  
Iker Lopez Calderero ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Neoadjuvant Treatment ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Target Lesion ◽  
Mucosal Inflammation ◽  
Clinical Activity ◽  
Biomarker Analysis ◽  
Grade 3

7544 Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown promising clinical activity in phase I and in the neoadjuvant treatment of head and neck cancer. This phase Ib study (NCT01185847) aimed to determine the safety, pharmacokinetics (PK), activity and recommended phase II dose (RP2D) of GA201 in combination with chemotherapy in non-squamous NSCLC. Methods: Successive cohorts received GA201 1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with chemotherapy at standard doses. Data cut off was 7 months after enrolling the last patient. Results: 14 patients (4 female) with performance status 0-1 were enrolled. No maximum tolerated dose was reached. Most common adverse events (AEs – all grades) included rash (100%), hypomagnesaemia (71%), infusion-related reactions (64%), mucosal inflammation (57%) and anemia (50%). AEs of ≥ grade 3 included rash (71%), skin fissure (21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction for 4 patients and discontinuation for 1 patient. There were 6 confirmed partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with stable disease >=9 weeks. Duration of response ranged between 5 and 42 weeks (3 patients still ongoing). Preliminary biomarker analysis shows a correlation between tumor-infiltrating CD16+ immune cells and target lesion shrinkage at first tumor assessment [R(spear)=-0.65 (p=0.02)]; no apparent correlation between EGFR H-score and response was found. PK data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The RP2D of GA201 in combination with chemotherapy was established to be 1400 mg. The incidence of EGFR associated rash was high and guidelines to reduce its severity were implemented with a noted improvement in tolerability. Promising antitumor activity was observed. Biomarker data support the mode of action of GA201 via ADCC. A randomized phase II trial of this combination is ongoing and fully recruited.

Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

1999 ◽  
Vol 17 (6) ◽  
pp. 1751-1751 ◽  
Author(s):  
Ernesto Wasserman ◽  
Caroline Cuvier ◽  
François Lokiec ◽  
François Goldwasser ◽  
Salima Kalla ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Two Phase ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Minute Period ◽  
Grade 3 ◽  
Febrile Episodes

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of ≤2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m2 for oxaliplatin and 150 to 250 mg/m2 for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients (pts) with stage III A/B non-small cell lung cancer (NSCLC): An interim report of the RTOG 0324 trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7531-7531 ◽  
Author(s):  
G. Blumenschein ◽  
J. Moughan ◽  
W. Curran ◽  
F. Robert ◽  
F. Fossella ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Pulmonary Complications ◽  
Model Systems ◽  
Stage Iii ◽  
Preclinical Model ◽  
Eligibility Criteria ◽  
Trial Testing ◽  
Grade 3

7531 Background: Cetuximab (C225) is a chimerized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). NSCLC commonly expresses the EGFR, which is associated with aggressive tumor behavior and poor clinical outcome. Preclinical model systems demonstrate radiosensitization following molecular inhibition of EGFR signaling. Methods: We report a phase II trial testing the combination of C225 with CRT in unresectable stage III NSCLC with a planned sample size of 84 PTS. Eligibility criteria included Zubrod performance status (PS) = 1, weight loss = 5% over past 3 months, FEV1 = 1.2 l, adequate hematologic, hepatic, and renal function. PTS received an initial dose of C225 (400 mg/m2) on day 1 of week 1, then weekly doses of C225 (250 mg/m2) until completion of therapy (weeks 2 –17). During week 2, patients started CRT (63 Gy/35 fractions) with weekly carboplatin (C) AUC 2 and paclitaxel (P) 45 mg/m2 × 6 doses followed by C (AUC 6) and P (200 mg/m2) × 2 cycles (weeks 12–17). Interim monitoring for severe (grade = 3) or excessive non-hematologic toxicities occurred after pts had been treated and followed for at least 90 days after RT. Primary endpoints include safety and compliance of concurrent C225 and CRT. Results: 93 pts were enrolled with 87 evaluable pts. Pts characteristics: 57% male, median age 64 years (range 42–85), 47% PS 0, 46% stage IIIA. Median follow-up is 14 months. Response rate is 62% (n=54) and 12 month overall survival (OS) is 68% (# at risk=56). Adverse events related to treatment include 20% (n=17) of pts with grade 4 hematologic toxicities and 7 pts who had grade 3 esophagitis. There was 1 infection related death, 1 death NOS, and 3 pts who died of pulmonary complications (adult respiratory distress syndrome, pneumonitis, and hypoxia). Conclusions: The combination of C225 with CRT is feasible. Further study will be needed to determine whether the addition C225 to CRT enhances toxicity or efficacy. Complete compliance and toxicity data along with 18 month OS will be reported. No significant financial relationships to disclose.

Phase I study of bortezomib plus cetuximab in patients with tumors expressing epidermal growth factor receptor (EGFR)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18143-18143 ◽  
Author(s):  
A. Dudek ◽  
P. Gada ◽  
K. Mulamalla ◽  
N. Shehadeh
Keyword(s):  
Head And Neck ◽  
Day Treatment ◽  
Growth Factor Receptor ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Human Antibody ◽  
Chimeric Mouse ◽  
Grade 3 ◽  
Dose Levels

18143 Background: Bortezomib is a proteasome inhibitor that augments EGFR inhibitor activity (Cancer Research 2007; 67:(2),1–8). Cetuximab is a chimeric mouse-human antibody against EGFR that has been found to induce tumor responses in patients with colon cancer and head and neck cancer. The purpose of this study was to establish a maximum tolerated dose (MTD) for the combination of bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumors. Methods: A 21-day treatment cycle was given with a maximum of six cycles per patient. Bortezomib was administered intravenously on days 1 and 8 via dose escalation, beginning with a minimum dose of 1.3 mg/m2 and increasing in one-tenth increments to 2.0 mg/m2 for a total of eight dose levels. Cetuximab was delivered with an initial dose of 400mg/m2 on day 1 cycle 1, with subsequent doses of 250mg/ m2 on days 1, 8 and 15. Results: Twenty patients (13 male and 7 female) with an ECOG PS <2 were enrolled in this study from November 2005 to December 2006. The median age was 59.5 (range: 41- 68), and the median number of prior chemotherapy regimens was 5 (range 1–7). Primary tumor sites included lung (9), head and neck (4), kidney (3), pancreas (2), bladder (1), and ovary (1). A total of 54 cycles of chemotherapy were administered; the median number of cycles per patient was 2.5 (range 1–6). Thirteen patients discontinued therapy because of disease progression. Two patients completed all six cycles of therapy. One dose-limiting toxicity (DLT) was seen at dose level 4 (bortezomib 1.6 mg/m2), which included grade 3 nausea, vomiting and dysphagia based on evaluation using CTCAE (version 3.0). Level 4 was expanded to enroll 3 additional patients, and no further grade 3 or 4 toxicities were observed. Grade 3/4 non- hematological toxicities were observed in 14 patients after their first cycle of therapy. Nine patients had delay in treatment. Conclusions: MTD for bortezomib plus cetuximab was not achieved at dose levels 1–6. This combination therapy has shown limited clinical activity in our extensively pretreated group of patients with solid tumors. Complete results for all dose levels, including dose levels 7–8, will be reported at the 2007 meeting of the American Society of Clinical Oncology. [Table: see text]

Phase I trial of metronomic cyclophosphamide (CTX) and lenalidomide (LEN) in patients with castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 164-164
Author(s):  
Jue Wang ◽  
Timothy R. McGuire ◽  
James K. Schwarz ◽  
Jane L Meza ◽  
James E E Talmadge
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Patient Characteristics ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Level 1 ◽  
Grade 3

164 Background: Angiogenesis and suboptimal antitumor immune response are important in the progression of CRPC. Both LEN and metronomic CTX have known anti-angiogenic and immunomodulatory activities. A phase I study of a novel combination of metronomic CTX with LEN in patients with CRPC who have failed prior docetaxel therapy was initiated to assess safety and effects on potential biomarkers. Methods: CTX was given 50 mg PO QD(day 1-28) and LEN 10-25 mg PO QD(day 1-21) on a 28 day cycle. Dose limiting toxicity was defined as any treatment-related grade 4 hematologic event or grade 3 / 4 non-hematologic event during cycles one. Quantification of circulating tumor cells (CTC), plasma cytokines, analgesic consumption and quality of life assessments were performed. Measurement of Treg and MDSCs were performed in some patients. Results: 17 patients with CRPC have been enrolled in L0-4; all patients are evaluable for toxicity. Patient characteristics include: ECOG performance status 0/1= 4/13; median age=77 (range 50–86); median PSA=36.7 (range 1.36–2287). Dose level 1 (CTX 50 mg/d, LEN 10 mg/d) was expanded to 6 patients after one out of three initial patients was removed from the study for Gr 3 gastrointestinal bleeding (in cycle 1). Dose level 1 (CTX 25 mg/d, LEN 10 mg/d) had no DLT’s. The maximum tolerated dose has not yet been reached. Other Grade 3/4 toxicities observed after cycle 1 included grade 3 pain (N=1), grade 3 neutropenia (N=4), grade 3 thrombocytopenia (N=2), grade 4 neutropenia (N=2). Most frequent grade 1 and 2 toxicities included anemia, fatigue, neutropenia, and hypocalcemia. Overall, 9 of 14 patients (64%) have experienced a reduction in PSA. One patient had partial response after one cycle. Stable disease was documented in 5 of 14 (36%) evaluable patients. Two inflammatory cytokines, IL-6 (N = 19; r = 0.64; p = 0.0035) and IL-8 (N = 9; r = 0.86; p = 0.0028), were found to significantly correlated with PSA. Conclusions: The combination of metronomic CTX and LEN can be safely administered. Preliminary clinical activity was observed in this heavily-pretreated patient population. Enrollment to this study continues and clinical and biomarker studies are ongoing.

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 492-492 ◽  
Author(s):  
Sang Joon Shin ◽  
Jeeyun Lee ◽  
Ik-Joo Chung ◽  
Tae Won Kim ◽  
Hoo Geun Chun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Phase Ii ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Open Label ◽  
Baseline Serum ◽  
Biomarker Analysis ◽  
Group A ◽  
Group B

492 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Oxaliplatin-based treatment (FOLFOX, CapeOX) combined with bevacizumab is one of the standard chemotherapies for metastatic CRC. However, several clinical studies performed using S-1 plus oxaliplatin (SOX) indicate that SOX is a treatment option for metastatic CRC. TSU-68 (orantinib) is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor and has promising efficacy and high safety. The recommended phase II dose of TSU-68 plus SOX has been determined in a phase I study. This trial aimed to evaluate the efficacy of TSU-68 in combination with SOX. Methods: We performed an open-label multicenter randomized phase II trial in Korea. Treatment-naive metastatic CRC patients with a performance status 0 or 1 were randomized in a ratio of 1:1 to receive either TSU-68 plus SOX (group A) or SOX (group B). The primary endpoint was progression-free survival (PFS). Results: We randomized 105 patients (52 patients, group A and 53 patients, group B). Median PFS was 7.0 months in group A (hazard ratio [HR], 1.057) and 7.2 months in group B (P = 0.8401). The most frequent grade 3/4 events were thrombocytopenia (9.6% vs 26.4%), neutropenia (13.5% vs 15.1%), and anemia (3.8% vs 13.2%). We observed a difference between the 2 groups in all grades of anemia (15.4% vs 32.1%), diarrhea (30.8% vs 47.2%), vomiting (50.0% vs 26.4%), and chromaturia (23.1% vs 0.0%). Analysis using a COX proportional hazard model showed that baseline interleukin 6 (IL-6) level was associated with survival benefit of TSU-68 (P = 0.012). Conclusions: TSU-68 plus SOX showed a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. Baseline serum IL-6 levels could be prognostic factors for TSU-68 efficacy. Further biomarker analysis is being performed to determine the efficacy of this treatment. Clinical trial information: JapicCTI-111403.

Phase II study of FOLFOX, bevacizumab and erlotinib as initial therapy for patients with metastatic colorectal cancer (MCRC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3545-3545
Author(s):  
J. A. Meyerhardt ◽  
K. Stuart ◽  
A. Zhu ◽  
C. Fuchs ◽  
P. Bhargava ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Tolerability Profile ◽  
Egfr Inhibition ◽  
Grade 3

3545 Background: Cytotoxic chemotherapy with targeted therapy against the vascular endothelial growth factor (VEGF) or the epidermal growth factor receptor (EGFR) has become a standard approach in MCRC, though combining VEGF and EGFR inhibition with chemotherapy as initial treatment is not well established. We conducted a phase II study of the combination of infusional 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX), bevacizumab, and erlotinib in chemotherapy naïve patients with MCRC. Methods: Eligible patients had measurable MCRC, no prior systemic therapy for MCRC or at least one year since completion of adjuvant therapy (only 5-FU and leucovorin acceptable), performance status 0–1. The regimen consisted of 14-day cycles of FOLFOX started on day 1 (oxaliplatin 85 mg/m2, bolus 5-FU 400 mg/m2, leucovorin 400 mg/m2 and 46-hour infusion 5-FU 2.4 g/m2), day 1 bevacizumab 5 mg/kg and erlotinib 150 mg daily. This isa single stage trial with goal of 35 patients. The primary endpoint was progression-free survival (PFS). Results: Between Jan and Dec 2005, 31 patients have been enrolled with the following characteristics: male/female, 19/12; PS ECOG 0/1, 15/16; median age 58, range 38–81. Of the 28 patients who completed at least 1 cycle, the most common grade 3/4 adverse events include: 8/28 (29%) diarrhea, 8/28 (29%) neutropenia, 5/28 (18%) rash, 4/28 (14%) fatigue, 3/28 (11%) nausea/vomiting, 3/28 (11%) neuropathy. 22/28 (78%) of patients had at least 1 grade 3/4 toxicity. 14/31 patients remain on trial, 13/31 (42%) came off for toxicity or withdrew consent due to treatment-related toxicities, 4 withdrew consent for other reasons. Efficacy data is not available at time of submission but will be more mature by June 2006. Conclusions: The combination of FOLFOX, bevacizumab and erlotinib appears to have moderate toxicity, with ∼40% of patients coming off trial due to side effects. Further characterization of the tolerability profile will be necessary when interpreting the efficacy of the combination. We expect full accrual as well as reasonable point estimates of PFS by June 2006. Supported by: Sanofi-Synthelabo, a member of the Sanofi-Aventis group, Genentech [Table: see text]

scholarly journals Report of a Multicenter Phase II Trial Testing a Combination of Biweekly Bevacizumab and Daily Erlotinib in Patients With Unresectable Biliary Cancer: A Phase II Consortium Study

2010 ◽  
Vol 28 (21) ◽  
pp. 3491-3497 ◽  
Author(s):  
Sam J. Lubner ◽  
Michelle R. Mahoney ◽  
Jill L. Kolesar ◽  
Noelle K. LoConte ◽  
George P. Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Primary Objective ◽  
Clinical Activity ◽  
Biliary Cancer ◽  
Vegf Inhibitor ◽  
Grade 3

Purpose Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Patients and Methods Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Results Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Conclusion Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.

Phase II study of lenalidomide (CC-5013) for patients with myelofibrosis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6510-6510
Author(s):  
S. Verstovsek ◽  
J. Cortes ◽  
D. Thomas ◽  
M. Beran ◽  
C. Koller ◽  
...  
Keyword(s):  
Phase Ii ◽  
Total Bilirubin ◽  
Phase Ii Study ◽  
Performance Status ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Grade 3 ◽  
Factor Α ◽  
Necrosis Factor ◽  
Baseline Hemoglobin

6510 Background: Lenalidomide (CC-5013, Revlimid), analogue of thalidomide, a new drug in a group known as ImiDs, with broad cytokine modulatory activity. Lenalidomide is less toxic than thalidomide without teratogenicity, sedation, or neurotoxicity, and is 50,000-fold more potent in inhibiting, tumor necrosis factor-α, that is involved in the pathophysiology of myelofibrosis (MF). Patients (pts) with MF currently have no approved standard effective therapy. Methods: Phase II study of lenalidomide for MF pts with plts >30×109, performance status ≥3, total bilirubin and creatinine of <3mg/dL, accrued 41 pts. Pts with prior hypersensitivity to thalidomide excluded. Pts received lenalidomide 10mg orally daily (5mg if platelets <100x109). Median age 65 (range, 42–83). 36 pts (88%) had received prior therapy for MF, including thalidomide 13 (32%), hydroxyurea 13 (32%), interferon 11 (27%), anagrelide 10 (24%), and erythropoietin 6 (15%). Baseline hemoglobin was <10g/dl in 19 (46%) (13 or 32% were transfusion dependent), platelets <100x109 in 12 (29%), absolute neutrophils <1.5x109 in 2 (5%), 20/34 (59%) had splenomegaly (median 10cm BCM, range 1–30; 7 with prior splenectomy), and 17 (42%) had cytogenetic abnormality. Results: Median follow is 5 months (range 1–14). Therapy has been well tolerated. Most common toxicities of any grade were rash 6(39%) and pruritus 9 (22%). Grade ≥3 toxicities were neutropenia 13 (32%), thrombocytopenia 11 (27%), fatigue 3 (7%) and rash 2 (5%). 8 (20%) pts required dose reduction; 4 discontinued therapy due to toxicity. Responses have been observed in 19 (46%) pts. These include CR 3(7%; normalization of hemoglobin and WBC), PR 5 (12%; improvement in platelets and hemoglobin ± spleen), and hematologic improvement 11 (27%) pts (improvement in platelets - 4, spleen - 2, WBC - 4, BM blasts - 1). 5 of 13 transfusion-dependent pts have become transfusion-independent. 6 of 12 (50%) pts with platelets <100x109 improved the count by >50%. Median time to response was 6 wks (range 1–22). Responses have been sustained for a median of 31+ wks (range 1+-40+). Conclusions: Lenalidomide has clinical activity in a subset of pts with MF with an acceptable toxicity profile. Studies using lenalidomide in combination with other agents are planned. No significant financial relationships to disclose.

A phase I study of YM155, a novel survivin suppressant, administered by 168 hour continuous infusion to patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3014-3014 ◽  
Author(s):  
A. W. Tolcher ◽  
S. Antonia ◽  
L. D. Lewis ◽  
A. Mita ◽  
J. Mahany ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Solid Tumors ◽  
Cell Model ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Mucosal Inflammation ◽  
Normal Tissues ◽  
Grade 3 ◽  
Renal Tubular ◽  
Anti Tumor Activity

3014 Background: Survivin is one of the family of inhibitor of apoptosis proteins (IAP) that suppresses apoptosis through inhibition of caspases and procaspases. Survivin is selectively expressed in most solid tumors but not normal tissues. In a PC-3 cell model YM155 inhibited survivin mRNA transcription and survivin protein expression and showed potent (nM) anti-proliferative activity in preclinical models including tumor regressions. Methods: The objectives were to determine the maximum tolerated dose (MTD) of 168 hour continuous infusion of YM155 every 3 weeks, to evaluate toxicity, characterize the pharmacokinetics and observe anti-tumor activity. Standard 3+3 dose escalation scheme was utilized. Additional pts were added to fully characterize toxicities at the MTD. Pharmacokinetic sampling was performed during cycles 1 and 2. Results: 41 pts (M/F: 31/10, median age 61, range 28–78) with performance status of 0–2 were enrolled into 4 dose cohorts [1.8 mg/m2/day (N = 8), 3.6 (6), 6.0 (2) and 4.8 (25)]. Most common tumor types were prostate (9), NHL (5), and colorectal (5). 2/2 pts experienced DLTs at 6.0 (renal tubular necrosis with grade 3 mucositis and increased serum creatinine), thus the MTD was 4.8 mg/m2/day. The most frequent AEs were: pyrexia, arthralgia, nausea, fatigue and diarrhea. The most common grade 3 or 4 drug related AEs were: mucosal inflammation (N = 2, 4.9%) and increased INR (N = 2, 4.9%). At MTD, the median clearance was 47 L/hr with a median steady state concentration of 7.5 ng/mL and a median terminal half-life of 22 hours. Two pts with chemotherapy refractory intermediate grade NHL had marked reduction of lymph nodes including one that was durable (PR reviewed independently). This pt went onto BMT and was in remission at the time of this submission. Two HRPC pts exhibited PSA response (> 50% reduction). Conclusions: YM 155, the first survivin inhibitor, was well tolerated, had a MTD of 4.8 mg/m2/day × 7 days and exhibited provocative anti-tumor activity in 4 pts that warrant broad phase II evaluation. No significant financial relationships to disclose.

A phase II study of mammalian target of rapamycin (mTOR) inhibitor RAD001 plus imatinib mesylate (IM) in patients with previously treated advanced renal carcinoma (RCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15600-15600 ◽  
Author(s):  
J. S. Chan ◽  
J. Vuky ◽  
L. A. Besaw ◽  
T. M. Beer ◽  
C. W. Ryan
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
High Dose ◽  
Grade 3 ◽  
Asco 2006 ◽  
Free Rate

15600 Background: The serine-threonine kinase mTOR is a valid target for RCC therapy with temsirolimus treatment resulting in improved overall survival in poor-risk patients (Hudes G et al., ASCO 2006). RAD001 is an oral inhibitor of mTOR which has demonstrated activity in RCC at 10mg/day (Amato R et al., ASCO 2006). IM is a tyrosine kinase inhibitor (TKI) of platelet-derived growth factor receptor (PDGFR), a target that may promote angiogenesis and growth of RCC. Combined mTOR and PDGFR inhibition with RAD001 and IM may achieve vertical blockade through the PI3K/AKT pathway. Methods: Eligibility: metastatic clear cell RCC, performance status (PS) 0–2, adequate organ function, and prior treatment with = 1 systemic therapy. Doses were based on a phase I study of the combination in GIST (Van Oosterom AT et al., ASCO 2005): RAD001 2.5 mg p.o. daily and IM 600 mg p.o. daily. Patients were reimaged every 6 weeks. This is a 2-stage phase II study to determine the 3-month progression-free rate. Results: 14 pts have been enrolled. Median age 66 years (51–79). 6 pts PS 0 and 8 pts PS 1. Median number of prior therapies 1.5 (1–4). 12 of 14 patients had prior TKI therapy. Prior therapies included sorafenib (11 pts), interferon (7), sunitinib (3), bevacizumab (2), erlotinib (1), panitumumab (1), high-dose IL-2 (1). Of 10 pts evaluable for the primary endpoint, 3 are progression-free = 3 months. Best response for 9 pts evaluable by RECIST: PR/CR 0, SD 7, PD 2. Most common adverse events in 11 evaluable patients include nausea (8), edema (7), increased creatinine (7), fatigue (7), transaminase elevation (6), thrombocytopenia (5), leukopenia (5), cough (5), diarrhea (5). Grade 3 adverse events include fatigue (3), LE edema, rash, pleural effusion, increased creatinine, abdominal pain, and thrombocytopenia (1 each). There were no grade 4 toxicities. Unique suspected RAD001 toxicities include grade 3 pneumonitis (1) and angioedema (1). Conclusions: The combination of RAD001 and IM has moderate toxicity. This is one of the first studies in RCC patients predominantly pretreated with a TKI. 3 month progression-free rate appears to be a clinically relevant endpoint in this population. [Table: see text]

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