A phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with nab-paclitaxel for patients with previously treated advanced pancreatic cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 307-307 ◽  
Author(s):  
Christine Campo Alewine ◽  
Raffit Hassan ◽  
M. Iqra Ahmad ◽  
Jane B Trepel ◽  
Cody Peer ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Exposure ◽  
Bowel Perforation ◽  
Advanced Pancreatic Cancer ◽  
Elongation Factor ◽  
Maximum Tolerated Dose ◽  
Pseudomonas Exotoxin A ◽  
Previously Treated ◽  
Grade 3 ◽  
Anti Tumor Activity

307 Background: LMB-100 is a Pseudomonas exotoxin A-based immunotoxin that targets mesothelin (MSLN). MSLN is expressed by >75% of pancreatic adenocarcinomas (PDAC). LMB-100 kills MSLN-expressing cells by irreversibly modifying elongation factor-2 to halt protein synthesis. Phase I studies of LMB-100 defined the maximum tolerated dose (MTD) of 140 mcg/kg IV given on D1, 3 and 5 of a 21-day cycle. Development of anti-drug antibodies (ADAs) limited patient drug exposure beyond cycle 2. Our pre-clinical data showed that combination of LMB-100 with a taxane resulted in synergistic anti-tumor activity. Methods: We conducted a phase I single center study (standard 3+3 design) to determine the MTD of LMB-100 given with nab-paclitaxel in patients with previously treated advanced PDAC. LMB-100 was given on D1, 3 and 5 of a 21-day cycle, and nab-paclitaxel (125 mg/m2) on D1 and D8. Initial patients could receive a maximum of 4 cycles, but subsequently a 2-cycle maximum was employed. Results: Fourteen patients (median age 58) were enrolled. Two of 6 patients experienced DLTs at the 100 mcg/kg dose of LMB-100 (myalgia- 2 pts, fatigue- 1 pt, hypotension- 1 pt; all grade 3). One of 8 patients had DLT at the 65 mcg/kg dose (edema, urine output decrease- both grade 3). Other toxicities related to LMB-100 included hypoalbuminemia, edema-associated weight gain, hyponatremia, fatigue, drug fever, infusion-related reaction, hypophosphatemia, nausea and anorexia. One patient died on treatment from complications of bowel perforation attributed to cancer. All patients achieved detectable serum levels of LMB-100 during the first cycle, even those with pre-existing ADAs, and 5 of 8 did so during cycle 2. One patient receiving the 65 mcg/kg dose had a confirmed partial response, and CA 19-9 dropped by > 50% in 5 of 8 evaluable patients. Conclusions: MTD of LMB-100 is 65 mcg/kg given with nab-paclitaxel on this schedule. Anti-tumor activity was observed. A phase II cohort is currently being accrued. Clinical trial information: NCT02810418.

Phase I study of BAY 73–4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3593-3593 ◽  
Author(s):  
S. Hedbom ◽  
S. Steinbild ◽  
A. Frost ◽  
M. Büchert ◽  
C. Unger ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Exposure ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Exposure Level ◽  
Phase Ii Trials ◽  
Multikinase Inhibitor ◽  
Dce Mri ◽  
Grade 3

3593 Background: BAY 73–4506 is a multikinase inhibitor targeting both the tumor and its vasculature. BAY 73–4506 inhibits VEGFR-2 and -3, and tumor cell signaling kinases (RET, KIT, PDGFR, and Raf). This drug shows potent, oral activity in a wide variety of preclinical xenograft models. Methods: This phase I dose-escalation trial investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of BAY 73–4506 given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers included dynamic contrast-enhanced MRI (DCE-MRI) and circulating sVEGFR-2 and VEGF levels assessed at each cycle. Tumor response was evaluated per RECIST criteria. Results: 22 patients (pts) with documented progressive disease were enrolled at doses of 10 mg to 120 mg once daily. Tumor types included CRC (27%), RCC (18%) and pancreatic cancer (14%). Pts had received a median of 3 prior therapies, including anti-VEGF agents in 5 pts. BAY 73–4506 PK appeared linear with dose; the AUC target exposure level of 13 mg*h/L (from preclinical models) was reached at 30 mg. The major metabolite of BAY 73–4506 (active in vitro) reached a similar AUC(0–24)ss as the parent drug at 120 mg. Commonly reported drug-related adverse events (=10% of pts) were hoarseness (7 [32%], all CTC grade 1), hypertension (5 [23%], all CTC grade 1–2), fatigue (3 [14%], CTC grade 3 in 1 pt [5%]), hand-foot-skin reaction (HFSR) (3 [14%], CTC grade 3 in 1 pt [5%], mucositis (3 [14%], all CTC grade 1). Maximum tolerated dose was exceeded at 120 mg with dose-limiting toxicities including fever without documented infection, HFSR, fatigue, and leukopenia. 2 pts (RCC & osteosarcoma) achieved RECIST partial response. 4 pts had stable disease, one of them a cervical cancer pt with extensive tumor cavitation. PD parameters (decrease in sVEGFR-2 levels, decrease in iAUC60s of Gd-DTPA by DCE-MRI) correlated with drug exposure. Conclusions: BAY 73–4506 was well tolerated at 60 mg with report of dose-limiting toxicities at 120 mg. 6 (28%) of 22 pts demonstrated antitumor activity. Optimal dose and regimen are under evaluation in preparation for phase II trials. No significant financial relationships to disclose.

Phase I study of vandetanib (ZD6474) administered during and after irradiation (RT) in children with diffuse intrinsic pontine glioma (DIPG)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10020-10020
Author(s):  
A. Broniscer ◽  
T. E. Merchant ◽  
C. Hillenbrand ◽  
Z. Patay ◽  
T. K. Chin ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Drug Exposure ◽  
Dosage Level ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pharmacokinetic Analysis ◽  
Dismal Prognosis ◽  
Grade 3

10020 Background: Children with DIPG have a dismal prognosis despite use of RT, which is the mainstay of therapy. All chemotherapy regimens used so far demonstrated no benefit. EGFR and VEGFR pathways are considered important in tumorigenesis of DIPG. Methods: We conducted a traditional phase I study combining oral vandetanib (VEGFR-2 and EGFR inhibitor) during and after local RT in children with DIPG. Five dosage levels were tested (50, 65, 85, 110, and 145mg/m2 per day). Vandetanib and RT started on the same day. The first 6 weeks of therapy constituted the dose-limiting toxicity (DLT)-evaluation period. Correlative studies consisted of pharmacokinetic analysis (PK), pharmacodynamic studies in blood, and standard and investigational imaging (before and 1, 3, and 6 weeks after start of therapy). Results: Twenty-one patients were enrolled on study (50 [n = 3], 65 [n = 3], 85 [n = 3], 110 [n = 6], and 145mg/m2 [n = 6]). Two patients experienced DLT consisting of rash/mucositis (level 4) and diarrhea (level 5). The maximum-tolerated dose (MTD) of vandetanib was not reached. Other significant toxicities included lymphopenia grade 3/4 (n = 10), grade 3 neutropenia and hypophosphatemia (one each), grade 2 proteinuria (n = 2), grade 2 hypertension (n = 4), and mild QTc prolongation (n = 7) .Once the phase I component was completed, two extra patients were enrolled at dosage level 5; one of them developed grade 4 seizure secondary to posterior reversible encephalopathy syndrome. PK (n = 21) showed similar drug clearance and volume of distribution compared to adults. However, drug exposure at steady state normalized by dose seemed higher in children. Increased tumor perfusion during the first 6 weeks of therapy was observed in the first 12 patients analyzed. Conclusions: Although MTD was not reached, we recommend administration of vandetanib at a dose of 110mg/m2 per day during and after local RT in children. Further combination studies of vandetanib in children with DIPG are planned. No significant financial relationships to disclose.

Effective Dosing of Topotecan With Carboplatin in Relapsed Ovarian Cancer: A Phase I/II Study

2001 ◽  
Vol 19 (13) ◽  
pp. 3255-3259 ◽  
Author(s):  
A. Bowman ◽  
T. Rye ◽  
G. Ross ◽  
A. Wheatley ◽  
J. F. Smyth
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Nonhematologic Toxicity ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Carboplatin Auc

PURPOSE: This phase I/II study was performed to evaluate the feasibility of administering the topoisomerase inhibitor topotecan in combination with carboplatin. PATIENTS AND METHODS: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m2/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m2/d and carboplatin AUC of 5, topotecan 0.75 mg/m2/d and carboplatin AUC of 5, and topotecan 1.0 mg/m2/d and carboplatin AUC of 5. RESULTS: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m2/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m2/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule. CONCLUSION: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m2/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m2/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.

scholarly journals Phase I study of intraperitoneal bevacizumab for treating refractory malignant ascites

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098666
Author(s):  
Furong Kou ◽  
Jifang Gong ◽  
Yan Li ◽  
Jian Li ◽  
Xiaotian Zhang ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Total Duration ◽  
Abdominal Distension ◽  
Malignant Ascites ◽  
Maximum Tolerated Dose ◽  
Duration Of Treatment ◽  
Grade 3 ◽  
Anti Tumor Activity

ObjectiveThis prospective, dose-escalation phase I study evaluated the safety and efficacy of intraperitoneal bevacizumab in managing refractory malignant ascites and explored the recommended dose of bevacizumab for further study.MethodsPatients with refractory malignant ascites were enrolled. Bevacizumab was intraperitoneal administered weekly at an initial dose of 2.5 mg/kg, with dose escalation to 5 and 7.5 mg/kg performed following the standard “3 + 3” rule. The total duration of treatment was 2 or 3 weeks.ResultsBetween December 2013 and September 2014, 13 patients (2.5 mg/kg, n = 4; 5 mg/kg, n = 3; 7.5 mg/kg, n = 6) with refractory malignant ascites were enrolled. Bevacizumab was well tolerated, and the most common treatment-related adverse events were abdominal pain (5/13), abdominal distension (2/13), and fatigue (2/13). The dose-limiting toxicity at 7.5 mg/kg was grade 3 bowel obstruction (1/13). The maximum tolerated dose (MTD) was not reached. The overall response and disease control rates were 7.7 and 61.5%, respectively.ConclusionsIntraperitoneal bevacizumab safe and well tolerated for treating malignant ascites, and the MTD was not reached at doses of 2.5 to 7.5 mg/kg. Intraperitoneal bevacizumab at 7.5 mg/kg weekly is recommended for further study to verify its anti-tumor activity. Trial registration: Clinical Trials NCT01852409.

Phase I Study of the Novel Surivin and cdc2/CDK1 Inhibitor Terameprocol in Patients with Advanced Leukemias.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1039-1039 ◽  
Author(s):  
Raoul Tibes ◽  
Kevin T. McDonagh ◽  
Lazaros Lekakis ◽  
Neal Frazer ◽  
Scott Mohrland ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
Drug Exposure ◽  
Hematological Malignancies ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
The Novel ◽  
Regulatory Pathways ◽  
Apoptosis Protein ◽  
Grade 3

Abstract Abstract 1039 Poster Board I-61 Background: The inhibitor of apoptosis protein (IAP) survivin is central in integrating proliferative and cell cycle regulatory networks. In leukemic cells, survivin mediates survival as well as resistance to chemotherapeutics and Flt-3 inhibitors. Experimentally targeting survivin has shown anti-leukemic activity and is a postulated therapeutic approach. Herein we report a clinical trial with the novel survivin and cdc2 (CDK1) inhibitor Terameprocol (EM-1421) in patients (pts) with advanced hematological malignancies. As little is known about in-vivo up- and downstream regulatory pathways of survivin and it's inhibition, specimens from pts were collected for correlative pharmacodynamic (PD) marker analysis. Methods: Open-label, single agent, phase I dose escalation study of Terameprocol (T) in pts with advanced, relapsed or refractory hematological malignancies (AML, ALL, MDS, advanced CLL or CML). Pts age > 18 years with adequate organ function and performance status (ECOG) ≤ 1were treated with 1000, 1500 and 2200 mg of intravenous Terameprocol 3x/week (wk) for 2 of 3 wks in cohorts of 3 pts to establish the safety, maximum tolerated dose (MTD) and to assess pharmacokinetics at the studied dose schedule (primary objectives). Secondary objectives were to select the recommended phase 2 dose (RP2D) and to assess anti-leukemic activity and PD marker regulation (baseline, cycle 1 day 5 and 12, end of study). Results: Between 8/2007 and 3/2009, sixteen pts (4 female, 12 male) with a median age of 68.5 years (range 42-78) and median of 2 prior regimens (range 0-5) were enrolled. Most pts had AML (n=13), 7 pts primary and 6 pts secondary or treatment related AML; one pt each had CML-BP, T-ALL and MDS. Ten pts had unfavorable or complex cytogenetics including 6 pts with 5q/7q and 2 pts with 11q23 aberrations. Four, 5 and 6 pts were treated at the 1000, 1500 and 2200 mg dose cohorts respectively. One pt did not start treatment on study. 15 pts received ≥ 1 dose/cycle, 6 of whom (38%) received ≥ 2 cycles of T (range 1-5). Common possible or probable treatment related adverse events (AE) were grade 1 or 2 headache (n=3, 20%), transaminitis (grade 2 n=2, grade 3 n=2) and pruritus (n=2). Treatment related serious AE's (SAE) was a grade 4 pneumonia in 1 pt. Non-drug related SAE's ≥ grade 3 or 4 included sepsis/febrile neutropenia (n=3), pneumonia (n=2), dyspnea (n=2), cerebral hemorrhage (n=1), confusion/mental status change (n=1), cardiac arrest (n=1) and AML progression (n=3) leading to death in 2 pts. No AE/SAE was felt to constitute a dose limiting toxicity (DLT) per protocol definition. However, due to grade 3 transaminitis observed in 2 pts together with concerns of compromised respiratory status of pts treated at the 2200 mg cohort, the investigators determined the maximum tolerated dose (MTD) to be 1500 mg 3x/week for 2 of 3 weeks, which is also the recommended RP2D. One heavily pretreated pt (3 prior regimens) with CML-BP myeloid, achieved a partial remission (1500 mg) and transfusion independence for 5 cycles prior to disease progression. Hematological improvement (HI-E, HI-P) was seen in 1 pt (1000 mg), and 5 pts had stable disease. Surprisingly, Cmax of T at 1500 mg was higher than at 2200 or 1000 mg. Overall concentrations of T were in the same range as measured in previous studies of T in solid tumors (daily x5), indicating adequate drug exposure at the schedule studied. PD samples at indicated time points were collected and are currently being analyzed to assess the effects of T on survivin, cdc2/CDK1 and survivin associated regulatory genes. Conclusion: The novel small molecule surivin inhibitor Terameprocol can be safely administered to pts with advanced leukemias. Sufficient drug exposure was seen in pts and the MTD and RP2D were established for future studies. Clinical activity was observed in a pt with myeloid CML-BP and potentially in pts with AML. Interestingly, previous work showed an association between progression to advanced stages of CML and survivin expression. Data on correlative PD marker experiments will be presented. Disclosures: Tibes: Erimos Pharmaceuticals : Research Funding. McDonagh:Erimos: Research Funding. Frazer:Erimos Pharmaceuticals: Employment. Mohrland:Erimos Pharmaceuticals: Employment. Von Hoff:Erimos Pharmaceuticals: Consultancy.

FOLFOX and nab-paclitaxel (nab-P) for advanced pancreatic cancer: A phase I study.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 258-258
Author(s):  
Howard Safran ◽  
Kevin Charpentier ◽  
Kimberly Perez ◽  
Kalyan Mantripragada ◽  
Trevor Clark Austin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Maximum Tolerated Dose ◽  
Level 3 ◽  
Grade 3 ◽  
Level 2

258 Background: FOLFIRINOX improves survival in advanced pancreatic cancer, however the contribution of irinotecan is uncertain. The addition of irinotecan to gemcitabine was not superior to gemcitabine alone in pancreatic cancer, however nab-P demonstrates a survival benefit. This phase I study was designed to evaluate the maximum tolerated dose (MTD) of the addition of nab-P to fluorouracil, leucovorin, oxaliplatin (FOLFOX-A). Methods: Patients with metastatic or locally advanced pancreatic adenocarcinoma without prior treatment received oxaliplatin, 85 mg/m2, leucovorin 400 mg/m2 and 5-FU 2400 mg/m2 with 3 dose levels of nab-P (125, 150 and 175 mg/m2) every 2 weeks. Pegfilgrastim was required during the first 2 cycles. Dose limiting toxicities (DLTs) were defined in the first 2 cycles of treatment. Results: Fifteen patients were entered: Dose level 1 (n=6), dose level 2 (N=6), dose level 3 (N=3). The median age was 64 (35-81). Ten patients had metastatic and 5 had locally advanced disease. DLTs of nausea and fatigue occurred in 2 of 3 patients at dose level 3. Two patients developed grade 3 neuropathy after >= 10 cycles of treatment. One patient had grade 3/4 neutropenia. Eight of fifteen patients (53%) had a partial response. Conclusions: The MTD of nab-P is 150mg/m2 every 2 weeks with FOLFOX. Cumulative peripheral neuropathy, similar to other FOLFOX regimens, is the most significant toxicity generally occurring after >= 10 cycles of treatment. FOLFOX-A has substantial activity and may represent a promising regimen in pancreatic cancer. Patients are currently being accrued to an expansion phase utilizing dose level 2. Supported by the Davis and Browning families and LIFEcycle. Clinical trial information: NCT01744353.

A Phase I Evaluation of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis: Clinical Response Is Accompanied by Significant Reduction in JAK2V617F Allele Burden.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 755-755 ◽  
Author(s):  
Animesh D. Pardanani ◽  
Jason R Gotlib ◽  
Catriona Jamieson ◽  
Jorge Cortes ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Drug Exposure ◽  
Maximum Tolerated Dose ◽  
Spleen Size ◽  
Allele Burden ◽  
Grade 3 ◽  
Wbc Count

Abstract Abstract 755 Background: TG101348 is a potent, orally bioavailable, JAK2-selective small molecule inhibitor, that is currently being evaluated in a Phase I study for the treatment of myelofibrosis. Data from the dose escalation cohort (n=28; 30-800mg administered as a single daily dose) showed dose-linear plasma exposure, with mean elimination T1/2 at steady state ranging from 20 to 52 hours. The dose-limiting toxicity was asymptomatic grade 3 or 4 amylasemia/lipasemia that was reversible, and the maximum tolerated dose (MTD) was 680mg. The most frequent non-hematological toxicities were mild nausea, vomiting, and/or diarrhea that were easily controlled or resolved spontaneously. Grade 3/4 neutropenia and thrombocytopenia were observed in 14% and 25% of patients, respectively. TG101348 had activity in reducing spleen size, leukocyte count, and JAK2V617F (VF) allele burden. Here, we present updated results with a focus on data from the dose confirmation cohort who initiated treatment at a dose of 680mg/day. Results: Fifty nine patients (median age=66 years; range 43-86) have been treated – 28 in the dose escalation phase, and 31 in the dose confirmation phase. Overall, 44 patients had PMF, 12 post-PV MF, and 3 post-ET MF; 86% were VF-positive. Median palpable spleen size was 18cm and 22 patients were RBC transfusion-requiring at study enrollment. After a median follow-up of 12 weeks (range <1-76), 18 (31%) patients have discontinued treatment due to toxicity (n=7; thrombocytopenia=3, neutropenia=1), comorbidities (n=5), withdrawal of consent (n=4), or non-compliance/lack of response (1 each). The remaining 41 patients are currently at the following dose levels: 680mg (n=14), 520-600mg (n=16), 360-440mg (n=10), and 240mg (n=1). The cumulative drug exposure to date is 362 patient-months; exposure at or above MTD (≥680mg) is 154 patient-months. Forty patients (68%) started treatment at ≥680mg. Toxicity: TG101348 is well tolerated. Of the patients who started at ≥680mg, Gr3/4 neutropenia was observed in 15/0% and Gr3/4 thrombocytopenia in 20/10%. Twenty four (60%) patients did not require RBC transfusions at baseline (median Hgb=9.6g/dL; range 7.4-13.1); of these, 42% and 8% of patients developed Gr3 and Gr4 anemia, respectively. The majority of patients who started at ≥680mg developed mild nausea (1 Gr3), vomiting (1 Gr3), and/or diarrhea (3 Gr3) that were self-limited or easily controlled. Other non-hematological toxicities included Gr1/2 transaminitis (38%), Gr1/2 serum creatinine elevation (38%), and asymptomatic hyperlipasemia (33%). Efficacy: Thirty three patients who started at ≥680mg have completed at least 3 cycles of treatment; at 3 months, reduction in palpable spleen size (baseline median=18cms; range 6-32) was at least 50% in 22 (67%) patients; the spleen became non-palpable in 9 (27%) patients. All 21 patients with leukocytosis at baseline (WBC range 11 to 203 ×109/L) who started at ≥680mg have experienced a marked reduction in their WBC count (range 4 to 90); 70% had a normal WBC count at their last follow-up visit. Overall, 48 of the 51 VF-positive patients completed at least 1 cycle and were evaluable for response in VF allele burden; at last available follow-up, the median decrease in granulocyte mutant allele burden was 48%; 21 (44%) patients have had a ≥50% reduction, and in the group who started treatment at ≥680mg, 48% have had a ≥50% reduction. Of those evaluable, there was clinically significant benefit or resolution of constitutional symptoms, including early satiety, fatigue, cough, pruritus, and night sweats. Conclusions: TG101348 continues to be well tolerated in patients with myelofibrosis. Spleen and leukocyte responses are frequent, observed early, and produce substantial clinical benefit for patients. These responses are associated with significant decrease in VF allele burden and point to activity of TG101348 against the malignant clone in myelofibrosis. Disclosures: Pardanani: TargeGen: Research Funding; Cytopia: Research Funding. Off Label Use: Data from ongoing clinical trial will be presented. Gotlib:TargeGen: Research Funding. Jamieson:Merck: Research Funding; Pfizer: Research Funding; Wintherix: Consultancy; TargeGen: Research Funding; Celgene: Research Funding. Cortes:Targegen: Research Funding. Stone:Cephalon: ad hoc advisory board. Silverman:TargeGen: Consultancy. Shorr:TargeGen: Employment, Equity Ownership. Gilliland:Merck: Employment. Tefferi:TargeGen: Research Funding.

A phase I study evaluating a novel schedule of oral eniluracil (EU) combined with escalating doses of oral 5-fluorouracil (5- FU)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2560-2560
Author(s):  
J. R. Infante ◽  
S. F. Jones ◽  
M. Lawton ◽  
P. Wing ◽  
R. K. Malik ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Dihydropyrimidine Dehydrogenase ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Peripheral Blood Mononuclear ◽  
Previously Treated ◽  
Proportional Increase ◽  
Grade 3 ◽  
Anti Tumor Activity

2560 Background: 5-FU, a commonly utilized cytotoxic, is rapidly catabolized by dihydropyrimidine dehydrogenase (DPD), and requires anabolic conversion for anti-tumor activity. It has poor oral bioavailability due to DPD in the GI tract and liver, and toxicities such as hand-foot skin reaction. In addition, high levels of DPD are associated with 5-FU resistance. EU is a mechanism-based irreversible inactivator of DPD. Early studies in combination with oral 5-FU demonstrated activity; however, 3 Phase 3 studies were negative, due to an unrecognized inhibition of 5-FU anabolic activation by EU (Fourie et al; 2006 ASCO Proceedings; a 2058). Lower doses of eniluracil given 12–20 hrs prior to 5- FU preserves the desired DPD inhibition, without inhibiting these anabolic enzymes. Methods: The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and DPD activity in peripheral blood mononuclear cells (PBMCs) following administration of a fixed dose of EU in combination with escalating doses of 5-FU. The combination of oral 5.0 mg EU 12 to 20 hours prior to oral 5-FU, is given qW for 3 weeks in 28 day cycles. Results: Twenty subjects have been enrolled, at 5-FU doses of 30, 40, 50, 60, and 70 mg. A total of 39 cycles have been administered, with 4 patients currently on study. The oral combination of EU and 5-FU has been well tolerated. All toxicities have been grade 1 or 2 with the exception of two grade 3 toxicities reported at the 50mg dose (anemia and neutropenia). The grade 3 neutropenia is the only observed DLT and resulted in a 1 week delay in initiation of cycle 2. No CR or PR noted, but 4 patients (2 previously treated with 5-FU) with 4 cycles of SD. 95–100% of DPD inhibition achieved at the time of 5-FU dosing and PK results demonstrate a dose proportional increase in 5-FU Cmax and AUC, and a half life of ∼3.5 hours. Conclusions: The oral combination of 5mg of EU given 12–20 hrs prior to 5-FU has been well tolerated and achieves full functional inhibition of DPD in all patients. The MTD is not yet defined and the next cohort is enrolling at the 80mg dose. EU in combination with 5-FU may provide a promising therapeutic option for patients with tumors known to be resistant to 5-FU due to high levels of DPD. No significant financial relationships to disclose.

Phase I study of the novel anticancer drug PM00104 as a 24-hour IV infusion every 3 weeks (q3w) in patients (pts) with advanced solid tumors or lymphoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2568-2568
Author(s):  
J. Capdevila ◽  
S. Clive ◽  
J. Tabernero ◽  
P. Lardelli ◽  
A. Soto-Matos ◽  
...  
Keyword(s):  
Phase I ◽  
Safety Profile ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Grade 3 ◽  
Ecog Ps ◽  
Anti Tumor Activity

2568 Background: PM00104 is a novel synthetic alkaloid related to the marine compounds jorumycin and renieramycins. Preliminary preclinical studies suggest changes in cell cycle and DNA binding properties and transcriptional inhibition as main mechanisms of action. PM00104 has shown broad in vitro and in vivo anti-tumor activity (IC50 ≤ 10-8 M) with an acceptable toxicology profile. Methods: The aim of this phase I study was to assess the safety profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), relationship between PK and pharmacodynamics (PD) and anti-tumor activity of PM00104 administered as a 24-hour i.v. infusion q3w. Sequential cohorts of 3–6 pts were treated at 133, 266, 400, 800, 900, 1600, 3200, 4000 and 5000 μg/m2. Results: Twenty nine pts have been treated (18 male, 11 female; median age: 59, range: 44–78; ECOG PS ≤2). Five pts developed DLTs: 2 pts at 5000 μg/m2 (grade 4 thrombocytopenia/neutropenia and grade 3 nausea/vomiting in 1 pt; and grade 3 nausea in 1 pt); 1 at 4000 μg/m2 (grade 4 neutropenia/thrombocytopenia and grade 3 asthenia); 1 at 3200 μg/m2 (grade 3 tumor pain) and 1 at 266 μg/m2 (grade 3 transaminase increase). The MTD was reached at 5000 μg/m2 and the RD at 4000 μg/m2. At the RD 6 more pts have been included in order to further evaluate the safety profile and anti-tumor activity. Other adverse events included nausea and vomiting (more frequent at doses ≥800 μg/m2), fatigue, anorexia and diarrhea; most of them being of ≤grade 2 severity. No objective responses were seen but 3 pts with pancreatic adenocarcinoma, hepatocarcinoma and lower esophagus adenocarcinoma presented stable disease lasting >3 months. PM00104 shows a dose-proportional PK profile, the half-life being 20–30 hours and the volume of distribution around 1000 L. Conclusions: PM00104 has shown an acceptable safety profile with signs of anti-tumor activity in pts with advanced malignancies when administered as a 24-hour i.v. infusion q3w. PM00104 is also being evaluated with other administration schedules as monotherapy and in combination with other anti-tumor agents. [Table: see text]

scholarly journals Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

2009 ◽  
Vol 27 (34) ◽  
pp. 5713-5719 ◽  
Author(s):  
Paul G. Richardson ◽  
Edie Weller ◽  
Sundar Jagannath ◽  
David E. Avigan ◽  
Melissa Alsina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Median Overall Survival ◽  
Progressive Disease ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Previously Treated ◽  
Grade 3

PurposeLenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM.Patients and MethodsPatients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m2on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination.ResultsThirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months.ConclusionLenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM.

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