A phase I trial of ABT-751 and carboplatin (C) in patients (pts) with previously treated non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17098-17098 ◽  
Author(s):  
K. H. Dragnev ◽  
J. R. Rigas ◽  
W. M. Disalvo ◽  
S. A. Simeone ◽  
A. E. Hagey ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Single Agent ◽  
Xenograft Model ◽  
The United States ◽  
Buccal Swabs ◽  
Previously Treated ◽  
Dose Levels

17098 Background: NSCLC is the leading cause of cancer mortality for men and women in the United States. More effective treatments are needed to prolong survival and improve quality of life. Platin-containing chemotherapy doublets are commonly used in NSCLC treatment. ABT-751 is a novel oral anti-microtubule agent targeting the colchicine binding site. As single agent, it was well-tolerated and showed a preliminary signal of activity in previously treated NSCLC. In vivo studies demonstrated additive activity between ABT-751 and cisplatin in a NSCLC xenograft model. Methods: A phase I trial of ABT-751 and C was conducted in pts with advanced previously treated NSCLC. Primary objective - maximum tolerated dose (MTD). Secondary objectives - toxicities, efficacy, and surrogate markers of response (cell cycle changes and cyclin D1 expression) in buccal swabs from pts at the phase II dose. Six dose levels - 1: ABT-751 100mg bid, C AUC 4.5; 2: ABT-751 125 mg bid, C AUC 4.5; 3: ABT-751 125 mg bid, C AUC 6; 4: ABT-751 150 mg bid, C AUC 6; 5: ABT-751 175 mg bid, C AUC 6; 6: ABT-751 200 mg bid, C AUC 6. ABT-751 was taken orally twice a day for 14 days in a 21 day cycle, C was administered intravenously on day 4 during cycle 1 and on day 1 on subsequent cycles. Rapid dose escalation was used for the first 3 dose levels followed by cohorts of at least 3 patients for the remaining dose levels. Results: Eight pts were enrolled, all stage IV NSCLC, 4 women, median age 62 (47–73), all KPS 80, 6 had one and 2 had 2 prior therapies. A median of 3.5 (1–4) cycles was administered. Dose-limiting toxiticies of grade 3 fatigue and grade 4 thrombocytopenia and neutropenia were observed in 2/5 patients on dose level 4. Common grade 2 toxicites were constipation and peripheral sensory neuropathy (levels 2–4). MTD was dose level 3. Seven pts were evaluable for response, 2 had partial responses (levels 2 and 4, both had one prior therapy), 4 had stable disease, 1 had disease progression. Median time to progression was 18.7 weeks (6–24+). Pharmacokinetic analyses and buccal swabs are being performed. Conclusions: The recommended phase II doses are ABT-751 125 mg twice daily for 14 days and carboplatin AUC 6 on a 21-day cycle. This regimen is well tolerated and shows preliminary evidence of activity for previously treated NSCLC. [Table: see text]

Phase I Study of Flavopiridol in Combination with Imatinib Mesylate (STI571, Gleevec) in Bcr/Abl+ Hematological Malignancies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1102-1102 ◽  
Author(s):  
Steven Grant ◽  
Judith E. Karp ◽  
Omer N. Koc ◽  
Brenda Cooper ◽  
Selina Luger ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Phase Ii Trials ◽  
Pronounced Increase ◽  
Dose Levels

Abstract Imatinib (Im), a rationally designed inhibitor of the Bcr/Abl kinase as well as other kinases, represents the standard treatment for Bcr/Abl+ malignancies. Im as a single agent, however, is not curative. Flavopiridol (Fl), an investigational cyclin dependent kinase inhibitor, is broadly active in vitro against human leukemia cells (Blood91:2482,1998). Previously we have shown that simultaneous disruption of a survival signaling pathway and a cell cycle regulatory pathway results in a pronounced increase in leukemic cell death (Cancer Res.61:5106,2001) and in more recent preclinical studies demonstrated synergistic interactions between Im and Fl in Bcr/Abl+ leukemia cells, including some that were resistant to Im (Clin Cancer Res8;2976,2002). Based on these considerations, we have initiated a phase I trial to identify appropriate doses of Im+Fl for further investigation. Eligible patients (pts) have CML with a suboptimal response to prior Im, CML in blast crisis, or Bcr/Abl+ acute lymphocytic leukemia (ALL). CML-BC and ALL patients may be Im-naïve. Pts receive Im by continuous daily oral dosing and Fl by 1 hour intravenous infusion weekly x 3 repeated every 4 weeks. Targeted dose levels are (Fl/Im; mg/m2): 30/400, 30/600, 45/600, 60/600, 60/800, 60/1000. Patients are divided into 2 strata based upon blast percentage in peripheral blood or bone marrow: stratum 1, <15%; and stratum 2, ≥15%. For stratum 1 dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelet for > 1 week or grade ≥ 3 non-heme toxicity; for stratum 2, DLT is profound marrow hypoplasia in the absence of persistent leukemia. In stratum 1, 16 pts have been treated at 4 dose levels; in stratum 2, 5 pts in the 1st and 3rd dose level. In stratum 1, 1 DLT has occurred at dose level 4 (cholecystitis requiring cholecystectomy); in stratum 2, 1 DLT has occurred at dose level 3 (sepsis/multi-organ failure which was not clearly related to treatment). The only frequent toxicities have been hematological. 4 pts have experienced objective responses including complete hematological remissions in 2 pts in stratum 1 treated with Im/Fl 30/600 who had been previously treated with Im 800 and complete hematological remissions in 2 pts in stratum 2 (who had not received prior Im). Preliminary studies indicate no Fl impact upon Im pharmacokinetics, and variable post-treatment effects on signaling pathways in CML cells. These findings indicate that a regimen consisting of Fl and Im is tolerable and active in at least some patients with Bcr/Abl+ hematologic malignancies, including some with Im-resistant disease. Pending identification of the MTD and the recommended Phase II dose (RPTD), Phase II trials will be necessary to assess the activity of this strategy more definitively.

Phase I trial of regorafenib, hydroxychloroquine, and entinostat in metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15580-e15580
Author(s):  
Timothy J Brown ◽  
Thomas Benjamin Karasic ◽  
Charles John Schneider ◽  
Ursina R. Teitelbaum ◽  
Kim Anna Reiss ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Weight Loss ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Dose Level ◽  
Phase I Trial ◽  
Level 3 ◽  
Previously Treated ◽  
Level 1 ◽  
Dose Levels

e15580 Background: The antiangiogenic tyrosine kinase inhibitor regorafenib provides a survival benefit in patients with previously treated metastatic colorectal cancer. Antiangiogenic therapy causes hypoxic stress within tumor cells, which activate autophagy as a survival mechanism. Entinostat, a histone deacetylase (HDAC) inhibitor, increases dependence on autophagy through epigenetic mechanisms. Hydroxychloroquine (HCQ) blocks autophagy by blunting lysosomal acidification and is synergistic with antiangiogenic therapies. We hypothesized that HCQ and entinostat would be tolerable with regorafenib and potentiate the antitumor response. Methods: This was a 3+3 phase I trial to find the recommended phase II dose (RP2D) of HCQ and entinostat with regorafenib in patients with metastatic colorectal cancer previously treated with a fluoropyrimidine, oxaliplatin, and irinotecan. No prior regorafenib or HDAC inhibitor therapy was permitted. Regorafenib was dosed at 160mg daily on days 1-21 of 28-day cycles, with provision to lower the starting dose to 80mg if toxicity was excessive. Entinostat was dosed at 3mg weekly in dose level 1 and at 5mg weekly in dose levels 2 and 3 while HCQ was dosed at 200mg qAM and 400mg qPM in dose levels 1 and 2 and at 600mg BID at dose level 3. Expansion was planned at the RP2D with a primary endpoint of objective response rate. Results: Twenty-eight patients were screened, and 20 patients were enrolled from November 2017 to January 2020. Six patients were treated at dose level 1 with no dose-limiting toxicity. The starting regorafenib dose was reduced to 80mg after 3 patients discontinued therapy early due to fatigue or rash due to regorafenib. At dose level 2, 7 patients were enrolled to achieve 6 evaluable patients. One DLT (G3 fatigue) was noted and one patient withdrew consent after 14 days due to fever and tumor pain flare possibly related to treatment. Six patients enrolled at dose level 3; no DLTs were seen. One additional patient received HCQ 400mg BID instead of 600mg BID due to a clerical error. Weight loss (60%), fatigue (50%), and anorexia (50%) were the most common toxicities. Thirteen grade 3 toxicities were noted, with rash (15%), fatigue (10%), and alkaline phosphatase elevation (10%) the most common. No grade 4 toxicities were observed. Seven patients discontinued therapy early due to toxicity. Nearly all patients experienced rapid weight loss, with a range of 1.5 lbs to 27.1 lbs and a median weight loss of 9.5 lbs at two weeks. No objective responses were observed. The median PFS was 1.8 months, the median OS was 5.2 months, and no patient remained on study longer than 4 months. Expansion was not pursued due to toxicity and lack of efficacy. Conclusions: The combination of regorafenib, HCQ, and entinostat was poorly tolerated without evident activity in metastatic colorectal cancer. The substantial weight loss suggests a potential adverse metabolic interaction between these drugs. Clinical trial information: NCT03215264.

Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

1993 ◽  
Vol 11 (3) ◽  
pp. 499-506 ◽  
Author(s):  
J Weber ◽  
J C Yang ◽  
S L Topalian ◽  
D R Parkinson ◽  
D S Schwartzentruber ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Interleukin 6 ◽  
Phase Ii Trials ◽  
Organ Toxicity ◽  
Advanced Malignancies ◽  
Major Organ ◽  
Dose Levels ◽  
Grade Iii

PURPOSE Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects. PATIENTS AND METHODS Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously. RESULTS Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen. CONCLUSION A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.

A Phase I Trial of Sirolimus (Rapamycin) in Pediatric Patients with Relapsed/Refractory Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2834-2834 ◽  
Author(s):  
Susan R. Rheingold ◽  
Nancy Sacks ◽  
Yueh J. Chang ◽  
Valerie I. Brown ◽  
David T. Teachey ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Stable Disease ◽  
Phase I Trial ◽  
Pediatric Patients ◽  
Loading Dose ◽  
Mtor Inhibition ◽  
Level 1 ◽  
Dose Levels

Abstract Background: Downstream inhibition of the mammalian Target of Rapamycin (mTOR) pathway by sirolimus affects a variety of cellular functions including cap-dependent protein translation and cell cycle progression from the G1-to-S phase. Inhibition of mTOR also leads to dysregulation of the upstream signaling pathway that couples growth factor-receptor binding to mTOR activation through the PI-3 kinase/Akt pathway and may render PTEN-induced resistant lymphoblasts sensitive to agents that target the mTOR pathway. This hypothesis is supported by preclinical data which shows that sirolimus inhibits growth of ALL lines in vitro and has activity in a murine model of leukemia including ALL xenografts. Based upon these preclinical data we have piloted a Phase I trial of sirolimus in pediatric patients with relapsed acute leukemia. Methods: Pediatric patients with ≥ 2nd relapse of acute leukemia were enrolled in a Phase I dose escalation trial of oral daily sirolimus. We used a starting dose that is known to be well tolerated in pediatric renal transplant recipients and results in levels that inhibit ALL growth in vitro. At dose level 1, a loading dose of 9 mg/m2 was given on day 0, and 3 mg/m2 was given daily on days 1 to 21 or 28. Dose level 2 has a loading dose of 12 mg/m2 and daily dose of 4mg/m2. Sirolimus trough levels were obtained on days 3, 7, and end of cycle. Bone marrow aspirates (BM) were performed prior to therapy, and on day 7 (if no peripheral blasts) and day 21 or 28. Peripheral blood (PB) mononuclear cells and PB and/or BM lymphoblasts were obtained on days 0, 3, 7, 14, and 21/28 to evaluate the effect of sirolimus on intracellular targets, including ribosomal protein S6 (a pharmocodynamic marker of mTOR inhibition), 4e-BP1 and STAT5. Results: To date, 5 males and 3 females, ages 1–21, have been enrolled on study at the first 2 dose levels. Six patients had ALL, 1 infant had MLL(r) ALL, and 1 had AML. They had received 2–4 prior therapies. Three patients with ALL had stable disease at the end of the first cycle. One had a decrease in BM lymphoblasts from 39% to 12% by day 28 and a drop in absolute blast count (ABC) in the PB from 1134 to 290 but remained thrombocytopenic. The patient with MLL(r) infant ALL had a decrease in PB ABC from 62,415 to 0 by day 14 but had no change in BM lymphoblast % on day 21. Two of the 3 patients with stable disease progressed during their second cycle of therapy. The remaining 5 patients had progressive disease or were removed from study prior to the end of cycle 1 and were non-evaluable. At dose level 1 average trough level on day 7 was 10.9 (range 1–20.7) and at the end of the first cycle for non-progressors was 8.5 (range 5.8–12.2). There have been no DLTs attributable to sirolimus in any cycle to date. Preliminary immunoblots show hypophosphorylation of S6 in patients’ PB and BM after initiating sirolimus therapy. Conclusions: Sirolimus was well tolerated in pediatric patients due to its ease of administration and lack of toxicity. At the first and second dose levels there have been 2 patients and 1 patient with stable disease, respectively. Preliminary biologic data shows evidence of inhibition of mTOR, manifested by a decrease in phosphorylated S6, suggesting that S6 may be used as a biomarker for response to mTOR inhibition. Although sirolimus at these doses had a modest impact on the leukemia burden, it may be more effective when used in concert with other cytotoxic agents that inhibit cell growth and survival. Combined therapy is being investigated.

Fludarabine-Based Conditioning for Allogeneic Marrow Transplantation From Unrelated Donors in Severe Aplastic Anemia (SAA): Serious and Unexpected Adverse Events in Pre-Defined Cyclophosphamide (CY) Dose Levels

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3009-3009
Author(s):  
Jakub Tolar ◽  
H. Joachim Deeg ◽  
Sally Arai ◽  
Mitchell Horwitz ◽  
Joseph H. Antin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Marrow Transplant ◽  
The Other ◽  
Unrelated Donor ◽  
Dose Levels

Abstract Abstract 3009FN2 Objective: To determine toxicity and efficacy of adding fludarabine (FLU) to a regimen of total body irradiation (TBI), anti-thymocyte globulin (ATG) and cyclophosphamide (CY), with de-escalation of the CY dose. The goal is to minimize CY-related toxicities while preserving (or improving) engraftment and survival in patients with SAA receiving an unrelated donor marrow transplant. Patients and Methods: Since May 2006, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), sponsored by the NHLBI and NCI, has conducted a prospective Phase I/II clinical trial of unrelated donor marrow transplantation in SAA (BMT CTN 0301). Patients with SAA are eligible if they are < 65 years, have adequate organ function, and have an available unrelated marrow donor matched 7 of 8 HLA-A, B, C, DRB1 loci. Patients with Fanconi anemia and other marrow failure syndromes are excluded. All patients receive TBI 200 cGy, ATG (either thymoglobulin: 3 mg/kg IV or ATGAM 30 mg/kg IV daily × 3, days –4 to –2), FLU (30 mg/m2 IV daily × 4, days –5 to –2). The Phase I portion of the trial sequentially tested four CY dose levels: 150 mg/kg (administered days –4 to –2); 100 mg/kg (days –3 to –2); 50 mg/kg (day –2); and, 0 mg/kg, and allowed enrollment of up to six patients at each CY dose level unless toxicity or graft failure boundaries were crossed. In the Phase II portion of the trial, patients enroll onto the optimal CY dose level, which is chosen using adaptive Bayesian criteria to rank desirability of the CY doses. All patients are followed for two years after transplantation. Early stopping guidelines are used to monitor for graft failure and early transplant-related mortality through day 100. Results: Twenty-one patients accrued to the Phase I portion of the trial. CY dose level 0 mg/kg was closed after all three enrolled patients developed secondary graft failure. All received a second allograft. One patient remains alive at 23 months after the first transplantation. The other two died from adult respiratory distress syndrome (ARDS) at 114 days after the first transplant and idiopathic pneumonia at 200 days after the first transplant. Review of Phase I results for the other three dose levels suggested CY dose 150 mg/kg as the optimal dose level for Phase II testing. However, after an additional eight patients were treated at this dose, the level was closed to further accrual because of excess toxicity. Seven of the 14 patients receiving 150 mg/kg of CY (and 7 of the last 8 enrolled) died. Causes of death were cardiac/pulmonary/multi-organ failure (n=4), ARDS (n=2), and parainfluenza virus type 3 pneumonia (n=1). Bayesian evaluation of the two remaining dose levels indicates very similar desirability scores and accrual continues at both the CY 100 mg/kg and 50 mg/kg levels. As of July 15, 2011, a total of 61 patients have been enrolled, 17 on the two closed levels, 33 on the 100 mg/kg level and 11 on the 50 mg/kg level. Conclusions: Early analysis of this trial, made necessary by these unexpected severe adverse events, revealed two important findings among patients receiving low-dose TBI, ATG, and FLU at the doses outlined: 1) CY dose 0 mg/kg is associated with higher than expected graft failure; and, 2) CY dose 150 mg/kg is associated with excess transplant-related toxicity. Neither CY dose level should be tested further in the context of the regimen used in this trial. To date, the two intermediate CY dose levels (100 mg/kg and 50 mg/kg) have not crossed the graft failure or fatality stopping boundaries and accrual is in progress. Disclosures: Pulsipher: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

A phase I trial of S-1 plus vinorelbine in patients with unresectable advanced or metastatic non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19098-e19098
Author(s):  
H. Suyama ◽  
Y. Shigeoka ◽  
T. Igishi ◽  
S. Matsumoto ◽  
M. Kodani ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Phase I Trial ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung

e19098 Background: We reported the efficacy of the combination treatment of tegafur-uracil (UFT) and vinorelbine (VNR) for the elderly patients (pts) (>70) with advanced non-small cell lung cancer (NSCLC) in ASCO 2007 (Abstract - No. 18075). Although the cisplatin-based doublets are still milestone for the pts with advanced NSCLC, non-platinum based doublet regimens remain as a matter of development judging from recent meta-analysis. Tegafur-5-chloro-2,4-dihydroxypyridine-potassium oxonate (S-1), a new oral fluoropyrimidine, has been studied extensively, and appears promising for various kinds of cancers including NSCLC. Thus, we conducted this phase I trial using VNR and new oral fluoropyrimidine, S-1. Methods: Pts with advanced NSCLC, who had received at least one prior platinum-containing regimen, were eligible. In this phase I study, VNR was infused on days 1 and 8, and S-1 was administered from day 2 to day 6 and from day 9 to day 13 of a 3-week cycle. The starting dose of S-1 was 80 mg/m2/day and, if necessary, the dose was decreased to 65 mg/m2/day; VNR was increased from 20 to 25 mg/m2 in this trial. Results: From August 14, 2007 to April 1, 2008, 8 pts enrolled in this study. Median age was 61 (range 49–75). Dose limiting toxicity (DLT) was evaluated during the first 6 weeks of the treatment. No DLT was observed at dose level I (80 mg/m2/day S-1, 20 mg/m2 VNR). At dose level II (80 mg/m2/day S-1, 25 mg/m2 VNR), DLT in the form of neutropenia, hyperglycemia and hyponatremia was observed in 3 of 5 pts. The maximum tolerated dose (MTD) for the present treatment was 80 mg/m2/day S-1 and 25 mg/m2 VNR; the recommended tolerable dose for future phase II trials is therefore 80 mg/m2/day S-1 and 20 mg/m2 VNR. Conclusions: Three-week cycle of VNR (20 mg/m2), infused on days 1 and 8; S-1 (80 mg/m2/day), administered from day 2 to day 6 and from day 9 to day 13, is being examined in our phase II trial for first-or second-line treatment of NSCLC. No significant financial relationships to disclose.

Survival of patients considered for participation to contemporary dose-seeking phase trial: Matter of tumour burden, nature of treatment or of dose-levels?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2549-2549
Author(s):  
Juliette Bouchet ◽  
Nicolas Isambert ◽  
Philippe Alexandre Cassier ◽  
Carlos Alberto Gomez-Roca ◽  
Stephanie Clisant ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Phase I ◽  
Dose Level ◽  
Cox Model ◽  
Phase 1 ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Phase 1 Trial ◽  
Dose Levels

2549 Background: We have analyzed the survival of pts considered for participation to contemporary phase 1 trial. Methods: All consecutive pts having signed the PIS/IC have been analyzed. OS have been measured using Kalan-Meier method. RMS had been calculated, RMS (0 to 3) is sum of the following prognostic factors: LDH>ULN, met. sites>2 and albumin <35 g/L. Comparisons have been done with Log-rank tests and Cox model. Results: OS of the entire cohort was 448 days. 73.4% of pts having been enrolled. Among not enrolled pts, 74.1% of pts received another treatment. The OS was 497, 247 and 110 days, in pts enrolled in phase I trial, in pts not enrolled but receiving another treatment and in non-treated pts (p=0.001). After adjustment to RMS and with pts not enrolled but receiving other treatment as reference, the HR was 0.47 (95-CI:0.34-0.66; p=0.0001) in pts enrolled in phase 1 compared and 3.54 (1.92-6.52; p=0.0001) in non-treated pts. We have then more specifically analyzed the pts enrolled in single-agent dose-escalating phase I. The OS was 894, 272 and 395 days in pts receiving the 2 first dose-levels, in those receiving intermediate dose-levels and those receiving the phase 2-recommended dose, respectively (p=0.001). The OS was 328 in pts receiving molecular targeted agent and 539 in those receiving cytotoxic agents (p=0.004). In a multivariate analysis, the nature of investigational agent and the dose-level were not associated with better outcome. The sole prognostic factor for OS in multivariate analysis was the RMS (0+1 vs 2+3: HR=3.80 [1.76-8.20], p=0.01). Conclusions: Inclusion in phase 1 trial was associated with better outcome in both crude analysis and after adjustment to RMS. Among enrolled pts, in multivariate analysis RMS reflecting the tumor burden was the sole prognostic factor, the nature of the drug and the dose-level were not associated with the outcome.

Concurrent treatment with everolimus (RAD001) and hormonoradiotherapy in high-risk locally advanced prostate cancer: Results of a phase I trial.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 150-150 ◽  
Author(s):  
David Azria ◽  
Xavier Rebillard ◽  
Nathalie Coux ◽  
Marta Jarlier ◽  
Rodolphe Thuret ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Advanced Prostate Cancer ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Locally Advanced Prostate Cancer ◽  
Grade 3 ◽  
Dose Levels

150 Background: Everolimus is able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with hormonotherapy and radiation therapy may kill more tumor cells. Methods: We conducted a phase I trial to evaluate the impact of everolimus (RAD001), an mTOR inhibitor, in patients treated concurrently with radiotherapy (RT) and ablative androgen treatment in high-risk locally advanced prostate cancer. Inclusion criteria were high-risk locally advanced non metastatic prostate cancer defined as clinical stage ≥ T3 or Gleason score ≥ 8 or PSA ≥ 20. The week before the beginning of RT, RAD001 was administered at different dose levels, twice daily, until the last day of irradiation. A nonsteroid antiandrogen was also given for 1 month at the beginning of RT. Prostate and seminal vesicle were irradiated up to 74Gy in 37 fractions of 2Gy with concomitant long-term LHRH analogue. The starting dose of RAD001 was 5mg/d with subsequent dose levels of 7.5 and 10 mg/d. The primary endpoint was the determination of the maximum tolerated dose (MTD). Dose escalation was implemented according to the continual reassessment method (CRM). Results: Fifteen patients were enrolled and 14 were assessable for toxicity and response. Significant toxicities were demonstrated at the 7.5 and 10 mg/d dose levels. Dose-limiting toxicity (DLT) occurred in two patients at dose level 7.5 mg/d and characterized by a grade 3 diarrhea and a grade 3 hydronephrosis due to dehydration and kidney lithiasis. DLT also occurred in two patients at dose level 10 mg/d (grade 3 diarrhea and grade 3 laryngopharyngeal infection). The MTD was reached at 7.5 mg/day (dose-level II). The recommended dose of RAD001 was 5 mg/d. After a median follow-up of 22 months, 12 patients are alive, 1 is dead (not related to cancer) and 2 patients had relapsed. Conclusions: Concomitant hormone-radiotherapy and everolimus is well-tolerated with mucositis, hypercholesterolemia, and urinary disorders. The recommended phase-II trial dose of everolimus in this combined setting is 5 mg/day. Clinical trial information: NCT00943956.

scholarly journals A Phase I Trial of Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 150-150 ◽  
Author(s):  
Peter Martin ◽  
Kristie Blum ◽  
Nancy L. Bartlett ◽  
Steven I. Park ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hematological Toxicity ◽  
Mantle Cell ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Levels

Abstract Background Single-agent ibrutinib confers a response rate of 77%, including a complete response (CR) rate of 19% in patients with previously treated mantle cell lymphoma (MCL); however, with a median progression-free survival (PFS) of 14.6 months and 1-year response duration (RD) rate of 69%, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK (Chiron et al. Cancer Discovery 2014). We conducted a phase I trial to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. Methods Adult patients who were ibrutinib and CDK4/6 inhibitor-naïve who had previously treated MCL were eligible to participate. The primary objective was to estimate the maximum tolerated dose of the combination. Consenting patients were enrolled to one of five dose levels, shown in Table 1. Patients were treated in 28 day cycles, with ibrutinib administered daily and palbociclib administered on days 1-21. (Table 1). Patients could continue to receive study treatment until progression, unacceptable toxicity, or withdrawal of consent. Doses were escalated according to a standard phase I 3+3 design. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. All CRs, as documented by CT, required confirmation by PET/CT; bone marrow biopsy and endoscopy were also required in patients with known marrow or GI tract involvement, respectively. Additional objectives included pharmacokinetics and evaluation of pretreatment samples for biomarkers of response or resistance. Results From August 2014 to June 2016 a total of 20 patients (15 males, 5 females) were enrolled (DL1 n=3, DL2 n=3, DL3 n=6, DL4 n=3, DL5 n=5). The patients' MIPI risk distribution were 7 low, 7 intermediate, and 6 high. The median number of prior therapies was 1 (range 1-5). Six patients were refractory to their last prior therapy. Three patients experienced dose limiting toxicity: One patient treated at DL3 experienced grade 4 thrombocytopenia lasting more than 7 days, and grade 3 rash was seen in two patients at DL5. Grade 3-4 hematological toxicity included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Grade 3-4 non-hematological toxicity regardless of attribution included one patient with each of the following: lung infection, ALT/AST increase, encephalitis, hyponatremia, sinus tachycardia, pneumonitis. Grade 1-2 adverse events related to treatment and occurring in at least 2 patients included the following: diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%). Other than the two patients that experienced grade 3 rash at DL5, no patients have required dose reductions; 6 patients required dose interruptions. Thirteen subjects continue on study therapy. The reasons for stopping treatment were disease progression (n=4), adverse event (elevated liver enzymes, n=1; and prolonged cytopenias, n=1), and allogeneic stem cell transplantation (n=1). Of the 18 patients that have had at least one response evaluation to date, 12 (67%) patients responded to treatment and 8 (44%) achieved a CR. The median time to CR was 3 cycles and no responding patients have progressed on study. With a median follow up of 11 months, the estimated 1-year PFS and RD are 68% and 100%, respectively (Figure 1). Conclusions The mechanism-based combination of ibrutinib plus palbociclib is well tolerated and active. Toxicity is primarily related to myelosuppression of grade 1-2 severity, although grade 3 rash was observed at the highest doses evaluated. In this small group of patients, the combination produced responses at all dose levels, with a CR rate of 44% and a median time to CR of 3 months. No responding patients have progressed to date. These preliminary CR, PFS, and RD rates appear better than those reported in other studies of single-agent ibrutinib although the numbers of patients was very small. A phase II multi-center clinical trial to evaluate time to progression is planned. Biomarker studies to evaluate mechanisms of primary resistance are ongoing. Disclosures Martin: Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Janssen: Research Funding.

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