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.

A Phase I Dose Escalation Study of the mTOR Inhibitor Sirolimus and MEC Chemotherapy Targeting Signal Transduction in Leukemic Stem Cells for Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 161-161 ◽  
Author(s):  
Selina Luger ◽  
Alexander Perl ◽  
Allison Kemner ◽  
Edward A. Stadtmauer ◽  
David Porter ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Phase I ◽  
Dose Level ◽  
Mtor Inhibitor ◽  
Loading Dose ◽  
Dose Escalation Study ◽  
Mtor Inhibition ◽  
Dose Levels

Abstract In vitro studies have suggested that AML cells are sensitive to treatment with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In particular, mTOR inhibition is known to enhance the sensitivity of primary AML cells and AML stem cells to etoposide based chemotherapy leading to inhibition of leukemic SRC activity in NOD/SCID mice. To determine the feasibility of applying this approach in vivo, we performed a Phase I dose escalation study of the mTOR inhibitor sirolimus (rapamycin) with a combination chemotherapy induction regimen in adults with relapsed or refractory non-M3 AML. The purpose of this trial was to determine the safety and dose limiting toxicities of sirolimus and chemotherapy in this patient population. Patients received a loading dose of oral sirolimus on day 1 followed 24 hours later by daily doses of oral sirolimus on days 2–7 plus MEC (mitoxantrone 8 mg/m2/day IV, etoposide 100 mg/m2/day IV, and cytarabine 1000 mg/m2/day IV) on days 1–5. Five sirolimus dose levels were explored by a standard 3+3 design. Sirolimus was studied at loading doses from 3–15 mg and daily doses from 1–5 mg/d. Clinical response was assessed by bone marrow biopsy upon hematologic recovery or day 42, whichever occurred first. 23 adults (14 women, 9 men) of median age 58 (range 22 to 65) with relapsed, refractory, or secondary AML were treated with sirolimus and MEC. Five subjects had antecedent hematologic disorders or prior leukemogenic chemotherapy, 18 had relapsed or refractory disease. Sirolimus was well tolerated and did not increase non-hematologic toxicity of MEC chemotherapy. Asymptomatic, reversible liver transaminase or bilirubin elevations occurred in 4 patients, two of which were > grade 2. One patient with a history of prior cytarabine cerebellar toxicity (unknown at the time of study entry) developed reversible cerebellar ataxia. Three patients died of complications related to bacterial infections during chemotherapy-induced aplasia. Dose limiting toxicity was prolonged myelosuppression at the highest planned dose level and was responsible for one treatment-related death due to infectious complications from unresolved aplasia on study day 119. For the first four dose levels the median time to ANC recovery >500/uL among evaluable patients was 27 days (range16–38). Pharmacokinetic data showed that doses of 3 mg and higher consistently achieved rapamycin levels considered therapeutic in solid organ transplantation (4–9.2 ug/L). Bone marrow studies in 2/2 evaluable patients on dose level 4 (12 mg loading dose and 4 mg per day sirolimus) showed inhibition of p70S6 kinase phosphorylation consistent with effective inhibition of mTOR at this dose level. Complete remissions occurred in four patients, all treated for first relapse. Two patients subsequently proceeded to allogeneic transplantation. These results indicate that the combination of mTOR inhibition and chemotherapy is feasible in human AML and establish an appropriate dose for phase II studies to be 12mg loading dose followed by 4 mg daily. Patient recruitment at this dose is ongoing. Confirmation of the efficacy of this regimen, which targets signal transduction in leukemic < stem cells, is planned in a randomized phase II trial at the cooperative group level.

Vincristine Sulfate Liposomes Injection (VSLI, Marqibo): Interim Results From a Phase I Study in Children and Adolescents with Refractory Cancer

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1497-1497
Author(s):  
Nirali N Shah ◽  
Melinda Merchant ◽  
Diane Cole ◽  
Kelly Richards ◽  
Cindy Delbrook ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Pediatric Patients ◽  
Pharmacokinetic Analysis ◽  
Motor Neuropathy ◽  
Vincristine Sulfate ◽  
Level 1 ◽  
Dose Levels

Abstract Abstract 1497 Background: Vincristine is active in many pediatric cancers, but cumulative neuromuscular toxicity is often dose limiting and requires a maximum dose cap. Liposomal carriers are capable of increasing the therapeutic index of anticancer agents by altering pharmacokinetic behavior. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a novel preparation of standard vincristine encapsulated in sphingomyelin/cholesterol liposomes. Clinical trials have demonstrated safety, tolerability and activity in adults with leukemias, lymphomas and solid tumors. Pediatric experience with VSLI is limited. Design: This single center Phase I dose-escalation study is designed to determine the maximum tolerated dose (MTD) and to assess safety, pharmacokinetics and activity of VSLI in pediatric patients with relapsed/refractory cancer. Patients with active central nervous system disease or ≥grade 2 sensory or motor neuropathy are excluded. Dose escalation is per a standard 3 + 3 Phase I trial design with enrollment following a rolling 6 strategy. VSLI is administered IV over 60-minutes every 7 days (± 3 days) for 4 consecutive weeks for a 28-day treatment cycle (4 doses/cycle). Cycles may be delayed by up to 1 week for toxicity. Two dose levels have been tested to date: 1.75 mg/m2 and 2.25 mg/m2(adult MTD). No individual dose cap is employed. A validated HPLC tandem mass spectrometry assay was used to quantitate total (liposomal encapsulated and non-encapsulated) vincristine. Results: 9 patients have been treated (Table): 6 with acute lymphoblastic leukemia (ALL) and 3 with solid tumors. All patients were heavily pre-treated and 2 had prior stem cell transplants. 6 of 9 completed at least 1 cycle of therapy, with 1 each removed early for alternative therapy, complications of ALL, or dose-limiting toxicity (DLT). Most treatment-related adverse events were reversible grade 1 and 2 severity including hepatic transaminase elevation, parasthesia, low white blood cell count, neutropenia and fatigue. 2 patients evaluable for hematologic toxicity developed grade 4 neutropenia that spontaneously and rapidly resolved. No DLT occurred on dose level 1. Grade 4 aspartate aminotransferase elevation was observed in one patient at the second dose level and this dose level is being expanded. 1 patient treated at dose level 1 had dose de-escalation starting with Cycle 2 Dose 3 due to neuropathy. No patient was taken off study due to neurotoxicity. 7 of 9 patients received a VSLI dose that exceeded the 2 mg dose limit set for standard vincristine. 6 patients were evaluable for response: 1 had a complete remission (CR) (minimal residual disease negative by flow cytometry); 3 had stable disease (SD); and 2 had progressive disease (PD). First-dose pharmacokinetic analysis revealed wide interpatient variation (Table). The median (range) maximum concentrations (Cmax) of total vincristine (ng/ml) were 1,485 (845-2,120) and 2,450 (1,690-3,690) at dose levels 1 and 2 respectively. The median plasma half-life (T½) was 8.5 and 13.5 hours at dose levels 1 and 2 respectively (range 1.8 to 40.4 hours). Conclusions: VSLI appears to be safe, tolerable and demonstrates preliminary activity in pediatric patients with refractory ALL and solid tumors. The toxicity spectrum appears to be similar in children and adults. Clearance of total vincristine in our study is approximately 100-fold lower in comparison to administration of standard vincristine. VSLI allows for intensification of vincristine therapy in children with cancer. Accrual to the Phase I component at the adult recommended dose is ongoing and an expanded Phase II cohort in pediatric patients with ALL is planned. This study was sponsored by Talon Therapeutics and is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Disclosures: No relevant conflicts of interest to declare.

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.

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 study of the safety and pharmacokinetics (PK) of XMT-1001 given as an intravenous (IV) infusion once every three weeks to patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2574-2574
Author(s):  
E. Sausville ◽  
L. Garbo ◽  
G. J. Weiss ◽  
S. Anthony ◽  
D. Shkolny ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Stable Disease ◽  
Phase I Study ◽  
Study Drug ◽  
Water Soluble ◽  
Therapeutic Window ◽  
Infusion Reactions ◽  
Dose Levels

2574 Background: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT pro- drug, CPT is conjugated with a 70 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal). XMT-1001 demonstrated an improved therapeutic window as compared with CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for its clinical development. Methods: This is an open label, dose escalation study of XMT- 1001 administered as an IV infusion once every 3 weeks. The objectives of this phase I study are to determine the maximum tolerated dose and to assess safety and PK of XMT-1001. Initially 3 patients (pts) are entered at each dose level. The cohort is expanded to 6 pts if a patient experiences a dose limiting toxicity. Analyses of plasma and urine were performed for XMT-1001 (conjugated CPT), 2 major drug release products, and for unconjugated (free) CPT. Results: Thirty two pts with refractory solid tumors have received 82 cycles of XMT-1001 at 8 dose levels ranging from 1.0 to 20.5 mg CPT equivalents/m2. Two pts had Gr 3 infusion reactions consistent with hypersensitivity to study drug. Symptoms reversed upon discontinuation of study drug. After the introduction of new clinical trial material with an improved formulation, to date, no infusion reactions suggestive of hypersensitivity have occurred (11 patients, 22 cycles). No hemorrhagic cystitis or ≥ Gr 3 diarrhea was noted. Myelosuppression was observed in 3 pts treated at 15.4 mg CPT equiv/m2 dose level. Stable disease was observed in 7 pts with the following tumor types and dose levels expressed in mg CPT equivalents/m2: NSCLC (1.0 mg/m2, 6 wks), ovarian (4.9 mg/m2, 12 wks), pancreas (4.9 mg/m2, 36 wks), appendiceal (7.3 mg/m2, 12 wks), bile duct (9.1 mg/m2, 18 wks), basal cell (11.6 mg/m2, 6 wks), and colon (15.4 mg/m2, 6 wks). PK demonstrates dose proportional increases in plasma levels of XMT-1001 (conjugated CPT) and confirms the formation of its expected release products. To date, levels of free CPT in urine are low. Conclusions: 1. XMT-1001 can be given safely to patients; 2. XMT-1001 has a favorable PK profile; 3. Prolonged stable disease was observed in patients with refractory tumors. [Table: see text]

A dose-escalating phase I study of biweekly docetaxel in older men with hormone refractory prostate cancer (HRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16117-e16117
Author(s):  
J. McDevitt ◽  
R. Hauser ◽  
J. Simon ◽  
L. Balducci
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Assessment Tool ◽  
Maximum Tolerated Dose ◽  
Self Report ◽  
Weekly Dose ◽  
Level 3 ◽  
Level 1 ◽  
Dose Levels

e16117 Background: Docetaxel has been shown to be effective and is used in the treatment of HRPC. This phase I study is designed to investigate the maximum tolerated dose, tolerability and activity of docetaxel administered on a biweekly schedule in older patients with HRPC. This study will also explore the feasibility of a self-report geriatric assessment tool in this population. Methods: HRPC patients with progression of metastatic disease during hormonal therapy received docetaxel q 2 wks at dose levels of 40 (level 0), 45 (level 1), 50 (level 2), or 55 mg/m2 (level 3). The trial is a conventional phase I 3+3 dose-escalation design. Treatment was continued until progression, refused further treatment, or unacceptable toxicity. Patients were given the Vulnerable Elders Survey (VES-13) for completion every 4 weeks. Results: 16 patients were enrolled in the study. All are evaluable for toxicity, 10 for response. Pts had a median (range) age 76 (72–87). Median doses administered was 6 (range 3–19). The maximum tolerated dose (MTD) was not reached in the study. No dose limiting side effects were reported for any of the dosing levels in the 8 week assessment period. Five patients had a ≥50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. Of the 10 patients with measureable disease, 2 patients (one at dose level 0 and one at dose level 3) achieved a complete response, 2 patients (one at dose level 1 and one at dose 2) achieved a partial response, and 3 patients had stable disease (one each at dose levels 1, 2, and 3). At the time of entry onto the study, 4 patients required narcotic analgesics for bone pain; after treatment, 1 (25%) discontinued their pain medications. The completion rate of the Vulnerable Elders Survey (VES-13) was 94.6%. Conclusions: Biweekly docetaxel can be safely administered in older metastatic HRPC patients and showed activity. For phase II evaluation, a bi-weekly dose of 55 mg/m2 appears to be suitable. The administration of the VES-13 was feasible in this population. [Table: see text]

Results of a phase I trial of the proteasome inhibitor carfilzomib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7077-7077
Author(s):  
Jennifer Ann Woyach ◽  
Joseph M. Flynn ◽  
Jeffrey Alan Jones ◽  
Leslie A. Andritsos ◽  
Margaret Lucas ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Lymphocytic Leukemia ◽  
Maximum Plasma ◽  
Maximal Dose

7077 Background: CLL is an incurable malignancy, and survival for patients (pts) with relapsed disease is limited. Carfilzomib (CFZ) has shown efficacy in multiple myeloma, and our group has shown significant in vitro activity in primary CLL cells. Therefore, we have undertaken a phase I trial of this agent in CLL. Methods: This is a single institution phase I trial of CFZ in pts with relapsed or refractory CLL. Primary endpoints were to determine maximal tolerated dose (MTD) and describe toxicity. Pts with CLL relapsed after at least one therapy were enrolled using a 3x3 design. CFZ was administered on the standard myeloma schedule. The first two doses were administered at 20 mg/m2 with remainder given at doses starting at 27 mg/m2 for dose level 1 with escalation to 56 mg/m2. Results: 17 pts received at least 1 dose of CFZ. 12 pts completed at least 1 cycle of therapy, with the remaining 5 experiencing PD during cycle 1. The MTD was not reached, with 3 pts accrued to each dose level to the maximal dose tested without dose limiting toxicity. Most adverse events (AE) were grade (G) 1 or 2. G3/4 AE were quickly reversible and included G3 neutropenia (4 pts), G4 neutropenia (2), G3 febrile neutropenia (1), and G3 thrombocytopenia (3). G1/2 toxicities observed in ≥ 20% of pts included anemia (10), thrombocytopenia (7), and hypocalcemia (8). Median number of cycles was 3, with 9 pts achieving stable disease after 2 cycles. Of 3 pts enrolled at maximal dose level, 2 remain on therapy after 5 and 7 months, with 1 achieving a clinical partial response. Of 5 evaluable pts, at least 50% proteasome inhibition was seen in all at 1 hour, with minimal recovery at 24 hours. PK was best characterized by a two-compartment model. Maximum plasma concentrations across all dose levels ranged from 0.81 to 8.1 uM. Across the evaluated dose range, area under the curve increased in an apparent dose-proportional manner. Conclusions: Despite relatively limited efficacy in this study, CFZ has acceptable toxicity in CLL, with no MTD identified up to 56 mg/m2. This suggests that CFZ may be better studied in CLL using a different schedule or in combination with other active agents. Clinical trial information: NCT01212380.

A phase I dose-finding study of everolimus in combination with capecitabine and oxaliplatin (XELOX) as the first-line chemotherapy for patients with advanced gastric cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 86-86
Author(s):  
Inkeun Park ◽  
Min-Hee Ryu ◽  
Baek-Yeol Ryoo ◽  
Myoung Joo Kang ◽  
Changsuk Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Dose Level ◽  
Dose Intensity ◽  
Dose Finding ◽  
Good Tolerability ◽  
Level 1 ◽  
Dose Levels ◽  
Line Chemotherapy

86 Background: The purpose of this phase I study is to determine the recommended dose (RD) of everolimus (E), an mTOR inhibitor, in combination with capecitabine (XEL) and oxaliplatin (OX) and to explore feasibility of EXELOX at the RD in advanced gastric cancer (AGC). Methods: The standard 3+3 method was used to determine the RD of 3-weekly EXELOX during the first cycle. The doses of each drug [E (mg/day, D1-D21)/XEL (mg/m2/day, D1-D14)/OX (mg/m2, D1)] were as follows: level 1, 7.5/1600/100; level 2A, 7.5/1,600/130; level 2B, 7.5/2,000/100; level 3A, 10/1,600/130; level 3B, 10/2,000/100; level 4, 7.5/2,000/130. Results: During the first cycle of chemotherapy, no dose limiting toxicity (DLT) was noted in each cohort of 3 patients (pts) at dose levels 1-3A. At dose level 3B, 1 DLT (delay of the next cycle over 3 weeks because of Gr2 thrombocytopenia and Gr2 AST) was observed out of 6 pts. At dose level 4, DLTs (Gr3 fatigue and Gr4 thrombocytopenia) were found in 2 out of 3 pts. However, with frequent dose delay or reduction in subsequent cycles, the actual dose intensity of XELOX during the first 3 cycles was not higher at dose levels 2 or 3 than at dose level 1. Accordingly, dose level 1 was finally considered more suitable to maintain the actual dose intensity over chemotherapy cycles. At dose level 1, with no DLT during the first 3 cycles in 3 more pts accrued to confirm the safety, 12 additional pts were enrolled in the extension cohort to explore feasibility of EXELOX in the aspect of efficacy. Among 16 patients with measurable disease at dose level 1, 8 (50%) pts achieved a confirmed PR, 7 (44%) had SD, and 1 (6%) showed PD as a best response. With a median follow-up period of 12 months (range 4.9–12.8 months), the median progression-free survival and overall survival were 5.5 and 8.1 months, respectively at dose level 1. Conclusions: In this study, the doses of XEL (1,600 mg/m2/day), OX (100 mg/m2), and E (7.5 mg/day) were recommended with good tolerability for the 3 weekly EXELOX combination as the 1st line chemotherapy for AGC. The efficacy of this combination needs to be evaluated in future trials. Clinical trial information: NCT01049620.

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.

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]

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