A phase I trial of TAS-102 administered on a three times a day schedule in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2053-2053 ◽  
Author(s):  
R. A. Wolff ◽  
P. M. Hoff ◽  
A. Mita ◽  
M. Fukushima ◽  
J. C. Blais ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Performance Status ◽  
Tumor Xenograft ◽  
Unknown Primary ◽  
Hematologic Toxicity ◽  
Prior Therapy ◽  
Grade 3 ◽  
And Performance

2053 Background: TAS-102 consists of trifluorothymidine (FTD) and an inhibitor of thymidine phosphorylase (TP). FTD, like 5-fluorouracil, is an inhibitor of thymidylate synthase. However, when orally administered, FTD is rapidly degraded to an inactive form, primarily by TP. Co-administration of FTD with an inhibitor of TP elevates FTD concentrations. Since tumor xenograft models demonstrated greater anti-tumor activity with divided daily dosing of TAS-102, and a phase I trial of once-daily TAS-102 showed a short FTD half-life, this trial was designed to explore a three times a day dosing schedule. Methods: Patients with advanced solid tumors having received prior therapy, with adequate organ function, and performance status Zubrod 0–2, were eligible. TAS-102 was administered orally three times a day for 5 days a week for two weeks, followed by two weeks off. Courses were repeated every 4 weeks. Results: A total of 15 patients (8 female, age 37–72 years) were enrolled into the study; three at 60 mg/m2/day, 6 each at 70 mg/m2/day and 80 mg/m2/day. Nine patients had colorectal cancer, 2 carcinoma of unknown primary, 2 pancreatic cancer, one each medullary thyroid cancer and cholangiocarcinoma. Toxicity was assessed throughout all courses of therapy. Grade 3 and 4 hematological toxicities were the most common, including 3 episodes of grade 3 neutropenia at 60 mg/m2/day, 5 at 70 mg/m2/day, 5 at 80 mg/m2/day with only 1 instance of grade 3 thrombocytopenia at 80 mg/m2/day. Non-hematological grade 3 toxicities included nausea/vomiting (1 at 70 mg/m2/day), colitis, gout, and hematuria (1 each at 70 mg/m2/day), and fatigue (1 at 70 mg/m2/day and 2 at 80 mg/m2/day) Two episodes of dose-limiting toxicity were observed at 80 mg/m2/day: grade 3 fatigue and grade 4 neutropenia. Although there were no objective responses, nine patients (60%) maintained stable disease with a median duration of disease stabilization of 4.3 months (range, 1.9 to 8.6 months). Conclusions: TAS-102 is well tolerated with manageable hematologic toxicity and few non-hematological toxicities. The most common grade 3 or 4 toxicity was neutropenia. The suggested phase II dose of TAS-102 is 70 mg/m2/day when administered orally three times a day for 5 days a week for two weeks followed by two weeks off every 4 weeks. [Table: see text]

Phase I trial of daily lenalidomide and docetaxel given every three weeks in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3570-3570 ◽  
Author(s):  
S. L. Sanborn ◽  
M. Cooney ◽  
J. Gibbons ◽  
J. Brell ◽  
P. Savvides ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Performance Status ◽  
Unknown Primary ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Ecog Performance Status ◽  
Combination Methods ◽  
Grade 3

3570 Background: Lenalidomide is a potent anti-angiogenic and immune modulating agent. This phase I trial of docetaxel and lenalidomide was undertaken to evaluate the maximal tolerated dose (MTD), dose-limiting toxicity (DLT), and secondarily, any tumor response for this novel combination. Methods: Patients with advanced solid tumors with adequate organ function were eligible. Lenalidomide was given orally days 1–14, and docetaxel was administered intravenously on day 1 of each 21-day cycle. DLT was defined as grade 3 or higher non-hematologic toxicity, grade 4 neutropenia with fever, and grade 4 anemia or thrombocytopenia. Results: Nineteen patients, 14 male and 5 female, with tumor types including prostate (7), sarcoma (3), head and neck (2), pancreatic, colon, melanoma, adenocarcinoma of unknown primary, gastric, bladder, and GIST have been enrolled. ECOG performance status was zero (10 patients) or one (9 patients). The median age was 59 years (range 35 to 86). Fourteen patients had zero or one prior treatment regimens (range 0 to 6). A total of 64 cycles have been administered (range 1 to 12). In the first nine evaluable patients, eight (89%) had grade 3 or 4 neutropenia. Docetaxel 75 mg/m2 given every 3 weeks with lenalidomide 5 mg on days 1–14 exceeded the MTD due to one grade 3 nausea/vomiting and one grade 4 neutropenia with fever. After the addition of pegfilgrastim on day 2, there has not been any neutropenia in the subsequent seven evaluable patients. Other grade 3 and 4 toxicities included leukopenia (31%), lymphopenia (19%), as well as nausea, vomiting, fatigue, anemia, infection, hyponatremia, and hypokalemia (6% each). Seven patients (44%) have had stable disease (range 3 to 12 cycles). One prostate cancer patient experienced a >95% reduction of PSA. Enrollment is ongoing and the current dose level is docetaxel 75 mg/m2, lenalidomide 10 mg days 1–14, and pegfilgrastim on day 2. Conclusions: The toxicity evaluation is ongoing. This trial will provide the MTD of docetaxel 75 mg/m2 given every 3 weeks with lenalidomide on days 1–14 in combination with pegfilgrastim support to avoid neutropenia. No significant financial relationships to disclose.

Phase I study of repeated cycles of high-dose cyclophosphamide, etoposide, and cisplatin administered without bone marrow transplantation.

1990 ◽  
Vol 8 (10) ◽  
pp. 1728-1738 ◽  
Author(s):  
J A Neidhart ◽  
W Kohler ◽  
C Stidley ◽  
A Mangalik ◽  
A Plauche ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Performance Status ◽  
Complete Response ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Tumor Type ◽  
Advanced Malignancy ◽  
Prior Therapy ◽  
And Performance

Forty-two patients with advanced malignancy judged unlikely to respond to standard treatment received high-dose combination chemotherapy with cyclophosphamide, etoposide, and cisplatin in a phase I trial. Twenty-two of these patients who had at least a partial response (PR) to the first cycle of therapy received a second cycle, and eight patients received three or more cycles of therapy. Bone marrow replacement was not used. The maximum-tolerated doses (MTDs) were cyclophosphamide 2.5 g/m2 on days 1 and 2; etoposide 500 mg/m2 on days 1, 2, and 3; and cisplatin 50 mg/m2 on days 1, 2, and 3. Hematologic toxicity was not dose-limiting by study design. Recovery to an absolute granulocyte count above 100/microL occurred at a median of 9 days from onset (range, 3 to 23 days) at the MTD. Recovery was delayed after the third cycle. Only one patient on his third cycle failed to recover peripheral blood counts and died of sepsis an day 43. Hematologic toxicity was not dose-dependent. Nonhematologic toxicities included emesis, fatigue, alopecia, diarrhea, and anorexia and were generally well tolerated. The dose-limiting toxicities were fatal pulmonary or cardiac toxicities in five of nine patients treated at the highest dose level. Patients likely to do well can be selected by tumor type, response to prior therapy, and performance status. Nine of 36 assessable patients had a complete response (CR) and 13 a PR for a response rate of 61%. Five patients (12%) remain alive and free of disease at 15 to 32 months. Repeated cycles of dose-intensive combination therapy can produce long-term disease-free remissions in patients with refractory tumor types. The toxicity of the regimen is acceptable if patients are carefully selected.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

2000 ◽  
Vol 18 (20) ◽  
pp. 3545-3552 ◽  
Author(s):  
Corinne Couteau ◽  
Marie-Laure Risse ◽  
Michel Ducreux ◽  
Florence Lefresne-Soulas ◽  
Alessandro Riva ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

Phase I study of erlotinib (E) for solid tumors in patients with hepatic or renal dysfunction (HD or RD): CALGB 60101

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3026-3026
Author(s):  
A. A. Miller ◽  
D. J. Murry ◽  
D. R. Hollis ◽  
K. Owzar ◽  
L. D. Lewis ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Progressive Disease ◽  
Performance Status ◽  
Direct Bilirubin ◽  
Hematologic Toxicity ◽  
Renal Obstruction ◽  
Reduced Dose ◽  
Grade 3 ◽  
Tolerable Dose ◽  
Dose Limiting Toxicity

3026 Background: We sought to determine a tolerable dose and characterize the pharmacokinetics (PK) of E in patients with HD or RD. Methods: Patients with biopsy-proven solid tumors that commonly express EGFR, refractory to or without available standard therapy, performance status 0–2, and without biliary or renal obstruction were assigned to one of 3 cohorts (C): C1, AST ≥ 3 × ULN but no RD; C2, direct bilirubin 1–7 mg/dl but no RD; C3, creatinine 1.6–5.0 mg/dl but no HD. After slow accrual of 3 patients, an amended C1 for albumin < 2.5 g/dl accrued 3 additional patients. E was administered po daily in groups of at least 3 evaluable patients in escalating doses of 50, 75, 100, 150 mg starting with 50 mg in HD and 75 mg in RD. Patients had to take E for at least 4 weeks to be considered evaluable for toxicity unless dose-limiting toxicity (DLT) occurred sooner. DLT was defined as: grade 4 neutrophils or platelets; bilirubin ≥ 1.5 × baseline in C1/2 and ≥ 2.5 × ULN in C3; creatinine ≥ 2 × ULN in C1/2 and ≥ 2.5 × baseline in C3; grade ≥ 3 nausea,vomiting,diarrhea despite optimal supportive care; or any other grade ≥ 3 non-hematologic toxicity. Blood samples were obtained before and 1, 2, 3, 4, 6, 24 hrs after the first dose. Plasma E concentrations were measured by HPLC. A 2-compartment PK model was used to estimate total clearance of E. Results: Between 12/01 and 5/05, 55 patients were accrued but 1 never started therapy: male/female, 34/20; white/black, 46/8; median age 56 (range, 39–78); PS 0/1/2, 12/25/17. The distribution of treated/evaluable patients was: 6/5 in C1, 30/16 (attrition due to progressive disease) in C2, and 18/18 in C3. DLT consisted of both total and direct bilirubin ≥ 1.5 × baseline in 3 patients: C1, 1 of 5 at 50 mg; C2, 2 of 6 at 100 mg. In C2, 1 of 7 patients had grade 4 diarrhea/dehydration and grade 3 hypotension at 75 mg. No DLT was encountered in C3 with 12 patients at 150 mg. Clearance (mean ± SD) was cohort-dependent: 1.51 ± 0.64 (C1), 2.36 ± 1.17 (C2), 4.34 ± 2.53 (C3) l/hr; 2-sided exact Kruskal-Wallis p < 0.0006. Conclusions: Patients with RD tolerate 150 mg and appear to have normal clearance of E. Patients with HD should be treated at a reduced dose (i.e. 75 mg) consistent with their reduced clearance. [Table: see text]

A phase I study of brostallicin (B) combined with either bevacizumab (BV) or irinotecan (I) in patients (pts) with advanced solid malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13531-e13531
Author(s):  
R. B. MacArthur ◽  
J. Singer ◽  
C. Becerra ◽  
S. Weitman ◽  
D. Von Hoff
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Performance Status ◽  
Single Agent ◽  
Primary Objective ◽  
Additional Patient ◽  
Dna Minor Groove ◽  
Grade 3 ◽  
Group Grade

e13531 Background: B is a DNA minor groove binding (MGB) agent with single agent cytotoxic activity. B has shown synergy with BV and I. The combinations were studied using a “complete” phase I design. Methods: The primary objective was to determine the maximally tolerated dose (MTD) and dose limiting toxicities (DLT) of B+BV and B+I. For B+BV cohort 1 both drugs were infused on day 1 of a 21 day cycle. BV was dosed at 15mg/kg, B was dosed at 6 mg/m2. For cohort 2, the BV dose was unchanged, and B dose reduced to 4 mg/m2. For B+I cohort 1 both drugs were also infused on cycle day 1. I was dosed at 200 mg/m2 with B at 4 mg/m2. For cohort 2, I was reduced to 125 mg/m2 and B reduced to 2 mg/m2. Cycle 1 DLT was defined: grade 4 neutropenia lasting ≥ 5 days, grade 3 or higher febrile neutropenia, grade 4 thrombocytopenia or grade 3 or 4 thrombocytopenia with bleeding, grade 3 or higher diarrhea, nausea or vomiting despite optimal management, grade 3 or higher for all other non-hematologic toxicities. For pts receiving BV, grade 2 or higher proteinuria. Eligible pts had treatment refractory metastatic/unresectable solid tumors, acceptable performance status, and adequate hematologic parameters and organ function. Results: 19 pts were enrolled. 11 pts received B+BV and 8 received B+I. Median age was 58 years. For B+BV 5 patients were treated in cohort 1, 6 in cohort 2. For B+I, 2 patients were treated in cohort 1, 6 in cohort 2. The MTD has not been defined for either treatment combination. In the current preliminary dataset 18/19 pts (93.3%) experienced one or more adverse events (AEs). In the B+BV group, grade 4 neutropenia was reported in 2/11 patients, both in cohort 1, and grade 3 neutropenia in one additional patient, also in cohort 1. In the B+I group, grade 4 AEs included neutropenia (DLT), febrile neutropenia (DLT), severe abdominal pain, and thrombocytopenia. Of the evaluable pts, no complete or partial responses were seen. For B+BV 5/11 pts have received 4 or more cycles, and for B+I 2/8. Conclusions: The combination of B+BV and B+I show manageable toxicity in advanced solid tumors at the doses reached in cohort 2. Additional data will be provided at the time of presentation. [Table: see text]

A phase I trial of MK 2206 in children with refractory solid tumors: A Children’s Oncology Group study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9581-9581
Author(s):  
Christine L. Phillips ◽  
Maryam Fouladi ◽  
John Peter Perentesis ◽  
Sarah Leary ◽  
Renee M. McGovern ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Pediatric Solid Tumors ◽  
Biological Studies ◽  
Grade 3 ◽  
Rhabdoid Tumors

9581 Background: AKT, a serine threonine protein kinase, is activated downstream of phosphatidylinositol 3-kinase (PI3K) which transmits signals from cytokines, growth factors and oncoproteins to multiple targets. Activated AKT regulates survival, proliferation, and growth. The PI3K/AKT pathway is downstream of most of the common growth factor tyrosine kinase receptors in cancer, e.g., EGFR, HER2, IGFR, etc., and is a driver of tumor progression in many cancers. AKT protein kinase is activated in many pediatric solid tumors, including glioblastoma, malignant rhabdoid tumors, neuroblastoma, synovial sarcoma, rhabdomyosarcoma and medulloblastoma. MK2206, an oral allosteric AKT1, 2,3 inhibitor, has demonstrated antitumor activity in in vitro and in vivo cancer models.A phase I trial evaluating MK2206 was conducted in children with refractory solid tumors. Methods: Using a rolling-6 design, MK2206 was administered either once every 7 days (schedule 1), or once every other day (schedule 2) in a 28-day cycle. Serial PK studies were obtained on day 1, cycle 1 and trough samples were obtained on days 7, 14, 21 and 28. Biological studies included analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Results: Forty-five patients [23 males, median age 13.6 years (range 3.1-21.9)] with malignant glioma (14), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 34 were fully evaluable for toxicity (schedule 1 n=17; schedule 2 n=17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2. There were no DLTs at 35 mg/m2 and dose level 4 (58 mg/m2) is currently open for patient accrual with one enrollment. Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m2; grade 3 rash in 1/6 patients at 120 mg/m2), and grade 3 rash in 2/6 patients at 155 mg/m2. Conclusions: The recommended pediatric phase II dose of weekly MK2206 is 120 mg/m2 and the last cohort of patients to the every other day dosing schedule of MMK206 is enrolling. PK and PD data are currently being analyzed and will be presented.

Phase I trial of ADI-peg 20 plus docetaxel (DOC) in patients (pts) with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2569-2569
Author(s):  
Ben Kent Tomlinson ◽  
John S. Bomalaski ◽  
Monica Diaz ◽  
Taiwo Akande ◽  
Nichole Mahaffey ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Trial ◽  
Tongue Cancer ◽  
Performance Status ◽  
Study Drug ◽  
Serum Levels ◽  
Serious Adverse Events ◽  
Combination Methods

2569 Background: ADI-PEG20 is an enzyme that degrades arginine (Arg), an amino acid relevant to biosynthetic pathways of normal and malignant cells. It has shown tolerability and activity in several solid tumors. Preclinical studies have shown that Arg deprivation by ADI-PEG 20 in cancer cells induces autophagy, caspase-independent apoptosis, and potentiates DOC-induced cytotoxicity in prostate cancer (PC) models. A phase I trial (standard 3+3 design) of ADI-PEG20 (IM weekly) plus DOC (IV on day 1 q 3 weeks) was conducted to assess feasibility and safety of the combination. Methods: Eligible pts were >18 years of age, had advanced malignant solid tumors, adequate end organ function, and performance status (PS) 0-2. ADI-PEG 20 was escalated over 4 dose levels (4.5, 9, 18, 36 mg/m2). DOC dose was 75 mg/m2. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: thrombocytopenia [grade (Gr) 3 with bleeding/transfusion, or Gr 4]; neutropenia with fever or documented infection attributable to ADI PEG20; or any ≥ Gr 3 non-heme toxicity related to study drug except alopecia. Allergic reaction associated with DOC was not considered a DLT. Serum levels of Arg were serially measured. Results: 18 pts were accrued: median age, 64.5 yrs; male, 83%; PS 0, 72%. Most common tumors were NSCLC (8), PC (3), and tongue cancer (TC) (2). Median number of prior systemic therapies was 3. One DLT was seen in dose level 1 (urticarial rash) requiring expansion of that dose level to 6 pts. No additional DLTs attributable to ADI PEG20 were seen. Serious adverse events (all expected and attributed to DOC) were recorded in 11/18 pts, including Gr IV neutropenia (6, 33%) and Gr IV anemia (2, 11%). There were 2 on-study deaths unrelated to protocol therapy. In 11 pts with evaluable disease, 1 with TC had a partial response (PR), 6 had stable disease (SD) (3 NSCLC, 2 PC, 1 TC). Arg levels decreased in the 1st cycle for 6/11 pts with available data, including 2 with SD, and 1 with PR. Conclusions: The combination of ADI PEG20 and DOC is feasible with reasonable tolerability in this heavily pre-treated cohort. Full doses of both agents were achievable: ADI-PEG 20 at 36mg/m2 with DOC 75 mg/m2. An expansion cohort of castration resistant PC pts is now accruing at this recommended dose. Clinical trial information: NCT01497925.

Phase Ib trial of combining aldoxorubicin plus doxorubicin.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Kamalesh Kumar Sankhala ◽  
Sant P. Chawla ◽  
Victoria S Chua ◽  
Doris Quon ◽  
Allison Bonk ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Safety Data ◽  
Tumor Xenograft ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3

2550 Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.

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