Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors.

PURPOSE AND METHODS Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer. RESULTS The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine. CONCLUSION This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.

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Dasatinib in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: Preliminary Results of a Phase I Study.

Blood ◽

10.1182/blood.v114.22.1876.1876 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1876-1876 ◽

Cited By ~ 2

Author(s):

Thierry Facon ◽

Xavier Leleu ◽

A. Keith Stewart ◽

Andrew Spencer ◽

Philip Rowlings ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Performance Status ◽

Randomized Study ◽

Single Agent ◽

Open Label ◽

Ecog Performance Status ◽

Advisory Committees ◽

Minor Response

Abstract Abstract 1876 Poster Board I-901 Background: Multiple Myeloma (MM) remains incurable in spite of new effective agents and combination regimens. SRC family kinases (SFK) are potential targets for therapy in MM: Hck, Fyn and Lyn are implicated in IL6-induced proliferation. Dasatinib is a potent inhibitor of not only BCR-ABL, but also SFK, c-KIT, PDGFRb, and EPHA. In myeloma and endothelial cells (ECs) isolated from MM patients (pts), dasatinib blocked proliferation, survival, adhesion, migration, and angiogenic potential, through a combined targeting of PDGFRβ as well as VEGF-triggered phosphorylation of SRC. Lenalidomide has clinical efficacy in the treatment of multiple myeloma (MM) as a single agent and in combination with dexamethasone. The combination of dasatinib, lenalidomide and dexamethasone exhibits synergistic inhibition of MMIS cells. Methods: The primary objective of this Phase I, multicenter, open-label, non-randomized study was to determine the maximum tolerated dose (MTD) of the combination of dasatinib, with lenalidomide and dexamethasone in pts with relapsed or refractory (RR) MM. Secondary objectives were to assess the tolerability of the combination, to establish the dose for future clinical investigations, and to assess the efficacy by International Uniform Response and EBMT Criteria. Pts ≥18 years with confirmed RR MM, measurable disease (at least 1 g/dL for IgG or 0.5 g/dL for IgA in serum or urinary excretion of 200 mg monoclonal light chain/24 hours), and at least one prior treatment were enrolled sequentially into increasing dose cohorts (using a 3+3 design). Pts received oral dasatinib daily on a continuous schedule, oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22). Cycles were repeated every 28 days. Dose-limiting toxicities (DLTs) were assessed in the first cycle. If there was no DLT, dose escalation continued to MTD, followed by an expansion phase of the established dose. Results: Enrollment is ongoing. 16 pts (6 M, 10 F; median age 70.5 years, range 51–80) were treated in cohorts 1, 2, 3 and 4; MTD has not been established (as by July 2009). The median number of prior lines of therapy was 3 (range 1–6). Seven pts had prior autologous stem cell transplantation; 8 pts had prior thalidomide, 4 prior lenalidomide and 3 pts both. Baseline β2 microglobulin levels of >3.5mg/L were reported in 4 pts. The most common (310%) treatment related adverse events (AEs) diarrhea 6 (38%); nausea 4 (25%); constipation 2 (13%); stomatitis 2 (13%); asthenia 3 (19%); weight decrease 5 (31%); dyspnea 2 (13%); rash 2 (13%); vertigo 2 (13%); insomnia 2 (13%). The most common grade 3 / 4 hematologic AEs included neutropenia 6 (38%), anemia 4 (25%) and thrombocytopenia 3 (19%). Two DLTs were identified in cohorts 1 and 4: 1 pt had 2 point decline in ECOG Performance Status and other pt had a drug interruption > 15 days due to nausea and vomiting, respectively. Six out of 16 pts discontinued treatment: 1 due to death in first cycle (D19); 3 for AEs (2 study drug related and 1 unrelated), 1 withdrawal of consent, 1 following maximal clinical benefit (minor response) after 12+ cycles. As of July 2009, 10 pts remain on treatment, with a median duration of treatment of 4.2 months (range 0.6–12). Responses were observed in 13 pts: 8 partial responses (PR), and 5 minor responses (MR). 1 pt had stable disease (SD) and 2 pts were not evaluable (1 pts died before completion of cycle 1 and other pt was too early for assessment). Conclusion: Dasatinib in combination with lenalidomide and dexamethasone is well tolerated and preliminary activity has been observed. Disclosures: Facon: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Garzon:BMS: Employment. Bleickardt:BMS: Employment. Gialelis:BMS: Employment. Tuozzoli:BMS: Employment. Derreumaux:BMS: Employment. Sonneveld:Janssen-Cilag: Honoraria.

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Phase I Trial of Oral Irinotecan and Temozolomide for Children With Relapsed High-Risk Neuroblastoma: A New Approach to Neuroblastoma Therapy Consortium Study

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.5918 ◽

2009 ◽

Vol 27 (8) ◽

pp. 1290-1296 ◽

Cited By ~ 60

Author(s):

Lars M. Wagner ◽

Judith G. Villablanca ◽

Clinton F. Stewart ◽

Kristine R. Crews ◽

Susan Groshen ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Phase I Trial ◽

Single Agent ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Time Curve ◽

Disease Stabilization ◽

Heavily Pretreated ◽

Grade 3

PurposeIrinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma.Patients and MethodsPatients received oral temozolomide on days 1 through 5 combined with oral irinotecan on days 1 through 5 and 8 through 12 in 3-week courses. Daily oral cefixime was used to reduce irinotecan-associated diarrhea.ResultsFourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m2/d for subsequent patients. Irinotecan was then escalated from 30 to 60 mg/m2/d. First-course grade 3 diarrhea was dose-limiting in one of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other toxicities were mild and reversible. The median SN-38 lactone area under the plasma concentration versus time curve at this dose was 72 ng · hr/mL. One patient with bulky soft tissue disease had a complete response through six courses. Six additional patients received a median of seven courses (range, three to 22 courses) before progression.ConclusionThis all-oral regimen was feasible and well tolerated in heavily pretreated children with resistant neuroblastoma, and seven (50%) of 14 assessable patients had response or disease stabilization for three or more courses in this phase I trial. SN-38 lactone exposures were similar to those reported with protracted intravenous irinotecan. The dosages recommended for further study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60 mg/m2/d when given with cefixime.

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Combinations of the Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor Gs-1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Previously Treated, Indolent Non-Hodgkin Lymphoma: Results From a Phase I Study

Blood ◽

10.1182/blood.v120.21.3645.3645 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3645-3645 ◽

Cited By ~ 2

Author(s):

Nathan H Fowler ◽

Sven de Vos ◽

Marshall T. Schreeder ◽

John P. Leonard ◽

Ian W. Flinn ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Progression Free Survival ◽

Tumor Control ◽

Advisory Committees ◽

Heavily Pretreated ◽

Previously Treated

Abstract Abstract 3645 Introduction: PI3Kδ drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kδ that has shown considerable monotherapy activity when given at dose levels of ≥100 mg BID in patients with heavily pretreated indolent non-Hodgkins lymphoma (iNHL). Methods and Patients: This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 with rituximab and/or bendamustine in patients with previously treated iNHL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles (GS-1101/BR regimen). Initial cohorts received a GS-1101 dose of 100 mg/dose BID. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Results: The study enrolled 76 patients with iNHL. Patient characteristics, histological sub-typing, safety, and efficacy results are depicted in the table. The majority of patients were >60 years of age and had undergone extensive prior therapy. Grade ≥3 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid and all evaluable patients had reductions in lymphadenopathy, resulting in overall response rates (ORR) of 77%, 85%, and 77% for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens, respectively. Complete responses (with bone marrow confirmation) were observed in 13%, 16%, and 30% of patients. With median follow-up duration ranging from 28 to 48 weeks, 1-year progression- free survival (PFS) rates were >75% in all treatment groups. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment. Conclusions: A lack of overlapping toxicities allows the oral PI3Kδ inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with iNHL. GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy. All 3 regimens provide durable tumor control. The data from this trial support the development of Phase 3 combination trials of GS-1101 with rituximab- and/or bendamustine-containing regimens in patients with iNHL. Disclosures: Fowler: Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Phase I trial of GS-1101, a PI3K delta inhibitor, in B cell malignancies. de Vos:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Schreeder:Gilead Sciences: Research Funding. Leonard:Gilead: Consultancy. Coutre:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Sharman:Gilead: Honoraria, Research Funding. Boccia:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Jahn:Gilead: Employment. Miller:Gilead: Employment. Godfrey:Gilead Sciences: Employment.

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A pediatric phase I trial and pharmacokinetic (PK) study of erlotinib (ERL) followed by the combination of ERL with temozolomide (TMZ): A Children’s Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9015 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9015-9015 ◽

Cited By ~ 1

Author(s):

R. I. Jakacki ◽

J. Tersak ◽

S. Blaney ◽

M. Krailo ◽

M. Hamilton ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Single Agent ◽

Phase 2 ◽

Dose Escalation Study ◽

Minor Response ◽

Pediatric Solid Tumors ◽

Phase 2 Trial ◽

Egfr Family ◽

A Minor

9015 Background: EGFR is potently inhibited by ERL. Aberrant cell signaling via the EGFR family has been implicated in the development of several human cancers, including certain pediatric solid tumors. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the maximal tolerated dose (MTD) and dose limiting toxicities (DLTs) of single agent ERL, determine the tolerability of the combination of ERL and TMZ, and to determine the PK of ERL. Pts received single agent ERL qd × 28 d followed by ERL qd continuously in combination with TMZ 180 mg/m2/day × 5d. Cycles were repeated q 28 d. ERL was initially administered using the IV formulation given orally. The tablet form was subsequently studied at the MTD to further evaluate PK. Results: 46 pts (36 fully evaluable for toxicity) median age 11.5 yrs (range 3–20 yrs), were enrolled in cohorts of 3–6 pts at ERL doses of 35, 50, 65, 85 and 110 mg/m2/d. At the 110 mg/m2/day dose level, 2/4 pts had DLT (1 rash, 1 hyperbilirubinemia). In the expanded cohort at the MTD of 85 mg/m2/d, (n=21), 3 pts had DLT (2 rash, 1 diarrhea). Non-DLTs observed during the single agent cycle included diarrhea (n=14), rash (n=9), hyperbilirubinemia (n=7), neutropenia and/or thrombocytopenia (n=5). 1 pt with a soft tissue sarcoma had a minor response after 28d of single agent ERL, continuing to a PR by cycle 4. 3 pts (2 neuroblastoma, 1 neurocytoma) had prolonged responses (13–20+ months) to the combination. Oral administration of the IV formulation resulted in a higher Cmax and a lower Cmin compared to the adult data using tablets. Median apparent clearance was 2.85 (range 1.61–6.37) L/hr/m2 with a terminal half of 8.45 (5.1–27.1) hr. No PK interaction was observed between ERL and TMZ and the combination was well tolerated. Conclusions: The pediatric recommended phase 2 dose of ERL of 85 mg/m2/day, either alone or in combination with TMZ, is well tolerated in children. A COG phase 2 trial is planned. [Table: see text]

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Activity of gemcitabine/5-FU combination in refractory esophagogastric (EG) cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.147 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 147-147

Author(s):

Elizabeth Won ◽

David H. Ilson ◽

Joanne F. Chou ◽

Marinela Capanu

Keyword(s):

Systemic Chemotherapy ◽

Response Rate ◽

Performance Status ◽

Single Agent ◽

Best Supportive Care ◽

Flat Dose ◽

Heavily Pretreated ◽

Previously Treated ◽

Grade 3 ◽

Modest Activity

147 Background: Systemic chemotherapy has been demonstrated to improve survival and palliate symptoms in metastatic EG cancer. 2ndline (or more) chemotherapy with best supportive care also improves progression free and overall survival. Single-agent gemcitabine did not show activity in EG cancers (Ann Oncol 11:1161, 2000). Addition of gemcitabine to 5-fluorouracil (5FU) has shown modest activity (Oncology 69:130, 2005). To determine the efficacy and tolerability of gemcitabine with 5FU, we reviewed our experience in patients (pts) with metastatic or advanced EG cancers treated with this regimen. Methods: Retrospective review of MSKCC database for pts with metastatic EG cancer treated with gemcitabine/5FU (or capecitabine) between 1/1/2000 - 12/31/2012. Gemcitabine given at 600-1000mg/m2 day1, day 8 of q21 day cycle or 600-1000mg/m2 q2 weeks. 5FU given at 600-1000m2/m2 IV/48 hrs, with bolus 5FU/Leucovorin (200-400mg/m2 IV) on day 1. Capecitabine most commonly given as 1500-4000mg flat dose daily, in two divided doses, 7 days on/7 days off. Results: Of 146 pts, median age was 60; KPS 70 (50-90); 84% adenocarcinoma, 6% squamous (SCC). Sites of disease: 45% liver; 22% bone, 21% peritoneum. 112(77%) had ≥ 2 sites of disease. Pts were heavily pretreated: 42(29%) 2 prior lines of treatment (tx) for metastatic disease, 37(25%) 3 lines of tx, and 7(5%) 4+ lines of tx. Prior tx: 5FU/platinum (37%); Taxanes (56%); Irinotecan (44%). With gemcitabine, 49(34%) received 5FU and 97(66%) received capecitabine. In 144 evaluable pts, partial response rate was 7%, and stable disease was seen in 33%. Median PFS 1.84 months (95% CI,1.38-2.04) and for adenocarcinoma 2.0 months (95%CI,1.2-2.2) vs 1.2 months (95%CI: 0.9-1.51) for SCC (p =0.068). In the PR group, median PFS was 5.0 months (range 3.7-16.3 mo). Grade 3 toxicity was seen in 19 (13%); 1 pt had Grade 4 toxicity. 3(2%) discontinued treatment due to toxicity. Conclusions: Combination gemcitabine/5FU or capecitabine in metastatic EG cancer may have some limited activity and is well tolerated in a previously treated population. This regimen may be an appropriate palliative option for patients with an intact performance status who have progressed on other regimens. Research supported by Foundation 14.

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A Phase I Open-Label Dose-Escalation Study of Intravenous BI 2536 Together With Pemetrexed in Previously Treated Patients With Non–Small-Cell Lung Cancer

Clinical Lung Cancer ◽

10.1016/j.cllc.2012.04.003 ◽

2013 ◽

Vol 14 (1) ◽

pp. 19-27 ◽

Cited By ~ 25

Author(s):

Peter M. Ellis ◽

Quincy S. Chu ◽

Natasha Leighl ◽

Scott A. Laurie ◽

Holger Fritsch ◽

...

Keyword(s):

Lung Cancer ◽

Phase I ◽

Small Cell ◽

Small Cell Lung ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose ◽

Previously Treated Patients ◽

Previously Treated ◽

Bi 2536

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Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.3522 ◽

2015 ◽

Vol 33 (7) ◽

pp. 732-739 ◽

Cited By ~ 58

Author(s):

Kyriakos P. Papadopoulos ◽

David S. Siegel ◽

David H. Vesole ◽

Peter Lee ◽

Steven T. Rosen ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Concentration ◽

Phase I ◽

Phase I Study ◽

Low Dose ◽

Single Agent ◽

Phase Iii ◽

Maximum Plasma ◽

Irreversible Inhibitor ◽

Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

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