Phase I study of obatoclax mesylate (GX15–070MS), a bcl-2 antagonist, plus topotecan in relapsed small cell lung carcinoma and other solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3504-3504
Author(s):  
A. B. Brown ◽  
C. Rudin ◽  
N. Rizvi ◽  
W. Travis ◽  
N. Takebe ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Cell Lung Carcinoma ◽  
Grade 3

3504 Background: Bcl-2 is a rational target in SCLC since it is overexpressed in 60%-90% of tumors and may play a role in resistance of SCLC to chemotherapy. Obatoclax is a small molecule BH3 mimetic that blocks bcl-2 binding to proapoptotic family members. Obatoclax has growth inhibitory effects in several solid tumor cell lines and xenografts, with at least additive effects in combination with topotecan. The primary objective of this study was to evaluate the safety profile and maximum tolerated dose (MTD) of obatoclax plus topotecan in patients with relapsed SCLC and other solid tumors. Methods: We conducted a phase I dose escalation study using a standard “3+3” design. Obatoclax was administered at 14 or 20 mg/m2 over 3 hours on day 1 every 21 days. A subsequent cohort received obatoclax 14mg/m2 on days 1 and 3. Topotecan was given at 1.25 mg/m2 days 1–5. All patients received pegfilgrastim on day 8. Eligible patients were adults with solid tumors appropriate for treatment with topotecan. Patients with neurologically stable, treated brain mets were eligible. Results: 14 patients have been treated including 8 SCLC, 3 extrapulmonary small cell, 1 carcinoid, 1 Merkel cell and 1 melanoma previously treated with 1 or 2 lines of chemotherapy. Nearly all patients experienced neurologic toxicities during the obatoclax infusion which included ataxia, dysarthria, somnolence and/or mood alteration; these typically resolved 1–2 hours after completion of the infusion. The MTD of obatoclax was 20 mg/m2 on day 1 with Dose Limiting Toxicities (DLT) including grade 3 neurotoxicity (2 pts) and febrile neutropenia. Hematologic toxicity included grade 3/4 anemia (6 pts), thrombocytopenia (5 pts) and neutropenia (5 pts). Other toxicities included mild nausea/vomiting, fatigue, pruritus, and constipation. Clinical activity was seen in patients with SCLC including 1 PR and 4 SD out of 7 evaluable. The median TTP for these SCLC patients was 11 weeks. Conclusions: The recommended phase II dose is obatoclax 14 mg/m2 on days 1 and 3 with topotecan 1.25 mg/m2 on days 1–5 in 21 day cycles. A phase II study in second-line SCLC is open. Supported by NCI U01-CA69856. No significant financial relationships to disclose.

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 II Study of Ifosfamide Combined with Mesna Uroprotection in Advanced Non-Small-Cell Lung Carcinoma and Other Solid Tumors

1984 ◽  
Vol 70 (5) ◽  
pp. 433-437 ◽  
Author(s):  
Maria Teresa Nobile ◽  
Riccardo Rosso ◽  
Fulvio Brema ◽  
Angela Cinquegrana ◽  
Leonardo Santi
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Lung Carcinoma ◽  
Phase Ii Study ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

Carboplatin, etoposide, and ifosfamide as intensive chemotherapy for small-cell lung cancer.

1990 ◽  
Vol 8 (5) ◽  
pp. 899-905 ◽  
Author(s):  
I E Smith ◽  
T J Perren ◽  
S A Ashley ◽  
J Woodiwiss ◽  
G V Forgeson ◽  
...  
Keyword(s):  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
World Health ◽  
Hematologic Toxicity ◽  
Small Cell Lung ◽  
Who Grade ◽  
Cell Lung Carcinoma ◽  
Median Response ◽  
Overall Response ◽  
Grade 3

Thirty-two previously untreated, fit patients with small-cell lung carcinoma (SCLC) were treated with an intensive combination chemotherapy regimen, with the aim of prolonging survival, as follows: carboplatin 400 mg/m2 intravenously (IV) day 1, ifosfamide 5 g/m2 IV day 1 in a 24-hour infusion with mesna, and etoposide 100 mg/m2 IV days 1 to 3, repeating at 28-day intervals for six courses. Limited-disease (LD) patients were given concurrent hyperfractionated radiotherapy for the first two courses, and all patients achieving a complete remission (CR) were offered prophylactic cranial irradiation (PCI). For 18 LD patients, the overall response was 94% with 72% CRs. For 14 extensive-disease (ED) patients the overall response was 100% with 29% CRs. Median response duration for LD patients was 11.5 months and for ED patients 7.5 months. Median survival for LD patients was 19 months with a predicted 24% 2-year survival and for ED patients 9.5 months with a predicted 14% 2-year survival. Hematologic toxicity was severe with 100% developing World Health Organization (WHO) grade 3-4 neutropenia and 94% WHO grade 3-4 thrombocytopenia during treatment. Seventy-two percent of patients required a dose reduction at some stage during treatment because of neutropenic infection or thrombocytopenia requiring platelet transfusions. Despite very high response rates, this intensive regimen achieves survival results only modestly better, if at all, than those reported for less toxic conventional regimens.

A phase I study of pegylated doxorubicin (DOX) and weekly topotecan (TOP) in patients (pts) with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12018-12018
Author(s):  
G. A. Masters ◽  
M. Guarino ◽  
C. Schneider ◽  
D. Biggs ◽  
S. Grubbs
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Level 1 ◽  
Grade 3 ◽  
Ecog Ps

12018 Background: The primary endpoint of this prospective phase I study of DOX-TOP in pts with advanced solid tumors was to identify the maximum tolerated dose and dose-limiting toxicities (DLT) of this combination. Other objectives included a description of additional toxicities and efficacy in this patient population with refractory cancers. Pharmacokinetic sampling of TOP plasma levels will be reported separately. Methods: Eligible pts had advanced solid tumors and had either failed standard chemotherapy (chemo) or were pts for whom no standard therapy existed. They had ECOG PS = 0–2, adequate organ function, and gave written, informed consent. Initial doses included DOX 40 mg/m2 day 1 and TOP 2 mg/m2 days 1, 8 and 15 q 28 days. TOP was to be escalated in cohorts of pts. DLT was defined as febrile neutropenia, grade 4 thrombocytopenia, any grade 3 non-hematologic toxicity, or the inability to receive subsequent treatment due to ongoing toxicity. Treatment was held for ANC < 1000 or platelets < 75,000. Results: Fourteen pts have been enrolled on this phase I study, all of whom were evaluable for toxicity. There were 12 males and 2 females, and the median age was 57 years (range 25–86). Four had ECOG PS = 0, 9 had PS = 1, and 1 had PS = 2. Cancer types included head and neck (3), renal (2), and breast, pancreas, liver, esophagus, germ cell tumor, sarcoma, and others (one each). In the 6 pts treated at dose level 1, toxicities included grade 3 anemia (1) and neutropenia (2), and grade 4 neutropenia (1). DLT consisted of grade 4 thrombocytopenia (1) and inability to deliver day 15 TOP in 3/6 pts at this dose. Thus, TOP was reduced to 1.5 mg/m2 weekly for dose level -1, and 8 pts have been treated. Toxicities included grade 3 anemia (1)and neutropenia (2), and grade 4 neutropenia (1) and thrombocytopenia (1). Enrollment continues at this dose level to confirm tolerability. No patient achieved an objective response to therapy, but 2 pts have stable disease for up to 4 cycles. Conclusions: DOX-TOP can be safely combined in pts with advanced solid tumors, with hematologic toxicity as the DLT. The preliminary recommended phase II dose is DOX 40 mg/m2 and TOP 1.5 mg/m2. We plan to explore an additional dose level of DOX 30 mg/m2 and TOP 2 mg/m2. Phase II evaluation is contemplated in selected tumor types. [Table: see text]

A phase I study of R-(-)-gossypol (AT-101) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13502-e13502
Author(s):  
T. B. Leal ◽  
W. Schelman ◽  
A. Traynor ◽  
J. Kolesar ◽  
R. Marnosha ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Unknown Primary ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Objective Evidence ◽  
Level 1 ◽  
Grade 3

e13502 Background: AT-101 [R-(-)-gossypol acetic acid] (AT) is an orally-administered BH3 mimetic that lowers the threshold for apoptosis by direct binding to Bcl-2, Bcl-xL, Mc1–1, Bcl-W, and through upregulation of the proapoptotic proteins Noxa and Puma. Bcl- 2 is over-expressed in >80% of SCLC. In vitro study using SCLC cells showed that treatment with EP had synergistic cytotoxic effects in suppression of Bcl-2. This is a phase I dose-escalation study of AT in combination with EP with an expanded cohort of patients with ES-SCLC. This study is being conducted to determine the maximum tolerated dose (MTD), pharmacokinetics and activity of AT with EP ± pegfilgrastim (F) in patients with advanced, refractory solid tumors and/or ES-SCLC. Methods: This study used standard eligibility criteria except patients must not have received prior therapy that inhibits the Bcl-2 family. At dose level 1, patients received P 60 mg/m2 on day 1 and E 100 mg/m2 on days 1, 2, and 3 every 21 days. AT was administered 30 mg orally BID on days 1, 2 and 3 of each cycle. Results: 10 patients have been enrolled; 7 men, 3 women. Tumor types: 6 lung; 2 prostate; 1 head & neck; 1 unknown primary. 2 of 5 patients enrolled at dose level 1 experienced a DLT of neutropenic fever in cycle 1. Three subsequent patients were enrolled to dose level -1 (20 mg BID x 3 days, d1–3) which was well tolerated. Additional patients are being enrolled at dose level 1a (EP+AT with F). Grade 3/4 toxicities related to AT without F at dose level 1 and -1 were as follows: ANC (8), leucopenia (7), febrile neutropenia (2), low hemoglobin (1), thrombocytopenia (1), elevated AST (1), cardiac ischemia/MI (1), diarrhea (1). There were no reported grade 3/4 toxicities in two patients at level 1a. Four patients had stable disease; two progressive disease and four patients were unevaluable. Conclusions: The MTD without F was established at AT 20mg orally BID, P 60 mg/m2 on day 1, and E 100 mg/m2 on days 1, 2, and 3 every 21 days. The MTD with F has not yet been established. Accrual continues at dose level 1a. Subjective and objective evidence of clinical activity has been observed in patients with refractory solid tumors. This study was supported by NCI, UO1 CA062491, SAIC 25XS097 and 1ULRR025011. No significant financial relationships to disclose.

scholarly journals Phase I dose escalation study of bortezomib in combination with lenalidomide in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6621-6621
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Amir Tahmasb Fathi ◽  
Steven L McAfee ◽  
Martha Wadleigh ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Escalation ◽  
Median Number ◽  
Severe Neutropenia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Number Of Cycles

6621 Background: Both bortezomib (Bz) and lenalidomide have clinical activity in patients with MDS and AML. We conducted a phase I dose escalation study to determine the maximal tolerated dose (MTD) of Bz in combination with lenalidomide. Methods: Patients with MDS (IPSS score ≥ 0.5 or therapy-related) received Bz by IV bolus on Days 1, 4, 8, and 11 and lenalidomide 10 mg/day PO on Days 1-21 in 28 day cycles for up to 9 cycles. Three doses of Bz were tested (0.7, 1.0, or 1.3 mg/m2). Cohorts consisted of 3-6 patients; the dose of Bz was escalated if there were < 2 dose limiting toxicities (DLTs). Growth factor support and transfusions were permitted. Dose limiting toxicities (DLTs) were assessed during the first cycle and were defined as severe neutropenia (absolute neutrophil count ≤ 250/ul), thrombocytopenia (platelet count < 10,000/ul), grade ≥ 2 neurotoxicity, or other grade ≥ 3 non-hematologic toxicity. Following determination of the MTD, enrollment opened to patients with relapsed and refractory AML and those with untreated high risk disease for whom induction therapy was not indicated. Responses were assessed by IWG 2006 criteria for MDS and IWG 2003 criteria for AML. Results: 23 patients (14 men) were enrolled; one patient was inevaluable due to disease progression prior to starting protocol therapy. The median age was 73 years (range 54-87). There was 1 DLT observed, neutropenia, in 6 patients treated with 1.0 mg/m2 Bz and no DLTs at 0.7 or 1.3 mg/m2. The median number of cycles was 2 (range 2-9). Grade ≥ 3 toxicities possibly attributable to the treatment at any dose level were: anemia (2), thrombocytopenia (10), leukopenia (3), infection (1), rash (2), dyspnea (1), dizziness (1), hypotension (1), pneumonia (2) and neuropathy (1). Among the 14 patients with MDS, 1 patient with RARS experienced a CR and 2 with RAEB-2 experienced marrow CR (mCR). Among the 8 patients with AML, there was 1 CR. Conclusions: The maximal tested dose of Bz (1.3 mg/m2) in combination with lenalidomide is safe. Responses were seen in MDS and high risk AML. Future testing of this regimen is planned.

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