Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

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.

Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
R. Sangha ◽  
C. Ho ◽  
L. Beckett ◽  
D. H. Lau ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Gene Copy ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Egfr Inhibition ◽  
Biomarker Analysis

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]

Phase I study of sirolimus plus gemcitabine in patients with advanced solid tumors: A Spanish Group for Research on Sarcomas (GEIS) study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3096-3096
Author(s):  
Juan Martin Liberal ◽  
Marta Gil ◽  
Laura Jimenez ◽  
Maria Ochoa de Olza ◽  
Carmen Munoz ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Mtor Pathway ◽  
Advanced Solid Tumors ◽  
Level 3 ◽  
Skin Biopsies ◽  
Grade 3 ◽  
Dose Levels

3096 Background: In preclinical studies, combination of sirolimus with gemcitabine enhances apoptosis in vitro and increases anti-tumor efficacy in vivo. Methods: Patients with advanced solid tumors, age 18-70 years, no prior mTOR inhibitor or gemcitabine, ECOG PS 0-1, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of the combination of sirolimus and gemcitabine. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Sirolimus was given po continuously. Gemcitabine was given iv 10mg/m2/minute on days 1 and 8 every 3 weeks. Dose levels 1, 2 and 3 corresponded to sirolimus 2, 2 and 5mg/24h plus gemcitabine 800, 1000 and 1000mg/m2 respectively. After observing DLTs at higher dose level and poorer mTOR signaling inhibition at lower doses, a new cohort of sirolimus 5mg/24h plus gemcitabine 800 mg/m2 was added. Skin biopsies pre and post treatment were performed to assess the inhibition of mTOR pathway. Results: 19 patients were enrolled: median age 51 years (36-70); gender 12M, 7F. Median number of cycles was 4. Patients were treated at 4 dose levels, the MTD was reached at level 3 and the RD was: sirolimus 5mg/24h and gemcitabine 800mg/m2. 3 DLTs were observed, 1 at dose level 2 and 2 at dose level 3: transaminitis grade 3, thrombocytopenia grade 3 and thrombocytopenia grade 4. Other toxicities grade 1-2 included anemia, neutropenia, asthenia, mucositis and high cholesterol levels. 2 patients achieved partial response (1 uterine cervix cancer and 1 colon cancer). Immunohistochemistry of pS6 in skin biopsies showed significative inhibition of mTOR pathway at RD. PK parameters estimated were in agreement with those previously reported in the literature. No influence of sirolimus administration on gemcitabine clearance was found. Conclusions: Combination of sirolimus and gemcitabine is feasible and safe, allowing administration of active doses of both agents and achieving mTOR signaling inhibition. A phase II study to assess the activity of this combination in sarcomas is ongoing.

Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
Shubham Pant ◽  
Lowell L. Hart ◽  
Johanna C. Bendell ◽  
Jeffrey R. Infante ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Hsp90 Inhibition ◽  
Grade 3 ◽  
Dose Levels

3564 Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90. Preclinical evidence suggests potential synergy between HSP90 inhibition and fluorouracil. This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Pts with refractory solid tumors received AUY922 with capecitabine in a standard 3+3 dose escalation. Dose levels were capecitabine 1000mg/m2 PO BID d 1-14 of 21-day cycles, with escalating doses of AUY922 IV days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 pts were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n= 6). No DLTs were observed until the 6th dose level (grade 3 diarrhea). Related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (43%; 17%), fatigue (30%; 13%), nausea (39%; 0), hand-foot skin reaction (30%; 5%), anorexia (30%; 4%), vomiting (30%; 0), and darkening vision (26%; 0). Vision darkening, a class effect of HSP90 inhibitors, was reversible with drug hold and retreatment was possible. Two pts (9%) had hematologic G 3/4 events of neutropenia. Of the 19 pts evaluable for response, partial response was noted in 4 patients (colorectal, 2; breast, 1; stomach, 1); 2 had progressed on prior fluorouracil, and remained on treatment for 13-35 wks. Stable disease was noted in 8 pts (35% [colorectal, 5; pancreas, 2; breast, 1]) with a median duration of 25.5 wks (range: 11-44+). All 5 colorectal pts were refractory to 5-FU. Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, particularly as seen in pts previously resistant to fluorouracil, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

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 Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with capecitabine for advanced solid tumors (including patients with progressive or recurrent HER2-negative metastatic breast cancer).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3057-3057 ◽  
Author(s):  
Ellis Glenn Levine ◽  
Andres Forero ◽  
Tracy O'Connor ◽  
Ben K. Seon ◽  
Manoj A Jivani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Phase Ii ◽  
Dose Escalation ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3

3057 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody being studied in phase II trials that potentiates chemotherapy in preclinical models. Methods: Pts with advanced solid tumors (for purposes of dose escalation) or pts with metastatic HER2-negative breast cancer (following completion of dose escalation), ECOG PS 0-1, and normal organ function were treated with intravenously administered TRC105 wkly plus capecitabine at 1,000 mg/m2 BID for 14 of every 21 days, and assessed for safety, PK, and response. Results: Fourteen patients (median age = 52; M:F 4:10; median of 3 prior regimens; 10 with breast and 4 with colorectal cancer) were enrolled. Dose escalation proceeded from 7.5 mg/kg TRC105 to the recommended single agent phase II dose of 10 mg/kg of TRC105 in combination with capecitabine, without development of dose limiting toxicity. Fourteen pts were treated at 7.5 mg/kg (n=4) or 10 mg/kg (n=10) TRC105 wkly + 1,000 mg/m2 BID/14d capecitabine of repeating 21 day cycles. Patients experienced expected TRC105 related adverse events of grade 1 or grade 2 infusion reaction, epistaxis, gingival bleeding, telangiectasia, headache, rash, and fatigue. Grade 3 headache and grade 3 vomiting were each seen in one patient. Adverse events characteristic of each individual drug were not increased in frequency or severity when the two drugs were administered together. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed at both dose levels. A heavily pretreated male breast cancer patient remained on study for 9 months with a RECIST-defined partial response. Stable disease beyond 9 weeks was observed in three patients. Conclusions: The recommended single agent phase II dose of 10 mg/kg TRC105 wkly was well tolerated in combination with capecitabine. The combination treatment could be advanced in HER2-negative breast or colorectal cancer. Clinical trial information: NCT01326481.

A first-in-human phase I study of CYH33, a phosphatidylinositol 3-kinase (PI3K) α selective inhibitor, in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15645-e15645 ◽  
Author(s):  
Xiao-Li Wei ◽  
Rui-hua Xu ◽  
Hongyun Zhao ◽  
Yang Zhang ◽  
Ben-Yan Zou ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Pik3ca Mutation ◽  
Selective Inhibitor ◽  
Advanced Solid Tumors ◽  
Mutation Status ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

e15645 Background: PI3Kα is the only subtype in PI3K family of which activated mutations occur frequently in tumors. CYH33 is a potent PI3Kα–selective inhibitor with anti-tumor activity in xenograft models. An open-label, Phase I dose-escalation & expansion study of CYH33 monotherapy (NCT03544905) is underway in patients (pts) with advanced solid tumors. Methods: This study evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of CYH33 administered daily orally in 28-day cycles until intolerable toxicity or disease progression (PD). Adult pts with advanced solid tumors who have progressed despite standard therapies are enrolled to this trial, and pts with or without PIK3CA mutant are eligible for dose-escalation and pts with PIK3CA mutant are eligible for dose-expansion. Results: As of the cut-off date 20 Dec 2019, 17 pts (median age 47.0 y) were enrolled in the first 6 dose levels (1mg, 5mg, 10mg, 20mg, 40mg and 60mg) of the dose-escalation cohorts, and 3 pts were enrolled in expansion cohort of 40 mg. Cohorts 1 mg to 20 mg were completed without dose-limiting toxicities (DLT), cohort 40mg was completed with 1 DLT (Grade 3 hyperglycemia) out of 6 evaluable pts, and 3 enrolled pts at 60 mg are still in the DLT evaluation. Most frequent treatment-related adverse events (TRAEs) (all grades, ≥ 20%) included hyperglycemia (17 pts, 85%), decreased appetite (5 pts, 25%), diarrhea (4 pts, 20%). Grade≥3 TRAEs were hyperglycemia (8 pts, 40%), nausea (1 pt, 5%) and decreased appetite (1 pt, 5%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. The preliminary PK profile of CYH33 showed dose proportionality across the tested dose levels, half-life (t1/2) was about 20 hours with minimum accumulation, and the maximum concentration (Cmax) achieved 2-4 hours after dosing. Over all, among 15 tumor response evaluable pts, partial response (PR) was observed in 2 pts treated with 40mg (1 colorectal cancer with unknown PIK3CA mutation status, 1 breast cancer with PIK3CA mutant), and stable disease (SD) was observed in 3 pts with unknown PIK3CA mutation status. After the cut-off date, 1 more pt (ovarian cancer with PIK3CA mutation) treated with 40mg achieved PR, so that 2 out of 3 enrolled PIK3CA mutant pts treated with 40mg achieved PR. Conclusions: The first-in-human study of the PI3Kα selective inhibitor CYH33 demonstrated a manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. CYH33 single agent and in combination with other anti-tumor agents have be planned in future studies. Clinical trial information: 03544905.

A phase IB study of the combination of selumetinib (AZD6244; ARRY-142886) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 609-609 ◽  
Author(s):  
Anuradha Krishnamurthy ◽  
A. Dasari ◽  
Albert C. Lockhart ◽  
Mark N. Stein ◽  
Hanna Kelly Sanoff ◽  
...  
Keyword(s):  
Phase I ◽  
Cyclosporin A ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Wnt Pathway ◽  
Response To Therapy ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Expansion Cohort

609 Background: Targeting MEK is of interest in the development of novel agents for treatment of many malignancies. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, Selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical WnT pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We are conducting an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628) of selumetinib and CsA combination. Biomarkers of response to therapy are being co-developed. We hypothesize that this combination will be safe and potentially effective in patients with mCRC and that upregulation of FZD2 may predict for sensitivity. Methods: Phase I trial with initial dose escalation investigating the combination of selumetinib and CsA in patients with advanced solid tumors (n = 18) followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilizes a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: 18 patients were enrolled in the dose escalation phase and 10 patients have been enrolled in the dose expansion phase as of September 2016. Grade 1 or 2 nausea and rash were reported as the most common AEs. Most commonly reported Grade 3 or 4 toxicities were hypertension, elevated liver enzymes and rash. Three DLTs were reported with Grade 3 hypertension noted at dose level 1 and 2 and grade 3 rash reported at dose level 2. The maximum tolerated dose was defined as Selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. Two partial responses and sixteen stable disease responses have been observed. Six patients have exhibited progressive disease. Conclusions: Selumetinib in combination with cyclosporin A appears to be well-tolerated with evidence of activity in solid tumors. Expansion cohort will complete enrollment this month. Clinical trial information: NCT02188264.

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

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

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

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