Optimally Tolerated Regimen Research Articles

Optimally tolerated dose of lapatinib in combination with docetaxel plus trastuzumab in first-line treatment of HER2-positive metastatic breast cancer

BackgroundThis phase IB, open-label, dose-escalation study evaluated the safety, tolerability, and optimally tolerated regimen (OTR) of lapatinib in combination with docetaxel and trastuzumab in patients with previously untreated stage IV metastatic breast cancer (MBC) tumors overexpressing human epidermal growth factor receptor 2 (HER2). Patients and methodsEvaluated dose regimens included lapatinib (500–1500 mg/day), docetaxel (triweekly; 60–100 mg/m²), and trastuzumab (weekly; 2 mg/kg fixed dose); prophylactic granulocyte colony-stimulating factor was included with regimens with ≥750 mg/day lapatinib. End points included OTR and safety/tolerability (primary), overall response rate (ORR), and pharmacokinetics (secondary). ResultsNone of the patients (N = 53) experienced dose-limiting toxic effects (DLTs) at the highest dose level; thus, the OTR of lapatinib with 100 mg/m2 docetaxel was not determined. Common adverse events included diarrhea, nausea, alopecia, fatigue, and rash; grade 3/4 (≥2 patients) were neutropenia, diarrhea, leukopenia, peripheral neuropathy, and rash. Seven patients had DLTs (cycle 1). In 45 patients with measurable disease confirmed by bone scan, investigator-assessed ORR was 31%; without bone scan, confirmation was 64%; 8 patients without measurable disease were evaluated as stable. Lapatinib/docetaxel plasma concentrations were positively associated with complete response. ConclusionsLapatinib/docetaxel/trastuzumab is a feasible and well-tolerated treatment of untreated HER2-positive stage IV MBC. Two lapatinib/docetaxel OTR doses were recommended (1250 mg/75 mg/m²; 1000 mg/100 mg/m²). Clinical trial numberNCT00251433.

A Phase I, Dose Escalation Study of Lapatinib in Combination with Carboplatin, Paclitaxel, with or without Trastuzumab in Patients with Metastatic Breast Cancer: An Update.

Abstract Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of erbB1 and erbB2 tyrosine kinases with clinical activity in erbB2-positive metastatic breast cancer (MBC). The combination of carboplatin, paclitaxel, and trastuzumab has been shown to have significant clinical activity in MBC as well as in the adjuvant setting. Given the synergy of dual inhibition with trastuzumab and lapatinib observed in both the preclinical and clinical settings, the feasibility, safety, and early clinical activity of paclitaxel, carboplatin, lapatinib with or without trastuzumab in patients (pts) with MBC was assessed.Methods: MBC pts previously untreated with trastuzumab or cytotoxic chemotherapy for metastatic or locally recurrent disease were enrolled into either Group (Grp) A (erbB2 positive) or B (erbB2 positive or negative). Escalating doses of lapatinib (planned range of 750-1500 mg/d) were administered in combination with (Grp A) or without (Grp B) trastuzumab (4 mg/kg followed by weekly 2 mg/kg infusions). Paclitaxel (80 mg/m2) and carboplatin (AUC 2 mg/ml*min) were administered on days 1, 8, 15 with cycles repeated every 28 days. Starting doses of lapatinib were 750 mg in Grp A and 1000 mg in Grp B (Dose Level 0). A standard 3 + 3 Phase I design was used to determine the optimally tolerated regimen (OTR) dose level.Results: Twenty-seven pts (Grp A n=15, Grp B n=12) have been enrolled in the study (median age 45 yrs, range 27-74). A median of 5 cycles (range 1-21) in Grp A and 5.5 (range 2-15) in Grp B have been administered. Drug-related toxicities were reported in 14 pts (93%) in Grp A and 11 pts (92%) in Grp B. In Grp A, drug-related grade 3 toxicities ≥ 10% include neutropenia (47%), diarrhea (33%), and rash (20%). Two drug-related grade 4 toxicities were reported (urinary tract infection and hypocalcemia). In Grp B, drug-related grade 3 toxicities ≥ 10% include diarrhea (17%), fatigue (17%), and rash (17%). Drug-related grade 4 toxicity (neutropenia) occurred in 3 pts in Grp B. In Grp A, there were two patients with dose-limiting toxicity (DLT) (Gr 3 diarrhea, Gr 3 rash) at lapatinib 1000 mg (Dose Level +1). The OTR (Dose Level 0) was identified as lapatinib 750 mg, paclitaxel 80 mg/m2, carboplatin AUC 2, and trastuzumab 2 mg/kg. In Grp B, two patients had DLT (one with Gr 4 neutropenia, one with Gr 3 rash and hypokalemia) at Dose Level 0 (lapatinib 1000 mg). At Dose Level -1 (paclitaxel reduced to 70 mg/m2), one pt had a DLT (Gr 4 neutropenia) and this dose level will be expanded to 6 pts. Clinical activity to date in Grp A (12 pts) includes 2 CR, 8 PR, and 1 SD and in Grp B (11 pts) 5 PR and 5 SD. Two pts in Grp B were ErbB2+, both had PR. Response assessments were not available for 4 pts (3 pts were awaiting response assessment and 1 pt was removed from the study prior to response assessment due to toxicity (neutropenia, catheter infection)).Conclusions: Lapatinib may be administered safely in combination with carboplatin, paclitaxel, with or without trastuzumab at known effective doses. Clinical activity has been observed. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3097.

Abstract A6: Pazopanib combination with paclitaxel and carboplatin in patients with advanced solid tumors and gynecological cancers: Results of two phase I studies

Abstract Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit with w/ a recommended dose of 800 mg/day as monotherapy. Preclinical activity supports combining PAZ with paclitaxel (P) and carboplatin (C). Safety, PK, and and clinical activity of PAZ with P and and C were evaluated in two Phase I studies. Methods: Two Phase I studies were conducted using a once daily QD regimen of PAZ (200–800 mg), and once every Q21 days of C (AUC 4–6 mg·min/mL) and P (175 mg/m2) to determine the optimally tolerated regimen (OTR) MTD defined as a dose limiting toxicity (DLT) frequency of <33% in Cycle 1. Study 1 (S1) was a 3 + 3 design expanded at the OTR in patients (pts) with w/ metastatic disease treated with w/ no more than 3 prior lines of therapy. Study 2 (S2) enrolled subjects with w/ gynecological cancer in 2 cohorts of 6 pts each as first-1st line treatment. Results: In Study 1S1, 34 pts (mean age 54; M/F: 17/17; ECOG 0/1: 19/15) were enrolled. Breast (29%) and esophagus (12%) were the most common primary tumor sites. In Study 2S2, 12 pts (mean age 53.754, M/F: 0/12; ECOG 0/1: 8/4) were enrolled. Ovary (50%) and endometrium/uterus (25%) were the most common primary tumor sites. The frequency of adverse events (AEs), regardless of causality, in the 2 studies (1 vs 2), were similar for neutropenia (82% vs 75%) and fatigue (68% vs 75%) and different for nausea (71% vs 50%), thrombocytopenia (68% vs 33%), anemia (65% vs 25%), and abdominal pain (24% vs 50%). The OTR MTD in Study 1S1 was P 175, C AUC 5, and PAZ 200; an OTR MTD was not determined for Study 2S2 due to poor tolerability. In Study 1S1, in the presence of PAZ 200 mg and 400, mg, the AUC (0–23) of C increased by 41 and 31%, respectively and while the Cmax for P increased by 43 and 40%, respectively. Best response in Study 1S1 at the OTRMTD (n=13) was CR [2 pts (15%); 406 and 446 days] and PR [3 pts (23%); 42–208 days]. Conclusions: Full doses of PAZ and C were not tolerated in combination with w/ P due predominantly to hematologicale toxicities in Study 1S1 and to non-hemeatological toxicities in Study 2S2. A drug interaction between PAZ and P and C along with more extensive prior therapy may explain increased myelotoxicity with this triplet in Study 1S1. Based on this PK interaction, lower doses of P and C may still provide adequate therapeutic exposure and better safety profile when combined with a higher dose of PAZ relative to the OTR MTD in study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A6.

Pazopanib and lapatinib in patients with relapsed malignant glioma: Results of a phase I/II study

2040 Background: Pazopanib (paz) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit; and lapatinib (lap) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER-2 (ErbB2). Combination of VEGFR, PDGFR, and ErbB1 inhibitors may provide synergistic antitumor activity in malignant glioma. Phase I determined the optimally tolerated regimen (OTR) of paz and lap when given with enzyme-inducing anticonvulsants (EIACs). Phase II, which evaluated the efficacy of daily paz/lap (400 mg/1000mg) in relapsed grade 4 glioma without EIACs, was previously reported. Methods: Patients (pts) with grade 3 or 4 glioma, on EIACs, and with adequate organ function were eligible. Doses of paz and lap were escalated in a 3 + 3 design. OTR was defined as the highest dose of paz/lap at which no more than 1 of 6 pts had dose limiting toxicity (DLT) and target concentrations were achieved. Results: 32 pts have been enrolled at doses of paz/lap (mg, daily unless specified) of 200/1500 (N = 4), 800/1500 (N = 6), 800/500 bid (N = 5), 800/750 bid (N = 7), 800/1000 bid (N = 6), and 600 bid/1000 bid (N = 4). Data on 28 pts: the most common adverse events (AEs) were: fatigue (25%); diarrhea (25%); headache (21%); ALT increase (18%); nausea (18%); and insomnia (14%). Hepatobiliary lab abnormalities were reversible, uncomplicated, and included: AST elevation (11%), hyperbilirubinemia (7%), ALT elevation (36%; 7% Gr 3), and Alk phos elevation (14%). DLTs were elevated liver enzymes (800/1500; 1 pt), elevated lipase (800/750 bid; 1 pt) and thrombocytopenia, fatigue, diarrhea, confusion (800/1000 bid; 1 pt). 2 pts dose reduced and 3 pts had a dose interruption. At 600 bid/1000 bid, the target paz Cmin of 17.5 μg/mL was achieved; median lap Cmin of 0.447 μg/mL approached the target of 0.5 μg/mL. Phase I best response (MacDonald criteria) was PR in 3 pts (11%) and SD ≥ 8 weeks in 5 pts (18%). Two pts remain on the phase II, at 21 months (PR) and 23 months (CR) of therapy. Conclusions: The paz/lap combination has a manageable safety profile with a preliminary OTR with EIACs of paz 600 mg bid/ lap 1000 mg bid. EIACs decreased plasma paz and lap concentrations. Responses and lengthy periods without disease progression were seen in some pts in phase I and II. [Table: see text]

A phase I study of pazopanib in combination with FOLFOX 6 or capeOx in subjects with colorectal cancer

4133 Background: Pazopanib (paz) is a tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGF-α, -β, and c-kit. Inhibition of angiogenic pathways in combination with chemotherapy has been shown to benefit patients (pts) with colorectal cancer (CRC). Methods: Pts with previously untreated advanced or metastatic CRC and adequate organ function were assigned to paz with FOLFOX6 (FO) or capeOx (CO) by their physician. Doses of paz were escalated with full strength chemotherapy, starting at 400mg daily. The optimally tolerated regimen (OTR) was the combination dose at which <1/6 pts experienced dose-limiting toxicity (DLT). Results: Fifty pts were enrolled in FO (paz 400 mg, n=6; 800, 15), CO (400, 12; 800, 9) and reduced capecitabine (rc) CO (800, 8) cohorts: median age = 55.5, M/F = 37/13. Pts have remained on therapy for a median of 3 (range 0–17) months. Three pts remain on study. Safety data is available on 41. The most common AEs are summarized in the table below. The OTR was exceeded with CO in combination with 800 mg and 400 mg of pazopanib, but was not exceeded with 800 mg pazopanib when capecitabine was reduced to 850 mg/m2 twice daily or with FO with 800 mg pazopanib. Efficacy and pharmacokinetic analyses are ongoing. Conclusions: The OTRs were achieved at 800 mg paz with full-dose FO, and at 800mg paz with rcCO. [Table: see text] [Table: see text]

Phase I dose-escalation study of thoracic radiotherapy in combination with gefitinib in patients with IIIB/IV non-small cell lung cancer (NCT00497250)

e14581 Background: Cinical studies have confirmed that gefitinib, an EGFR-TKI, is effective for some advanced NSCLC patients. Patients with Asian ethnicity are reported to have a higher response rate with gefitinib monotherapy. However, a higher incidence of interstitial lung disease, sometimes lethal, is also found. The combination of gefitinib and radiotherapy has been observed to have a synergistic, anti-proliferative effect against NSCLC in vitro. This phase I study assessed the safety, clinical feasibility and optimally tolerated regimen (OTR) of this combination in patients with pretreated locally advanced or metastatic (IIIB/IV) NSCLC. Methods: Patients with stage IIIB or selected stage IV, failure of platinum-based chemotherapy regimen NSCLC were eligible. Four Cohorts of eight patients each were planned to be treated with escalating doses from 54 to 60 Gy of conformal or intensity- modulated radiotherapy (2Gy/Fx) administered in combination with gefitinib 250mg daily during RT and 60 days after the completion of RT to determine the OTR. Results: Since June 2007, 2 cohorts, a total of 16 patients, were enrolled and treated: 8 stage IIIB and 8 stage IV; 2 squamous-cell carcinoma and 14 adenocarcinoma; 8 smokers and 8 nonsmokers. Prior-chemotherapy regimen was consisted of NP, GP and TP for a median of 3.5 cycles (range, 1–5). Median follow-up time was seven months. Mean progression-free survival time was 5.2 months (median, 3.9; range, 1.7–12.3). Overall, adverse events were mild to moderate in severity. The most frequent grade 2 events included pneumonitis (31%) and dysphagia (19%). There were one treatment-related grade 3 event, which was nausea, and no grade 4 events. Most of the failure patterns were out-of-field (11/13) and the most common distant metastasis organ was the lungs. Three patients are progression-free to date. Conclusions: Thoracic radiotherapy up to 56 Gy concurrent with gefitinib 250 mg daily was well tolerated and clinically active in this group of pretreated Chinese NSCLC patients, including nonsmokers with adenocarcinoma. Accrual is continuing. Sponsorship: This work was partly supported by Program for New Century Excellent Talents in University (NCET), Ministry of Education. No significant financial relationships to disclose.

A phase I, dose escalation study of lapatinib in combination with carboplatin, paclitaxel, with and without trastuzumab in patients with metastatic breast cancer.

Abstract Abstract #3121 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of erbB1 and erbB2 tyrosine kinases with clinical activity in erbB2-positive metastatic breast cancer (MBC). The combination of carboplatin, paclitaxel, and trastuzumab has been shown to have significant clinical activity in MBC as well as in the adjuvant setting. Given the synergy of dual inhibition with trastuzumab and lapatinib observed in both the preclinical and clinical settings, we assessed the feasibility, safety, and early clinical activity of paclitaxel, carboplatin, lapatinib with and without trastuzumab in patients (pts) with MBC.
 Methods: MBC pts previously untreated with trastuzumab or cytotoxic chemotherapy for metastatic or locally recurrent disease were enrolled into either Group (Grp) A (erbB2 positive) or B (erbB2 positive or negative). Escalating doses of lapatinib (planned range of 750-1500 mg/d) were administered in combination with (Grp A) or without (Grp B) trastuzumab (4 mg/kg followed by weekly 2 mg/kg infusions). Paclitaxel (80 mg/m2) and carboplatin (AUC 2 mg/ml*min) were administered on days 1, 8, 15 with cycles repeated every 28 days. Starting doses of lapatinib were 750 mg in Grp A and 1000 mg in Grp B. A standard 3 + 3 Phase I design is being used until the optimally tolerated regimen (OTR) dose level is determined. An additional 14 - 17 pts will be enrolled into each grp at the OTR dose level to further assess safety and tolerability.
 Results: Fourteen pts (Grp A n=8, Grp B n=6) have been enrolled in the study (median age 42 yrs, range 27-66). A median of 5.5 cycles (range 4-17) in Grp A and 3.5 (range 1-7) in Grp B have been administered. All pts had at least one adverse event (AE). In Grp A, grade 3 toxicities include neutropenia (50%), diarrhea (38%), rash (25%), vomiting (13%), hypokalemia (13%), and syncope (13%). No grade 4 toxicities were reported. In Grp B, grade 3 toxicities include fatigue (33%), hyponatremia (17%), menorrhagia (17%), dermatitis (17%), and rash (17%). One pt (in Grp B) had grade 4 neutropenia. No febrile neutropenia was observed. In Grp A, there was one DLT (Gr 3 diarrhea) at lapatinib 1000 mg. In Grp B, one DLT (Gr 4 neutropenia) at lapatinib 1000 mg has been observed. Clinical activity to date includes 8/8 objective responses in Grp A, (1 CR, 7 PR) and 2/6 objective responses (2 PR) in Grp B (all pts in Grp B were erbB2 negative). Dose escalation continues in both grps.
 Conclusions: Lapatinib may be administered safely in combination with carboplatin, paclitaxel, with and without trastuzumab at known effective doses for each. Clinical activity has been observed. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3121.

A Phase I and Pharmacokinetic Study of Lapatinib in Combination with Letrozole in Patients with Advanced Cancer

The main objectives of this phase I and pharmacokinetic, open-label study were to determine the optimally tolerated regimen (OTR), safety, pharmacokinetics, and clinical activity of lapatinib in combination with letrozole in patients with advanced solid malignancies. Patients with advanced breast cancer with immunohistochemically detectable estrogen or progesterone receptors or other cancers were eligible. Doses of lapatinib were escalated in cohorts of three subjects from 1,250 to a maximum of 1,500 mg/d based on dose-limiting toxicities in the first treatment cycle. The letrozole dose was fixed at 2.5 mg/d. Additional patients were enrolled at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. Thirty-nine patients were enrolled in the study: 12 in the dose-escalation group, 7 in the OTR safety group, and 20 in the pharmacokinetic group. The OTR dose level was identified as 1,500 mg/d lapatinib and 2.5 mg/d letrozole. The most common (>25% of patients) drug-related adverse events were diarrhea (77%), rash (62%), nausea (46%), and fatigue (26%). No significant differences were observed in the pharmacokinetic variables (C(max) and AUC) of lapatinib and letrozole when coadministered compared with single-agent administration. One patient with endometrial cancer had a confirmed partial response. Clinically relevant doses of lapatinib in combination with letrozole were well tolerated and did not result in a pharmacokinetic interaction, and clinical antitumor activity was observed.

Phase I and Pharmacokinetic Study of Lapatinib and Docetaxel in Patients With Advanced Cancer

This phase I study assessed the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of lapatinib and docetaxel in patients with advanced solid tumors. Doses of lapatinib (oral once daily, continuous) and docetaxel (intravenous, every 3 weeks) were escalated in cohorts of at least three patients based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. The protocol was amended to include pegfilgrastim because of dose-limiting toxicity (neutropenia), and a second dose-escalation phase was conducted to determine the OTR for the combination of docetaxel, lapatinib, and pegfilgrastim. After the determination of the OTR, the pharmacokinetics of lapatinib and docetaxel were determined to estimate the potential for an interaction between docetaxel and lapatinib at the OTR dose level. Fifty-two patients with advanced solid tumors were enrolled. The OTR dose level for lapatinib and docetaxel with pegfilgrastim was 1,250 mg (once daily) and 75 mg/m(2) (once every 3 weeks), respectively. Overall, adverse events (AEs) were mild to moderate in severity. The drug-related AEs reported by most patients (>or= 25%) were diarrhea (56%), rash (52%), fatigue (27%), and nausea (25%). Of 43 patients assessable for clinical response, two patients had confirmed partial responses. The pharmacokinetics of lapatinib (area under the curve, maximum serum concentration) and docetaxel (area under the curve, clearance) in combination were not significantly different than when the drugs are administered separately. The combination of docetaxel and lapatinib with pegfilgrastim was well tolerated. No pharmacokinetic interaction was observed. Clinical activity was seen in this phase I drug combination trial.

Phase I study of the safety, tolerability, and pharmacokinetics (PK) of weekly paclitaxel administered in combination with pazopanib (GW786034)

3552 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit with demonstrated activity in renal cell cancer, sarcoma, and ovarian cancer when administered at 800 mg daily. Improved efficacy of weekly paclitaxel with the anti-VEGF agent bevacizumab in metastatic breast cancer provides a rationale for combining an angiogenesis inhibitor with a taxane. Methods: Patients (pts) with advanced cancer (ECOG PS 0–1) were eligible. Dose escalations of paclitaxel (15–80 mg/m2) on days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) daily were evaluated for safety, PK, and clinical response. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK; the optimally tolerated regimen (OTR) consisted of ≤ 1/6 pts experiencing a DLT; 9 additional pts were enrolled to confirm the OTR. Results: 25 pts received paclitaxel/pazopanib at doses of 15/400 (3), 15/800 (3), 50/800 (3) and 80/800 (16) mg. Median age was 58 y; M: 48%; 92% Caucasian. Most common tumor types were breast (5), CRC (3), esophageal (3), and NSCLC (3). Most frequent adverse events (AEs) (mostly Gr 1/2) were nausea (68%), fatigue (56%), diarrhea (52%), vomiting (48%), rash (44%), anorexia (32%), visual disturbance (24%), alopecia (24%), and constipation (24%). Hepatic enzyme elevations: ALT (48%), AST (44%), alkaline phosphatase (24%), and bilirubin (12%) were mainly Gr 1/2. The OTR was defined as 80 mg/m2 paclitaxel and 800 mg pazopanib (median 2.5 cycles [range 1–8]; median no. of 2 prior regimens [range 1–5]); 1 DLT (Gr 3 groin abscess) was observed at this dose. 12/16 pts at the OTR required dose modifications; 3 of these were withdrawn due to an AE. For pazopanib, 7 pts required interruptions and 3 pts required dose reductions. For paclitaxel, 11 pts required interruptions/delays and 5 pts required dose reductions. Liver enzyme elevation was the most common reason for dose modification. Pazopanib increased mean paclitaxel AUC (45%) and Cmax (40%). Clinical activity at the OTR: PR in 5/16 (31%) pts and SD > 8 wks in 10/16 (63%) pts. Conclusions: Therapeutic doses of daily pazopanib and weekly paclitaxel can be combined with a manageable toxicity profile and evidence of clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline Eli Lilly, Genentech™ BioOncology Aventis, Celgene, GlaxoSmithKline, OSI Oncology

Phase I Dose Escalation and Pharmacokinetic Study of Lapatinib in Combination With Trastuzumab in Patients With Advanced ErbB2-Positive Breast Cancer

The combination of lapatinib and trastuzumab has been observed to have a synergistic, antiproliferative effect against ErbB2-positive breast cancer cells in vitro. This phase I study assessed the safety, clinical feasibility, optimally tolerated regimen (OTR), pharmacokinetics (PK), and preliminary clinical activity of this combination in patients with ErbB2-positive advanced breast cancer. Cohorts of three patients with ErbB2-positive advanced breast cancer were treated with escalating doses of lapatinib (750 to 1,500 mg) administered once daily (continuous) in combination with trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) to determine the OTR. Once the OTR was determined, additional patients were enrolled to provide the PK profile of both agents alone and in combination. A total of 54 patients were treated: 27 in the dose-escalation group and 27 in the PK group. Overall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone. The OTR of the lapatinib/trastuzumab combination was lapatinib 1,000 mg per day with standard weekly trastuzumab. At these doses, the regimen was well tolerated and clinically active in this heavily pretreated ErbB2-positive breast cancer population.

A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan

This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination. Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination. The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease. The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.

Phase I and Pharmacokinetic Study of Lapatinib in Combination With Capecitabine in Patients With Advanced Solid Malignancies

This phase I trial (EGF10005) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies. Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m(2)/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and alpha-fluoro-beta-alanine, were not meaningfully altered by coadministration. Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.

Phase I Pharmacokinetic Study of the Safety and Tolerability of Lapatinib (GW572016) in Combination with Oxaliplatin/Fluorouracil/Leucovorin (FOLFOX4) in Patients with Solid Tumors

This phase I study was designed to determine the optimally tolerated regimen (OTR), safety, and clinical activity of lapatinib in combination with FOLFOX4 [oxaliplatin/leucovorin/5-fluorouracil (5-FU)] in patients with solid tumors. Furthermore, the pharmacokinetics of lapatinib, oxaliplatin, and 5-FU when given alone and in combination were evaluated. This study was conducted in two parts. Part 1 was designed to determine the OTR and part 2 was the pharmacokinetic part of the study. Lapatinib was administered once daily for the entire duration of the study. Leucovorin and oxaliplatin were given concurrently over 2 h as an i.v. infusion, after which 5-FU was given as a bolus followed by continuous infusion over 22 h on day 1. 5-FU and leucovorin administration were repeated in an identical manner on day 2. Cycles were repeated every 2 weeks. Once the OTR was determined, it was to become the dose level for patients included in the pharmacokinetic part of the study. A total of 34 patients was treated in this study. No dose-limiting toxicities were observed and the OTR was established at 1,500 mg/d lapatinib in combination with the standard FOLFOX4 regimen. Nonhematologic toxicities consisted mainly of nausea, diarrhea, vomiting, fatigue, neuropathy, and mucositis. The most important hematologic toxicity was neutropenia. No drug-drug interactions between lapatinib and the FOLFOX4 regimen were observed. Lapatinib can be safely administered in combination with the standard FOLFOX4 regimen. Further studies are warranted to explore the potential additive antitumor effect of lapatinib in combination with the FOLFOX4 regimen.

Phase I study of ispinesib in combination with carboplatin in patients with advanced solid tumors

2027 Background: Kinesin spindle protein (KSP) is required for establishment of mitotic spindle bipolarity and cell cycle progression. Ispinesib (SB-715992), a KSP inhibitor, blocks assembly of a functional mitotic spindle leading to G2/M arrest. Carboplatin is a platinum compound that produces predominantly interstrand DNA cross-links. In vivo combination of a platinum-containing agent (cisplatin) and ispinesib resulted in synergistic activity and an increase in maximum tolerated dose (MTD) of ispinesib. In a phase I study of single agent ispinesib on a once every 21-day schedule, the MTD was 18 mg/m2 with prolonged gr 4 neutropenia and febrile neutropenia as DLTs. Methods: Patients (pts) with advanced solid tumors, PS ≤ 1, and ≤ 3 prior chemotherapy regimens were eligible for this study. Escalating doses of carboplatin (AUC 4-6) were administered over 30 minutes followed by a 1-hour infusion of escalating doses of ispinesib (9– 21 mg/m2) on a 21-day schedule. At least 3 pts were treated at each dose level. The primary objectives of this study included characterizing safety and tolerability and defining the optimally tolerated regimen (OTR). Limited pharmacokinetic (PK) samples were obtained. Clinical response assessments per RECIST criteria were performed every 2 cycles. Results: 24 pts [15 M/9 F; median age 63yrs, ECOG PS 1], were treated at 6 dose levels. The most common tumor types were prostate (7) and breast (4). A median of 3 cycles were administered (range 1–7; total 75 cycles). In 17 pts, the most common toxicities were (# pts, [grade]): nausea (10, Gr 1–2), vomiting (8, Gr 1–3), fatigue (8, Gr 1–2), neutropenia (8, Gr 2–4), anemia (7, Gr 1–3), and thrombocytopenia (7, Gr 1–4). Gr 4 thrombocytopenia was the observed DLT in 2 pts [ispinesib (mg/m2)/carboplatin (mg/ml·min) (# pts): 15/6 (1); 18/6 (1). PK assessment of ispinesib and carboplatin will be completed when the OTR has been defined. Unconfirmed minor responses have been observed in 3 pts (breast, prostate, NSCLC) starting at doses of 18/6. Conclusions: Determination of an OTR is ongoing. Ispinesib doses ≥ single agent MTD when combined with carboplatin AUC 6 have an acceptable tolerability profile and demonstrate preliminary evidence of anti-tumor activity. [Table: see text]

Phase I study of GW572016 (lapatinib), a dual kinase inhibitor, in combination with irinotecan (IR), 5-fluorouracil (FU) and leucovorin (LV)

3086 Background: Lapatinib is an orally active reversible inhibitor of ErbB1/ErbB2 tyrosine kinases. This study evaluated the safety, tolerability and pharmacokinetics (PK) of daily lapatinib in combination with IR/FU/LV (FOLFIRI) q14d. Methods: Cohorts of 3 patients (pts) each (25 total) with solid tumours received lapatinib (1000 or 1250mg daily) and FOLFIRI (80% or 60% of the standard doses) to determine the optimally tolerated regimen (OTR). Additional pts were enrolled at the OTR to evaluate the PK of lapatinib and FOLFIRI alone and in combination. Results: The standard FOLFIRI doses were reduced to 80% and 60% due to DLTs of diarrhea and/or myelosuppression at the starting doses. Toxicity required the lapatinib dose to be interrupted or reduced at these doses. The OTR was defined as lapatinib 1250mg with IR 120mg/m2, FU 240mg/m2 bolus and 360mg/m2 infusion, plus LV 200mg/m2on days 1 and 2, every 14 days. At the OTR, common non-hematological adverse events were grade 1 or 2 diarrhea, nausea/vomiting,...

A phase I, open-label study of the safety, tolerability and pharmacokinetics of lapatinib (GW572016) in combination with letrozole in cancer patients

3001 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases leading to cell growth arrest and/or apoptosis in ErbB1 and ErbB2 dependent tumor cell lines and xenografts. Co-expression of ErbB2 and ER is associated with a reduced response rate to hormone therapy in breast cancer. A rational approach to treatment may be to block simultaneously both ER and ErbB2 pathways. Methods: Patients (pts) with advanced breast cancer, ER or PR +, or other tumors (e.g., ovarian, endometrial) that would be likely to respond to the combination therapy were enrolled. Escalating doses of lapatinib (1250–1500 mg/d) were administered in combination with letrozole (2.5 mg/d). Three pts were treated at each dose level, with expansion to 6 in the event of dose-limiting toxicity (DLT). Once the optimally tolerated regimen (OTR) was determined, an additional 8 - 16 pts were to be enrolled to establish the pharmacokinetic profiles of lapatinib and letrozole when administered alone and in combination. Results: Thirty-six pts (35 F, 1 M, median age 55 yrs, median Karnofsky PS 90%) were enrolled at the 2 dose levels (1250 mg 4 pts, 1500 mg 32 pts). One hundred and twenty-three treatment periods (4 weeks = 1 treatment period) were completed: median 2. One DLT (Gr 3 diarrhea) was reported at the 1500 mg/d dose level. The optimally tolerated regimen was determined to be letrozole 2.5 mg + lapatinib 1500 mg/d. Gr 1–2 diarrhea, nausea, rash and fatigue were the common non-hematologic toxicities. Out of 36 evaluable pts, 4 pts experienced SD for > 5 mo. (breast 2 pts, ovarian 2 pts). One endometrial pt experienced a PR at treatment period 8. Conclusions: Lapatinib may be administered safely in combination with letrozole at known effective single agent doses for each. The pharmacokinetic portion of the study is enrolling pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline

Phase I trial to determine the safety and tolerability of GW572016 in combination with oxaliplatin (OX)/5-fluorouracil (5-FU)/leucovorin (LV) [FOLFOX4] in patients with solid tumors

2044 Background: EGFR and erbB2 receptor expression in tumors predicts a poor outcome. GW572016 (GW) is a potent EGFR/erbB2 RTK inhibitor. The FOLFOX4 is an effective therapy in colorectal cancer. It is hypothesized that inhibition of kinase activation by GW will contribute to the cytotoxicity of FOLFOX4. This phase I trial aimed to determine the safety and optimally tolerated regimen (OTR) of FOLFOX4 with daily oral GW in patients (pts) with solid tumors. Methods: Pts were sequentially enrolled into 3 cohorts: cohort 1 - GW 1250 mg/day + FOLFOX4 at –20% of the standard dose; cohort 2 –GW 1250 mg/day + FOLFOX4 at standard dose; cohort 3 –GW 1500 mg/day + FOLFOX4 at standard dose. OTR was the dose level at which ≤ 1/6 pts experiences a DLT. DLT was based on hematological and non-hematological toxicity in cycle 1. Assessments of anti-tumor activity and left ventricular ejection fraction (LVEF) were performed every 4 cycles. Results: 13 pts were treated (cohort 1 - 3; cohort 2 - 3; cohort 3 - 7). Median age was 57 years (39–70). Histology: 2 colon, 1 ovary, 3 rectum, 2 cholangio, 2 cervix, 2 pancreas, and 1 esophagus. Total of 57 cycles were delivered: median 4 (2–9). Main toxicities are summarized in the table. 2 Pts had grade ≥ 3 hematological toxicities, which resolved after delay of the next cycle. No DLTs have been reported. LVEF values were relatively unchanged compared to pre-study values. 7 pts are evaluable for response. 2 PR, 2 SD and 3 PD. Conclusion: Standard dose FOLFOX4 in combination with GW 1500 mg/day is well tolerated. Enrollment continues at this dose level including pharmacokinetic assessments. No significant financial relationships to disclose.

Phase I clinical, biology & pharmacokinetic study of the combination of GW 572016 and capecitabine in patients with advanced solid tumors

3070 Background. GW572016 (GW), a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, which induces growth arrest and/or apoptosis in ErbB1 or ErbB2 expressing tumor cell lines. Capecitabine (C), an orally administered fluoropyrimidine, is preferentially converted to 5-FU by thymidine phosphorylase (TP) in tumor cells. Inhibition of EGFR may upregulate TP and downregulate thymidylate synthase (TS), leading to synergistic antitumor effect when combined with C. Methods. A 2-part Phase I study combining GW with C was conducted in 45 patients (pts) with advanced solid tumors: (A) dose-escalation phase (24 pts) and (B) pharmacokinetic phase at the optimally tolerated regimen (OTR) (21 pts): M/F (23:22), median age 57 yrs (34–78), ECOG (0/1/2:29/13/3), heavily:lightly pretreated (23:22), tumor types (H&N (8); breast (8), colorectal (7), lung (6), others (16)) and median cycle 3 (1–9). Pts were treated with 14 days of C (1500–2500 mg/m2) and daily GW (1250–1500 mg) every 3 weeks. Results. Dose-limiting toxicities (DLT) were: Gr 3 mucositis, fatigue and anorexia- 1250 GW/2000 C (n=1); Gr 3 rash (n=1), Gr 3 diarrhea (n=1)- 1500 GW/2000 C & Gr 2 bleeding stomatitis (n=1), Gr 3 diarrhea (n=1)- 1250 GW/2500 C. Other toxicities included stomatitis (36%), nausea/vomiting (30%), diarrhea (45%), unconjugated hyperbilirubinemia (14%), fatigue (19%), rash (38%) and hand foot syndrome (29%). OTR was 1250 GW/2000 C. Responses (RECIST criteria) included 1 CR in a woman with inflammatory breast cancer refractory to trastuzimab-and chemotherapy. Her tumor overexpressed ErbB2 (3+) with low TS. In addition, 4 PRs (1 @ erlotinib-resistant H&N; taxane refractory-H&N; breast; gastric) and 6 SD >12 weeks were observed. Conclusions. GW (1250 mg)/C (2000 mg) was active and tolerable. Use of biomarkers (e.g., ErbB2, TS) may identify potential responders. Complete PK data will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline

Phase I trial to determine the safety and tolerability of GW572016 in combination with oxaliplatin (OX)/5-fluorouracil (5-FU)/leucovorin (LV) [FOLFOX4] in patients with solid tumors

2044 Background: EGFR and erbB2 receptor expression in tumors predicts a poor outcome. GW572016 (GW) is a potent EGFR/erbB2 RTK inhibitor. The FOLFOX4 is an effective therapy in colorectal cancer. It is hypothesized that inhibition of kinase activation by GW will contribute to the cytotoxicity of FOLFOX4. This phase I trial aimed to determine the safety and optimally tolerated regimen (OTR) of FOLFOX4 with daily oral GW in patients (pts) with solid tumors. Methods: Pts were sequentially enrolled into 3 cohorts: cohort 1 - GW 1250 mg/day + FOLFOX4 at –20% of the standard dose; cohort 2 –GW 1250 mg/day + FOLFOX4 at standard dose; cohort 3 –GW 1500 mg/day + FOLFOX4 at standard dose. OTR was the dose level at which ≤ 1/6 pts experiences a DLT. DLT was based on hematological and non-hematological toxicity in cycle 1. Assessments of anti-tumor activity and left ventricular ejection fraction (LVEF) were performed every 4 cycles. Results: 13 pts were treated (cohort 1 - 3; cohort 2 - 3; cohort 3 - 7). Median age ...