Fa-Chyi Lee

A Phase I Study of Sunitinib Plus Capecitabine in Patients With Advanced Solid Tumors

PURPOSE This open-label, phase I, dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors. PATIENTS AND METHODS Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous daily dosing (CDD schedule). Capecitabine (825, 1,000, or 1,250 mg/m(2)) was administered orally twice daily on days 1 to 14 every 3 weeks for all patients. Sunitinib and capecitabine doses were escalated in serial patient cohorts. RESULTS Seventy-three patients were treated. Grade 3 adverse events included abdominal pain, mucosal inflammation, fatigue, neutropenia, and hand-foot syndrome. The MTD for Schedule 4/2 and the CDD schedule was sunitinib 37.5 mg/d plus capecitabine 1,000 mg/m(2) twice per day; the MTD for Schedule 2/1 was sunitinib 50 mg/d plus capecitabine 1,000 mg/m(2) twice per day. There were no clinically significant pharmacokinetic drug-drug interactions. Nine partial responses were confirmed in patients with pancreatic cancer (n = 3) and breast, thyroid, neuroendocrine, bladder, and colorectal cancer, and cholangiocarcinoma (each n = 1). CONCLUSION The combination of sunitinib and capecitabine resulted in an acceptable safety profile in patients with advanced solid tumors. Further evaluation of sunitinib in combination with capecitabine may be undertaken using the MTD for any of the three treatment schedules.

Capecitabine plus 3-weekly irinotecan (XELIRI regimen) as first-line chemotherapy for metastatic colorectal cancer: Phase II trial results

Background:Capecitabine results in superior response rate, improved safety, and improved convenience compared with 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (MCRC). Irinotecan in combination with 5-FU/LV has been shown to improve efficacy compared with 5-FU/LV alone in MCRC. Therefore, we evaluated the efficacy and safety of capecitabine plus irinotecan every 3 weeks (XELIRI regimen) as first-line treatment. Methods:Patients with MCRC who were <65 years of age received irinotecan 250 mg/m2 i.v. on day 1 + capecitabine 1000 mg/m2 orally twice daily on days 1 to 14, every 3 weeks. Patients ≥65 years of age and those with impaired renal function or with a history of prior radiotherapy received lower doses of both agents (200 mg/m2 and 750 mg/m2 twice daily, respectively). Results:A total of 52 patients (29 men, 23 women) were enrolled between October 2001 and August 2003. Median age was 57.5 years (range, 30–79 years); median Karnofsky performance status was 90 (range, 70–100). Treatment led to a response rate of 50% (ITT population) and a disease control rate of 71%. With a median cohort follow-up of 30.5 months, median time to progression and overall survival are 7.8 months (95% confidence interval, 5.6–10.0) and 16.8 months (95% confidence, 11.9 to not reached), respectively. Most common treatment-related grade 3/4 adverse events were neutropenia (25%), diarrhea (20%), vomiting (16%), dehydration (10%), nausea (6%), abdominal pain (6%), and hand-foot syndrome (6%). Conclusion:XELIRI is an active first-line treatment of MCRC. Implementation of upfront dose reductions for both agents in patients with risk factors for toxicity appears to have produced a safer regimen compared with previous studies of XELIRI without such dose reductions.

Capecitabine (X) plus irinotecan (XELIRI) as first-line treatment for metastatic colorectal cancer (MCRC): Final safety findings from a phase II trial

3602 Background: The oral fluoropyrimidine X (Xeloda) has superior efficacy and improved safety compared to 5-FU/LV in MCRC. Twice-daily oral X mimics 5-FU infusion and is replacing 5-FU in combination regimens. The efficacy and safety of X plus weekly irinotecan (XELIRI) were evaluated in first-line MCRC. METHODS Recommended doses from two independent phase I trials were: irinotecan 250 mg/m2 i.v. on day 1 plus capecitabine 1000 mg/m2 orally twice-daily on days 1-15, every 3 weeks. Patients (pts) ≥65 years received lower doses of both agents (200 mg/m2 i.v. on day 1 and 750 mg/m2 twice-daily on days 1-15, respectively). RESULTS Baseline characteristics of the 52 pts enrolled between Oct 2001 and Aug 2003: 29 men, 23 women; median Karnofsky PS 90 (70-100); median age 57.5 (30-79); colon cancer (85%), rectal cancer (11%), both (4%). Tumor differentiation was 15% poor, 63% moderate, 12% well, and 10% unknown. Most common metastatic sites were the liver (77%), lymph nodes (58%), and lung (33%), with 69% of pts having stage IV disease at initial diagnosis. Eleven pts (22%) had received prior adjuvant 5-FU. The median number of treatment cycles is currently 6 (maximum 12 cycles allowed). In the 51 patients evaluable for safety, the most common (>5%) treatment-related grade 3 adverse events were diarrhea (20%), vomiting (16%), dehydration (8%, 1 patient grade 4), nausea (6%), and HFS (6%). Grade 3/4 neutropenia was seen in 26% of pts. There were no treatment-related deaths. Twenty-seven of 44 evaluable pts (61%) showed a response to treatment (1 unconfirmed) and disease control (CR+PR+SD) was achieved in 37 pts (84%). Median time to progression (TTP) and overall survival are currently 6.1 months and 15.6 months, respectively. CONCLUSIONS XELIRI is a highly active and well-tolerated first-line therapy for MCRC. Efficacy compares favorably with previous studies of infusional 5-FU/LV/irinotecan, and safety of XELIRI is comparable to that of FOLFIRI and IFL regimens. Capecitabine should replace 5-FU in combination with irinotecan to create an effective, safe, and convenient treatment option in first-line MCRC. [Table: see text].

A phase I study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer.

Background:Flavopiridol (HMR 1275) is a synthetic flavone with antineoplastic properties through inhibition of cyclin-dependent kinase inhibitor. Flavopiridol synergizes in a sequence-dependent fashion with chemotherapy. Major adverse events of flavopiridol in single agent phase I studies are secretory diarrhea, neutropenia, thrombosis, and fatigue. Patients and Methods:Patients with advanced solid tumors were treated with gemcitabine 800 mg/m2 and irinotecan 80 mg/m2 on day 1, followed by flavopiridol, starting dose of 30 mg/m2 on day 2 with increment of 15 mg/m2 per dose level, repeated on days 8 and 9 for the first 6 patients (3-week cycle), and then repeated on days 15 and 16 for the remainder patients (4-week cycle). The protocol had to be amended for inability to redose after 1 week. Results:Fourteen women and 7 men with advanced solid tumors were enrolled. The median age was 51 years and the median number of prior chemotherapies was 3 (0–9). Neutropenic sepsis (1 patient), grade 3 diarrhea (1 patient), and neutropenia (2 patients) preventing retreatment on day 8 were observed among the 6 subjects treated on the first schedule. The recommended phase II dose of flavopiridol was 45 mg/m2 in combination with irinotecan and gemcitabine every 2 weeks. Dose-limiting toxicities were electrolyte imbalance with fatigue (1 patient), and renal failure and dyspnea with hypoxia (1 patient each), seen at 45 and 60 mg/m2 doses, respectively. The most common side effects were fatigue (81%), nausea (71%), diarrhea (67%), transient myelosuppression (43%), and vomiting (24%). Conclusions:The every 2 week dosing is well tolerated with a phase II recommended dose of 45 mg/m2 of flavopiridol in combination with irinotecan (80 mg/m2) and gemcitabine (800 mg/m2).

A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers

Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.

Octreotide scans are positive in a subset of patients with hepatocellular carcinoma

Purpose In vitro data suggest that a proportion of hepatocellular carcinomas express the somatostatin receptor. However, in vivo data are lacking. There has been little reported use of octreotide scans in hepatocellular carcinomas. This study was performed to determine the percentage of positive results of octreotide scanning in patients with hepatocellular carcinoma. Materials and Methods In-111 octreotide scans were performed in the standard manner in eight patients with unresectable hepatocellular carcinoma. Computer fusion imaging of the nuclear medicine and computed tomographic scans was performed in selected patients. Results Five of eight (63%) patients tested had hepatocellular carcinomas that displayed focal tracer uptake. Conclusions This is the first report of positive uptake of octreotide scans in patients with hepatocellular carcinoma. These findings may have implications for the treatment of hepatocellular carcinoma with octreotide. Furthermore, these results may broaden the differential diagnosis in patients with positive results of octreotide scanning.

Development of bronchiolitis obliterans organizing pneumonia with platinum-based chemotherapy for metastatic rectal cancer.

Bronchiolitis obliterans organizing pneumonia (BOOP) is an adverse event known to occur after cancer chemotherapy and radiotherapy. We present a case of a 47-year-old patient who was diagnosed with BOOP after treatment for metastatic rectal cancer with oxaliplatin/capecitabine/bevacizumab. Removal of oxaliplatin from the regimen and replacement with irinotecan resulted in a resolution of his pulmonary symptoms.

Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib with Concurrent Radiation for Newly Diagnosed Resectable Rectal Cancer

Abstract Lessons Learned. Colorectal cancers exhibit a high level of cyclooxygenase‐2 (COX‐2) expression with strong preclinical rationale for improved clinical outcomes with COX‐2 inhibition. Celecoxib is a COX‐2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer. There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single‐agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential. Background. Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase‐2 (COX‐2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX‐2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity. Methods. Patients with resectable (T3‐4, N1‐2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m2 b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions. Results. Thirty‐two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16%–50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%–89%) and sphincter‐sparing surgery (SSS): 56% (95% CI: 38%–74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease‐free survival and overall survival (OS) were 84% (95% CI: 65%–93%) and 94% (95% CI: 77%–98%), respectively. Conclusion. Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43%–78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy.

90Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies

BACKGROUND For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering (90)Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine. METHODS Fifty-eight patients with three (2-7) median prior treatments were treated on Arm A (N=29, (90)Y-clivatuzumab tetraxetan, weekly 6.5 mCi/m(2)doses×3, plus gemcitabine, weekly 200 mg/m(2) doses×4 starting 1 week earlier) or Arm B (N=29, (90)Y-clivatuzumab tetraxetan alone, weekly 6.5 mCi/m(2)doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated. RESULTS Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3-9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan-Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29-0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1 year. CONCLUSIONS Clinical studies of (90)Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting.

A Phase 2 Randomized, Double-Blind, Multicenter Trial of Imexon Plus Gemcitabine Versus Gemcitabine Plus Placebo in Patients With Metastatic Chemotherapy-naïve Pancreatic Adenocarcinoma.

Background: Imexon is a cyanoaziridine-derived iminopyrrolidone which has synergistic cytotoxicity with gemcitabine. A phase 1 study of the combination demonstrated good tolerance with encouraging clinical activity and thus we conducted this randomized phase II study. Materials and Methods: Patients with measurable, metastatic, treatment-naive pancreatic adenocarcinoma were randomized 1:1 to receive gemcitabine at 1000 mg/m2 days 1, 8, and 15 with either imexon, 875 mg/m2 or placebo days 1, 8, and 15 every 28 days. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and response rate. Results: A total of 142 patients were randomized, 72 to the imexon containing arm and 70 to the placebo arm. Patients in the imexon arm received an average of 3.6 cycles (range, 1 to 23) compared with 4.4 (range, 1 to 21) in the placebo arm. There was no increased rate of ≥grade 3 toxicity in the imexon arm. Seven patients had objective responses in the imexon arm (13.7%), whereas 9 did in the placebo arm (17%). In the imexon arm, 23 patients had ≥50% reduction in CA 19-9 from baseline (33%), whereas 22 did in the placebo arm (31.4%). The median progression-free survival was 2.8 months in the imexon arm (95% confidence interval [CI], 2.0-4.1 m) and 3.8 months in the placebo arm (95% CI, 2.2-4.7 m), P=0.504. The median overall survival time in the imexon arm was 5.2 months (95% CI, 4.2-6.7 m) as compared with 6.8 m (95% CI, 4.9-8.5 m) in the placebo arm, P=0.6822. Conclusions: The combination of imexon and gemcitabine does not result in improved outcome as initial therapy of metastatic pancreatic adenocarcinoma.