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Cancer. Author manuscript; available in PMC Aug 2, 2012.
Published in final edited form as:
Published online Aug 24, 2010. doi:  10.1002/cncr.25346
PMCID: PMC3410640
NIHMSID: NIHMS287611
Phase 1 Clinical Trials in 83 Patients With Pancreatic Cancer
The M. D. Anderson Cancer Center Experience
Christos Vaklavas, MD,1 Apostolia-Maria Tsimberidou, MD, PhD,1 Sijin Wen, PhD,2 David Hong, MD,1 Jennifer Wheler, MD,1 Chaan S. Ng, MD,3 Aung Naing, MD,1 Cynthia Uehara,1 Robert A. Wolff, MD,4 and Razelle Kurzrock, MD1
1Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas M. D. Anderson Cancer Center
2Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center
3Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center
4Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center
Corresponding author: Apostolia-Maria Tsimberidou, MD, PhD, Department of Investigational Cancer Therapeutics, Unit 455, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: (713) 794-3249; atsimber/at/mdanderson.org
The first and second authors contributed equally to this article.
BACKGROUND
The outcomes of patients with pancreatic cancer treated on early phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase 1 clinical trials at a single institution.
METHODS
The authors reviewed the records of consecutive patients with metastatic pancreatic cancer who were treated in the Phase I Clinical Trials Program at The University of Texas M. D. Anderson Cancer Center from November 2004 to March 2009. Data recorded and analyzed included survival, response, and disease characteristics.
RESULTS
Eighty-three patients were identified. The median age was 62 years (range, 39–81 years). Of 78 patients evaluable for response, 2 (3%) had a partial response (PR), and 10 (13%) had stable disease (SD) for ≥4 months. With a median follow-up for survivors of 3.7 months, the median survival from presentation in the phase 1 clinic was 5.0 months (95% confidence interval [CI], 3.3–6.2). The median overall survival from diagnosis was 22.1 months (95% CI, 17.9–26.5). The median time to treatment failure was 1.5 months (95% CI, 1.3–1.8). Independent factors associated with lower rates of PR/SD were liver metastases (P = .001) and performance status >0 (P = .01). Independent factors associated with shorter survival were liver metastases (P = .007), low calcium level (P = .015), and elevated CEA level (>6 ng/mL) (P = .005).
CONCLUSIONS
Our results suggest that phase 1 clinical trials offer a reasonable therapeutic approach for patients with advanced pancreatic cancer.
Keywords: phase 1, pancreatic cancer, survival, response
Pancreatic cancer is the ninth and 10th most common cancer type in women and men, respectively, but it is the fourth leading cause of cancer death, with uniformly poor long-term survival.1 It is estimated that approximately 42,500 patients were diagnosed with pancreatic cancer in 2009 and 35,250 died2 in the United States. The median survival is 5 to 7 months,3 and the 5-year survival rate is <5%.4,5 Surgical resection provides the only potential for cure, but because of the disease’s typically late presentation, only 20% of patients are eligible for pancreatectomy.
The only medications approved by the US Food and Drug Administration (FDA) for the treatment of pancreatic cancer are gemcitabine and erlotinib. Gemcitabine was shown to reduce pain, improve performance status, and help patients maintain weight,6,7 but the objective tumor response rate was low (5.4%–10.5%).6,7 The addition of erlotinib, an epidermal growth factor receptor inhibitor, modestly prolonged survival.8 In a randomized trial, the 1-year survival rates in the gemcitabine plus erlotinib and gemcitabine alone groups were 23% and 17%, respectively (P = .023).8 Gemcitabine has been combined with other cytotoxins, such as 5-fluorouracil,9 cisplatin,10,11 docetaxel,1215 oxaliplatin,16,17 capecitabine,18 irinotecan,19 or 5-fluorouracil plus cisplatin and epirubicin.20 Meta-analyses demonstrated a survival benefit with the gemcitabine-based combinations, and in a subset analysis, gemcitabine combinations with platinum compounds and capecitabine were superior to gemcitabine and irinotecan or 5-fluorouracil combinations.21,22
Patients with pancreatic cancer are sometimes referred for investigational treatment, including phase 1 clinical trials. However, the outcomes of these patients have not been systematically analyzed. Here we report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer who were referred to the phase 1 clinic at The University of Texas M. D. Anderson Cancer Center.
We reviewed the medical records of consecutive patients with pancreatic cancer who were treated in the Phase I Clinical Trials Program at M. D. Anderson Cancer Center from November 2004 to March 2009, and we assessed their associated characteristics and clinical outcomes. Data were collected from transcribed notes in the electronic database. Patient records were reviewed from the time of presentation in the Phase I Clinical Trials Program.
Patients eligible for phase 1 clinical trial participation were ≥18 years old and had metastatic or unresectable pancreatic cancer for which approved curative therapies were no longer effective. Patients had progressive disease, evidence of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST),23 performance status 0 to 2, and a life expectancy >3 months. Premenopausal women were required to have a negative pregnancy test and patients of childbearing potential to use contraception. Further eligibility criteria varied according to the particular study. All patients provided written informed consent before enrollment onto a trial. All trials were approved by the M. D. Anderson institutional review board, which also granted a waiver of informed consent and a waiver of authorization for this retrospective study.
Phase 1 treatment was determined after clinical, laboratory, and pathologic data were reviewed. The allocation of patients to investigational treatments varied over time according to protocol availability at the time the patients were seen. After initiation of an investigational therapy, patients were evaluated at 3- to 4-week intervals. At each visit, a history review and physical examination were performed, and a comprehensive series of metabolic and hematologic tests was conducted. Patients were assessed for the onset of new symptoms and medicine compliance related to the study drug.
Endpoints and Statistical Methods
Descriptive statistics were used to summarize the patients’ characteristics. The chi-square test was used to examine the association between 2 categorical variables. The following covariates were analyzed: age; sex; history of smoking; Eastern Cooperative Oncology Group performance status (PS); tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigens [CAs] CA 19–9, CA 125, CA 27.29); history of pancreatectomy; number of prior therapies; local recurrence; metastases in the liver, lung, lymph nodes, peritoneum, or omentum; number of metastatic sites; leukocyte count; hemoglobin level; platelet count; and albumin, lactate dehydrogenase (LDH), calcium, phosphorus, alkaline phosphatase, bilirubin, alanine aminotransferase, aspartate aminotransferase, and serum creatinine levels.
Best response was assessed by an M. D. Anderson radiologist every 2 cycles of therapy (cycle = 3–4 weeks, depending on the protocol), using RECIST guidelines23. Partial response (PR) was defined as a ≥30% decrease in the sum of the longest diameter of target lesions, excluding complete disappearance of disease. Progressive disease (PD) was defined as a ≥20% increase in the sum of the longest diameter of target lesions. Stable disease (SD) was defined as small changes that did not meet the criteria for a PR or PD. Waterfall plot analysis was used to illustrate response, if any, as previously described.24 Responses shown in the waterfall plot were also grouped according to RECIST guidelines.23
Survival was measured from the date of presentation to the Phase I Clinical Trials Program until death from any cause or last follow-up. Time to treatment failure (TTF) was measured from the first day of treatment on a clinical trial in our Phase I Clinical Trials Program to the date the patient went off study because of toxicity, disease progression, or death. For patients treated with > 1 therapy, data of TTF from the first therapy was used. Toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.25 A P value <.05 was considered statistically significant. Statistical analyses were carried out using SAS 9.1 (SAS Institute, Cary, NC) and S-Plus, version 7.0 (Insightful Corp., Seattle, Wash) software.
Patient Characteristics
Overall, 83 patients with pancreatic adenocarcinoma were treated on phase 1 trials during the study period. The median age was 62 years (range, 39–81 years). There were 40 men and 43 women. The most common metastatic sites were liver (54% of patients), lung (51%), lymph nodes (37%), and peritoneum and omentum (24%) (Table 1). The median number of prior therapies was 2 (range, 0–7). Thirty-two (39%) patients had a history of pancreatectomy.
Table 1
Table 1
Presenting Characteristics of 83 Patients With Pancreatic Cancer Referred to the M. D. Anderson Phase I Clinical Trials Program
Sixty-seven (81%) patients had 1 or more comorbidity. The most common comorbidities were cardiovascular (hypertension and/or coronary artery disease, n = 35 [42%]), endocrinologic (diabetes mellitus, n = 19 [23%]; hypothyroidism n = 10 (12%), and gastrointestinal (gastroesophageal reflux disease, diverticulitis/diverticulosis, or ulcerative colitis, n = 18 [22%]). Six (7%) patients had a history of prior cancer (breast, n = 3; prostate, n = 1; squamous cell carcinoma of the esophagus, n = 1; and papillary thyroid carcinoma, n = 1). Two patients had 2 prior malignancies: 1 with prostate cancer and follicular lymphoma and the other with prostate cancer and colorectal carcinoma. All prior malignancies were in remission at the time of diagnosis of pancreatic cancer.
Treatment
Sixty (72%) of 83 patients were treated with a single agent and 23 (28%) with combination therapy. Of 60 patients, 45 were treated with a natural compound (curcumin, n = 43; S-dimethylarsino-glutathione, n = 1; and a cardiac glycoside, n = 1), 11 with a targeted therapy, and 4 with a cytotoxic agent. Of 23 patients treated with combination therapy, 9 were treated with targeted agent combination therapy, 2 with cytotoxic agent combination therapy, 8 with cytotoxic and targeted agents, and 4 with targeted and cytokine combination therapies (Table 2).
Table 2
Table 2
First Phase 1 Clinical Trials in 83 Patients
After treatment failure in the first phase 1 clinical trial, 25 patients received further treatment. Sixteen patients enrolled in another phase 1 clinical trial, 8 received single-agent or cytotoxic and targeted combination therapies, and 1 patient underwent surgical excision of a retroperitoneal metastatic lesion.
Response
Of 83 patients, 78 were evaluable for response. Overall, 62 reached the time of response assessment (after 2 cycles of therapy), and 16 patients had clinical evidence of disease progression, including 3 patients who died while on the investigational therapy (waterfall plot, ≥20% response). Five patients were not evaluable for response (2 died from pulmonary embolism, 2 withdrew consent, and 1 was lost to follow-up).
Of 78 patients, the maximum response was PR in 2 (3%) patients and SD in 30 (39%) patients (Fig. 1). Overall, 10 (13%) patients had SD for ≥4 months.
Figure 1
Figure 1
Waterfall plot shows response in 78 evaluable patients. For the 16 patients with clinical progression, a tentative 20% increase was assigned.
Factors predicting higher rates of PR and SD were PS of 0 (P = .02), absence of liver metastases (P = .001), and normal CA 27–29 values (≤38 U/mL, P = .03) (Table 1).
Survival
The median follow-up duration of surviving patients from the date of presentation to the Phase I Clinical Trials Program was 3.7 months (range, 0.3–18 months). The median overall survival from the date of presentation to the Phase I Clinical Trials Program was 5.0 months (95% confidence interval [CI], 3.3–6.2 months) (Fig. 2A). The 1-year survival rate was 15.8% (95% CI, 9%–28%). Overall, 63 patients died (37 [80%] of 46 with PD, 22 [69%] of 32 with PR or SD; 2 patients died of pulmonary disease, and the cause of death was unknown in 2 patients).
Figure 2
Figure 2
(A) Overall survival in 83 patients with advanced/ metastatic pancreatic cancer from the time of presentation to the Phase 1 Clinical Trials Program. (B) Overall survival in 83 patients with advanced/metastatic pancreatic cancer from the time of diagnosis. (more ...)
When survival was calculated from the time of diagnosis of pancreatic cancer to death or last follow-up, the median survival duration was 22.1 months (95% CI, 17.9–26.5 months) (Fig. 2B). Survival by response (RECIST) is shown in Figure 2C. The median survival durations of patients who had PR, SD, or PD were 8.9 months, 7.7 months, and 3.3 months, respectively (P<.001). In univariate analysis, factors predicting shorter overall survival were elevated levels of CEA (>6 ng/mL, P = .02), CA 27–29 (>47 U/mL, P = .02), or CA 125 (>35 U/mL, P = .02). Liver metastases (P = .10), calcium ≤8.4 mg/dL (P = .09), and bilirubin >1 mg/dL (P = .08) were marginally associated with shorter overall survival (Table 1).
TTF
The median TTF for 83 patients was 1.5 months (95% CI, 1.3–1.8 months) (Fig. 3A). The median TTF for patients who had PR, SD, or PD was 5.3 months, 2.2 months, and 1.3 months, respectively. Figure 3B shows that TTF was longer in patients with PR or SD compared with patients who had PD (P < .001).
Figure 3
Figure 3
(A) Time to treatment failure in 83 patients with advanced/metastatic pancreatic cancer treated in the Phase 1 Clinical Trials Program. (B) Time to treatment failure by response in 78 patients with advanced/metastatic pancreatic cancer evaluable for response (more ...)
In univariate analysis, factors associated with shorter TTF were smoking history (P = .01), liver metastases (P = .03), and elevated serum levels of bilirubin (>1 mg/dL; P = .01), LDH (>618 IU/L; P = .03), CEA (>6 ng/mL; P = .01), or CA 27–29 (>47 U/mL; P = .01) (Table 1).
Of 83 patients, 73 had received systemic antitumor therapy before referral to the Phase I Clinical Trials Program (10 patients underwent only pancreatectomy and/or chemoradiation therapy before the referral). In paired analysis, TTF (median TTF, 2.3 months; 95% CI, 2.0–3.0) was longer with the therapy before referral to the Phase I Clinical Trials Program compared with TTF on a phase 1 treatment (median TTF, 1.5 months; 95% CI, 1.3–1.8; P = .004; Fig. 3C).
Multivariate Analysis
In multivariate analysis, independent factors associated with lower rates of PR or SD were liver metastases (P = .001) and PS >0 (P = .01) (Table 3). Independent factors associated with shorter survival were liver metastases (P = .007), calcium ≤8.4 mg/nL (P = .015), and elevated serum levels of CEA (>6 ng/mL; P = .005). Independent factors associated with shorter TTF were history of smoking (P = .009), liver metastases (P = .001), serum bilirubin levels >1 mg/dL (P = .007), and >1 prior therapy (P = .002).
Table 3
Table 3
Multivariate Analyses (Logistic Model for Response and Cox Model for Survival and Time to Failure)
This is the first study to systematically analyze the clinical outcomes of patients with advanced or metastatic pancreatic cancer referred to a phase 1 clinic. Our analysis demonstrates that treatment on phase 1 clinical trials is a reasonable approach for these patients. The median TTF was 1.5 months (range, 1.3–1.8 months). The PR rate was 3% (2 of 78 patients evaluable for response), and 13% of patients (10 of 78) had stable disease for ≥4 months. With a median follow-up of 3.7 months, the median survival from the time of presentation to the Phase I Clinical Trials Program was 5.0 months (range, 3.3–6.2 months).
Several clinical trials are investigating the role of new agents or FDA-approved drugs in the treatment of pancreatic cancer.26 More recently, a phase 1/2 clinical trial in pancreatic cancer demonstrated that the combination of albumin-bound paclitaxel (Abraxane) and gemcitabine27 induced a response rate of 26.5% (RECIST).27 Overexpression of the secreted protein acid rich in cysteine (SPARC) in pancreatic cancer cells and surrounding stroma was correlated with clinical outcomes.28 In addition, the molecular elucidation of the pathway of KRAS, a protein mutated in 90% of pancreatic cancer cases, may spawn the investigation of novel targeted agents.29
Other investigators have reported on the clinical outcomes of patients with metastatic pancreatic cancer. The median survival in the current study (5 months) compares favorably to the median survival reported with best supportive care (3 months).30 The reported median survival in patients with locally advanced and metastatic pancreatic cancer ranges from 8 to 12 months and from 3 to 6 months, respectively.31 Our findings are consistent with the recommendation by the National Cancer Institute that patients with advanced pancreatic cancer at any stage should be considered for clinical trials, before considering palliative measures.31
The current study identified independent factors predicting response, survival, and TTF by multivariate analyses in patients with advanced pancreatic cancer. Liver metastases and performance status >0 predicted lower rates of PR or SD. Independent factors associated with shorter time to failure were history of smoking, liver metastases, bilirubin levels >1 mg/dL, >1 prior therapy. Independent factors associated with shorter survival were elevated CEA, liver metastases, and hypocalcemia. The role of CA 19–9 in pancreatic cancer has been extensively investigated.32 Although our study did not show that CA 19–9 levels had prognostic significance, it did show that tumor markers are associated with clinical outcomes.
As expected, the current analysis also demonstrated that liver metastases are an independent adverse factor for overall survival and time to treatment failure. This is concordant with the results of a previous analysis in patients with advanced cancer in which liver metastasis was an independent factor predicting poor survival.33 In addition, smoking predicted shorter time to treatment failure, but it did not predict response and survival.
In contrast with other types of cancer treated in our Phase I Clinical Trials Program, such as thyroid cancer, which showed superior TTF with phase 1 treatments compared with prior standard of care therapies,34 phase 1 therapies in pancreatic cancer were not associated with longer TTF. This observation may be because of late referral and advanced underlying disease of the patients referred, as evidenced by the fact that 21% of evaluable patients (16 of 78) did not reach the time of tumor response assessment secondary to clinical progression. Also, patients who received >1 therapy before referral to the Phase I Clinical Trials Program had shorter TTF in multivariate analysis (Table 3).
Considering the relatively small number of patients included in the current series, which precludes robust statistical results, some caution is warranted in the interpretation of some observations. In general, patients with pancreatic cancer referred to our program had good PS and adequate organ function. Another limitation of our study is that quality of life was not assessed.
The fact that the median overall survival duration from the time of diagnosis was 22.1 months (range, 18.1–26.5) suggests that there was a selection bias toward more favorable patients being referred. Even so, our results suggest that treatment on a phase 1 clinical trial is a reasonable approach for these patients. Identification of molecular mechanisms involved in the development of pancreatic cancer may lead to the discovery of novel agents with greater antitumor activity.
Acknowledgments
This publication was made possible by grant number RR024148 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.
Footnotes
CONFLICT OF INTEREST DISCLOSURES
Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp.
1. Jemal A, Thun MJ, Ries LA, et al. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst. 2008;100:1672–1694. [PMC free article] [PubMed]
2. National Cancer Institute. [Accessed November 15, 2009];Surveillance, Epidemiology, and End Results. Available at: http://seer.cancer.gov/statfacts/html/pancreas.html.
3. Burris HA., III Recent updates on the role of chemotherapy in pancreatic cancer. Semin Oncol. 2005;32:S1–S3. [PubMed]
4. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96. [PubMed]
5. Ghaneh P, Costello E, Neoptolemos JP. Biology and management of pancreatic cancer. Gut. 2007;56:1134–1152. [PMC free article] [PubMed]
6. Burris HA, III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–2413. [PubMed]
7. Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol. 1996;7:347–353. [PubMed]
8. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–1966. [PubMed]
9. Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB., III Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002;20:3270–3275. [PubMed]
10. Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006;24:3946–3952. [PubMed]
11. Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer. 2002;94:902–910. [PubMed]
12. Schneider BP, Ganjoo KN, Seitz DE, et al. Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: a Hoosier Oncology Group study. Oncology. 2003;65:218–223. [PubMed]
13. Stathopoulos GP, Mavroudis D, Tsavaris N, et al. Treatment of pancreatic cancer with a combination of docetaxel, gemcitabine and granulocyte colony-stimulating factor: a phase II study of the Greek Cooperative Group for Pancreatic Cancer. Ann Oncol. 2001;12:101–103. [PubMed]
14. Jacobs AD, Otero H, Picozzi VJ, Jr, Aboulafia DM. Gemcitabine combined with docetaxel for the treatment of unresectable pancreatic carcinoma. Cancer Invest. 2004;22:505–514. [PubMed]
15. Lutz MP, Van Cutsem E, Wagener T, et al. Docetaxel plus gemcitabine or docetaxel plus cisplatin in advanced pancreatic carcinoma: randomized phase II study 40984 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group. J Clin Oncol. 2005;23:9250–9256. [PubMed]
16. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23:3509–3516. [PubMed]
17. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:3778–3785. [PMC free article] [PubMed]
18. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007;25:2212–2217. [PubMed]
19. Stathopoulos GP, Syrigos K, Aravantinos G, et al. A multi-center phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer. 2006;95:587–592. [PMC free article] [PubMed]
20. Reni M, Passoni P, Panucci MG, et al. Definitive results of a phase II trial of cisplatin, epirubicin, continuous-infusion fluorouracil, and gemcitabine in stage IV pancreatic adenocarcinoma. J Clin Oncol. 2001;19:2679–2686. [PubMed]
21. Sultana A, Ghaneh P, Cunningham D, Starling N, Neoptolemos JP, Smith CT. Gemcitabine based combination chemotherapy in advanced pancreatic cancer-indirect comparison. BMC Cancer. 2008;8:192. [PMC free article] [PubMed]
22. Sultana A, Smith CT, Cunningham D, Starling N, Neoptolemos JP, Ghaneh P. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol. 2007;25:2607–2615. [PubMed]
23. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. [PubMed]
24. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebocontrolled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505–2512. [PubMed]
25. National Cancer Institute. [Accessed on February 4, 2010];Common Terminology Criteria for Adverse Events v3.0. Available at: ctep.cancer.gov/protocolDevelopment/electronic./ctcaev3.pdf.
26. National Institutes of Health. [Accessed October 27, 2009];ClinicalTrials.gov. Available at http://clinicaltrials.gov/
27. Von Hoff DD, Ramanathan R, Borad M, et al. SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: a phase I/II study [abstract] J Clin Oncol. 2009;27(suppl) Abstract 4525.
28. Smith LS, Drengler RL, Wood TE, et al. SPARC and CA19-9 as biomarkers in patients with advanced pancreatic cancer treated with nab paclitaxel plus gemcitabine [abstract] J Clin Oncol. 2008;26(15 suppl) Abstract 15592.
29. Scholl C, Frohling S, Dunn IF, et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell. 2009;137:821–834. [PubMed]
30. Ciuleanu TE, Pavlovsky AV, Bodoky G, et al. A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine. Eur J Cancer. 2009;45:1589–1596. [PubMed]
31. National Cancer Institute. [Accessed on October 27, 2009];Pancreatic Cancer Treatment: Treatment Option Overview. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/pancreatic/HealthProfessional/page5.
32. Maisey NR, Norman AR, Hill A, Massey A, Oates J, Cunningham D. CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. Br J Cancer. 2005;93:740–743. [PMC free article] [PubMed]
33. Wheler J, Tsimberidou AM, Hong D, et al. Survival of patients in a Phase 1 Clinic: the MD. Anderson Cancer Center experience. Cancer. 2009;115:1091–1099. [PubMed]
34. Tsimberidou AM, Vaklavas C, Wen S, et al. Phase I clinical trials in 56 patients with thyroid cancer: the M. D. Anderson Cancer Center experience. J Clin Endocrinol Metab. 2009;94:4423–4432. [PubMed]
35. Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14:4491–4499. [PubMed]
36. Naing A, Reuben JM, Verschraegen CF, et al. Phase I dose-escalation study of sodium stibogluconate, a protein tyrosine phosphatase inhibitor, combined with interferon-alfa for patients with solid tumors [abstract] J Clin Oncol. 2008;26(suppl) Abstract 3011. [PMC free article] [PubMed]
37. Adjei AA, Cohen RB, Kurzrock R, et al. Results of a phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies [abstract] J Clin Oncol. 2009;27(15 suppl) Abstract 3511. [PubMed]
38. National Institutes of Health. [Accessed October 12, 2009];An open label phase I study to evaluate the effects of patupilone on the pharmacokinetics of midazolam and omeprazole in patients with advanced malignancies (NCT00420615) Available at: http://clinicaltrials.gov.
39. Falchook GS, Moulder S, Wheler JJ, et al. Combination trastuzumab, lapatinib, and bevacizumab in HER2+ breast cancer and other malignancies. 32nd Annual San Antonio Breast Cancer Symposium; December 9–13, 2009; San Antonio, Texas.
40. Chintala L, Kurzrock R, Fu S, et al. Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancer (NCI protocol 7156) J Clin Oncol. 2008;26(15 suppl):3593.