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%) (). The median number of prior therapies was 2 (range, 0–7). Thirty-two (39%) patients had a history of pancreatectomy.
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.
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 ().
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.
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 (). Overall, 10 (13%) patients had SD for ≥4 months.
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) ().
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) (). 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 (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) (). Survival by response (RECIST) is shown in . 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 ().
The median TTF for 83 patients was 1.5 months (95% CI, 1.3–1.8 months) (). The median TTF for patients who had PR, SD, or PD was 5.3 months, 2.2 months, and 1.3 months, respectively. shows that TTF was longer in patients with PR or SD compared with patients who had PD (P < .001).
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) ().
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; ).
In multivariate analysis, independent factors associated with lower rates of PR or SD were liver metastases (P = .001) and PS >0 (P = .01) (). 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).
Multivariate Analyses (Logistic Model for Response and Cox Model for Survival and Time to Failure)