Of the 72 patients with GC and CC referred to the Phase I Clinical Trials program, 32 patients (30 CC and 2 GC) were not enrolled in a phase I clinical trial due to deterioration of performance status (N=25), decision to pursue alternate therapies including treatments closer to home (N=6), and insurance denial (N=1). Forty patients who participated in a phase I trial are included in this analysis. Pretreatment characteristics at presentation to the Phase I Clinic are summarized in Table . The median age at diagnosis was 60 years (range, 41.4-73.6 years). There were 23 women and 17 men. Thirty-one (78%) were White, 5 (12%) were African American, and 4 (10%) were Hispanic. Seven patients (18%) had an ECOG PS of 0, 29 patients (72%) had a PS of 1 and 4 (10%) patients a 2. Of the 40 patients treated, 6 had gallbladder carcinoma, 4 had extrahepatic cholangiocarcinoma and 30 had intrahepatic cholangiocarcinoma; the tumor histology for all 40 patients was consistent with adenocarcinoma. The median number of metastatic sites was 3 (range 0-6). The most common sites of metastases at time of phase I referral were liver (90% of patients), lymph nodes (83%), peritoneum (40%), retroperitoneum (38%) and lung (38%). The median time from initial phase I consultation to day one on a phase I trial was 16 days.
Therapy before patient inclusion in phase I trials
Overall, of the 40 patients enrolled on a phase I trial, two patients had received no prior therapy because of the unavailability of reasonable, conventional therapy for the extent of their disease. The remaining 38 patients had a median of 3 prior systemic therapies before referral to the Phase I Clinic (range, 1 – 11). Fifteen patients (38%) also underwent a prior surgical resection, whereas 13 (33%) received prior radiation and 3 (8%) had prior chemoembolization.
The National Comprehensive Cancer Network (NCCN) guidelines for unresectable gallbladder and cholangiocarcinoma include a gemcitabine/cisplatin combination therapy, fluoropyrimidine-based or other-gemcitabine based regimen.[4
] For their first-line treatment in the advanced/metastatic setting, 4 of 38 patients received experimental therapy on phase II trials with a novel paclitaxel conjugate or a campotothecin analog. The remaining 34 patients received a first-line regimen based on gemcitabine (N
=24, 71%), a fluoropyrimidine (N
=7, 21%), or single-agent sorafenib (N
=3, 8%). As their second-line therapy in the advanced disease setting, 36 patients received a regimen including gemcitabine (N
=17, 47%), a fluropyrimidine (N
=16, 45%), or a targeted agent (N
=3, 8%); 2 patients did not received a second line treatment and instead began phase I therapy. All 38 patients were treated on a regimen based on FDA-approved drugs as their last antineoplastic therapy before beginning a phase I trial; 58% received a fluoropyrimidine-based regimen (26% received fluoropyrimidine agents in combination with platinum), whereas 23% received a targeted agent, most commonly an angiogenesis inhibitor. Thus FDA-approved agents formed the backbone of the systemic combination therapy prior to enrollment in a phase I trial.
Overall, patients were initially treated on 1 of 22 phase I clinical trials; of these trials, 8 patients received therapy on six first-in-human trials with novel targeted inhibitors against MEK, VEGF, gamma-secretase, aurora kinase and the IGF-IR pathway. Of 40 patients, 30 (75%) were treated on a trial with combination therapy of two or more agents while 10 patients (25%) received treatment with a single agent. Seventeen (43%) patients received locoregional treatment with direct infusion of a cytotoxic agent into the hepatic artery; 24 (60%) received intravenous angiogenesis inhibitors, of whom 13 (33%) received the antiangiogenic agent in combination with hepatic arterial infusion therapy. Fifteen (38%) patients received targeted agent(s) alone, 20 (50%) received targeted agent(s) in combination with cytotoxic chemotherapy, and 5 (12%) received cytotoxic chemotherapy alone. The median number of cycles received was 2 (range 1 – 12). Six patients went on to receive therapy under a second phase I trial; of these patients, 3 received treatment on 3 phase I trials.
Six patients were not restaged prior to end of cycle 2 due to clinical deterioration and early disease progression. Of the 40 patients treated on clinical studies, 3 (8%) had a partial response (PR), 17 had stable disease (43%) including 8 (20%) who had SD > 6 months, and 20 patients had progressive disease (PD) with a SD> 6 months/PR rate of 27.5% (Figure ). The highest rates of prolonged SD > 6 months/PR were observed in patients treated with protocols that included hepatic arterial infusion (HAI) of oxaliplatin or paclitaxel (7 of 17 patients treated on HAI regimens, 41%) or antiangiogenic agents (9 of 24 patients, 38%) with 6 of those patients receiving treatment that included HAI of oxaliplatin combined with systemic bevacizumab (Figure ; Table ). A prolonged SD of 10.8 months was observed in a patient with metastatic GC with HER-2/neu amplification who was treated on phase I protocols, first combining the anti-HER-2/neu antibody trastuzumab and the HER-2/neu tyrosine kinase inhibitor lapatinib, and then with trastuzumab and erlotinib. Prolonged SD lasting 9 months was also seen in one patient treated on a first-in-human trial using a novel MEK inhibitor.
Waterfall plot of the best RECIST response to the best phase I trial of all 40 treated patients
Prolonged partial response for 12.1 months noted in the primary hepatic lesion of a patient with advanced cholangiocarcinoma treated with hepatic arterial infusion of a cytotoxic agent along with intravenous anti-angiogenic agent
Characteristics of patients with clinical benefit rate (PR + SD > 6months)
Survival and toxicities
For the 40 patients treated on phase I trials, the time from diagnosis of advanced (metastatic) disease to primary evaluation in the Phase I Clinical Center for Targeted Therapy was 13.1 months. The median time from the initial phase I consultation to day 1 of a trial was 16 days. The overall median survival from day 1 on a phase I trial was 4.2 months (95% CI 3.8 – 8.6 months). Median PFS for 40 treated patients was 2.0 months (95% CI 1.8, 3.4) on phase I clinical trials. Among these 40 patients, the median PFS on their first-line and second-line prior therapies with FDA-approved agents given in the advanced setting was 3.0 months (95% CI 2.4, 5.0) and 3.0 months (95% CI 2.3, 4.6), respectively. Median PFS on their last FDA-approved treatment before phase I referral was 3.0 months (95% CI 2.4, 3.9). In comparison, the median PFS on phase I therapy did not differ significantly from that on their first-line or second-line FDA-approved agents given for advanced disease or their last treatment prior to phase I referral (P=0.95, 0.98, 0.76, respectively) (Figure ). Data were also analyzed from the 32 patients who were not enrolled on phase I trials and the PFS of their first-, second-line, and last treatment with FDA-approved agents prior to phase I referral (3.1, 2.4, 3.0 months, respectively) also did not differ significantly from the PFS of the phase I-treated patients.
Figure 3 (A) PFS of patients treated on phase I trials compared to their first-line, second-line and last systemic antitumor therapy given in the advanced setting prior to phase I referral. (B) Median overall survival after starting a phase I trial. Dotted lines (more ...)
Overall survival from enrollment on a phase I trial to date of death is shown in Figure . Among the 40 treated patients, 38 (95%) had died at the time of analysis. The 90-day mortality was 38% with 25 patients alive at 3 months after beginning phase I therapy; the 6-month mortality was 63% with 15 patients alive at 6 months after beginning therapy on phase I trials. Importantly, there was no treatment-related mortality. Two patients treated on different combination regimens that included an angiogenesis inhibitor experienced grade 3 gastrointestinal bleeding, prompting a change of regimen, with overall progression-free period of 10.8 and 16.8 months, respectively, on their subsequent phase I trials. The only other grade 3 toxicity that prompted removal from study was the development of an arteriovenous fistula in one patient due to the placement of the hepatic arterial infusion catheter.
Prognostic Factors for Survival
We conducted univariate analysis to evaluate the effects on survival of variables including age, sex, race/ethnicity, ECOG performance status, tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigens [CAs] CA 19-9, CA 125, CA 27.29); history of thromboembolism; number of prior therapies; presence of liver metastases; number of metastatic sites; leukocyte count; hemoglobin level; platelet count; and albumin, lactate dehydrogenase (LDH), alkaline phosphatase, bilirubin, alanine aminotransferase, aspartate aminotransferase, RMH score and serum creatinine levels (Table ). In univariate analysis, factors associated with a shorter Phase I PFS were a higher number of metastatic sites (1-2 versus >3; hazard ratio [HR] 3.2, P=0.070), elevated serum ALT (> 56 IU/L; HR 5.3, P=0.007), elevated serum creatinine (>1.6 mg/dL; P=0.022), and high CA19-9 (>35 U/mL; HR 4.8, P=0.010).
Univariate Proportional Hazards Regression Model for Phase I Progression Free Survival (PFS)
Molecular analyses of the 40 treated patients treated on Phase I trials
Testing for mutations in KRAS, NRAS, BRAF, cKIT, EGFR, PIK3CA, TP53
, as well as immunohistochemistry for PTEN loss and HER-2/neu FISH amplification was completed on patients with adequate available tissue in the MD Anderson CLIA-certified laboratory. DNA was extracted from micro-dissected paraffin-embedded tumor and analyzed by a PCR-based DNA sequencing method to examine codons 12, 13 and 61 of the KRAS
proto-oncogene. Of 11 tested patients, a KRAS
mutation was detected in the tumor of two patients with cholangiocarcinoma, one in codon 12 and another in codon 13.[15
] A third patient's gallbladder carcinoma demonstrated FISH amplification of HER-2/neu (HER-2/neu: CEP17 signal ratio: 6.49). This patient maintained SD for 27 months with a HER-2/neu targeting agent prior to progression; then, phase I therapy including HER-2/neu targeting agents resulted in SD for an additional 10.8 months.