Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer

Purpose: To determine the acute toxicity, post-operative complications, pathologic response and extent of downstaging to high dose pre-operative radiation using a hyperfractionated radiation boost and concurrent chemotherapy in a prospective Phase I trial.Materials & Methods: To be eligible for this study, patients had to have adenocarcinoma of the rectum less than 12 cm from the anal verge with either Stage T4 or T3 but greater than 4 cm or greater than 40% of the bowel circumference. All patients received 45 Gy pelvic radiation (1.8 Gy per fraction). Subsequent radiation was given to the region of the gross tumor with a 2 cm margin. This “boost” treatment was given at 1.2 Gy twice daily to a total dose of 54.6 Gy for Level I, 57 Gy for Level II, and 61.8 Gy for Level III. 5-FU was given at 1g/m² over 24 hours for a four day infusion during the first and sixth weeks of radiation, with the second course concurrent with the hyperfractionated radiation. Surgical resection was carried out 4–6 weeks following completion of chemoradiation (in curative cases) and additional adjuvant chemotherapy consisting of 5-FU and Leucovorin was given for an additional 4 monthly cycles Days 1 through 5 beginning four weeks post surgery.Results: Twenty-seven patients, age 40–82 (median 61), completed the initial course of chemoradiation and are included in the analysis of toxicity. The median follow-up is 27 months (range 8–68). Eleven patients were treated to a dose of 54.6 Gy, nine patients to 57 Gy, and seven patients to 61.8 Gy. Twenty-one patients had T3 tumors, and six patients T4 tumors. Grade III acute toxicity from chemoradiation included proctitis (5 patients), dermatitis (9), diarrhea (five), leukopenia (1), cardiac (1). Grade IV toxicities included one patient with diarrhea (on dose Level I) and one patient (on dose Level III) with cardiac toxicity (unrelated to radiation). Surgical resection consisted of abdominal perineal resection in 16 and low anterior resection in 7. Four patients did not undergo a curative resection; three initially presented with metastases and one developed metastasis during the pre-operative regimen. Post-operative complications included pelvic or perineal abscess in two (on dose Levels I & II), and delayed wound healing in two (one of whom, on dose Level III, developed perineal wound dehiscence requiring surgical reconstruction). Of the 23 patients who had a curative resection, four manifested pathologic complete responses (17.4%). Thirteen of 23 patients (57%) had evidence of pathologic downstaging and only 1/23 patients (on dose Level I) had a positive resection margin. Of these 23 patients (with a minimum follow-up of 8 months), the patient with positive margins was the only one who developed a local failure (Fisher’s Exact p = .04). The 3-year actuarial OS, DFS and LC rates are 82%, 72% and 96%, respectively. Twelve of 13 patients (92% at 3 years) ≥ 61 years vs. 5/10 patients (45% at 3 years) < 61 years remained disease-free (log-rank p = 0.017).Conclusion: This regimen of high dose pre-operative chemoradiation employing a hyperfractionated radiation boost is feasible and tolerable and results in significant downstaging in locally advanced rectal cancer. The vast majority of patients (96%) achieved negative margins, which appears to be a prerequisite for local control (p = 0.04). Older age (≥61 years) was a significant predictor for improved DFS. This regimen (at dose Level III, 61.8 Gy) is currently being tested in a Phase II setting.     

Combined chemoradiotherapy for unresectable pancreatic cancer.

This study was undertaken to evaluate the efficacy of a regimen of combined chemoradiotherapy in patients with unresectable adenocarcinoma of the pancreas. An analysis was undertaken on 27 patients from January 1992 to May 1996. Patients had a median age of 70 years (range, 40-78) and Eastern Cooperative Oncology Group Performance Status of 0-2. Eighteen patients had locoregional disease (T2-T3, N0-N1, M0), and nine had metastatic disease. Chemotherapy consisted of four cycles of 5-fluorouracil 1 gm/m2/day as a continuous infusion over 110 hours, streptozotocin 300 mg/m2/day over 30 minutes on days 2-4, and cisplatin 100 mg/m2 over 2 hours on day 4 only, followed by a maintenance regimen of 5-fluorouracil and leucovorin every 2 weeks. The radiotherapy was administered as a split course concurrently with chemotherapy to a total dose of 6000 cGy. Toxicity was frequent, but there were no treatment-related deaths. Grade III and IV toxicity was primarily limited to myelosuppression, stomatitis, and gastrointestinal side effects. Fifteen patients (56%) were able to complete either three or four cycles of chemoradiotherapy. All patients were evaluable for toxicity, response, and survival. Nine patients (33%) had an objective response (four complete response 5 partial response), two remained stable, and 16 (59%) had disease progression. Median survival for the entire group was 19 weeks (2-139), and the median survival for overall responders was 56 weeks (15-139). No patient with localized disease underwent subsequent surgical resection. The authors conclude that those patients who are able to tolerate the entire treatment regimen may achieve a useful prolongation of time to tumor progression.     

Phase II study of induction chemotherapy with gemcitabine plus 5-fluorouracil followed by gemcitabine-based concurrent chemoradiotherapy for unresectable locally advanced pancreatic cancer

AIMS AND BACKGROUND: To evaluate the efficacy and tolerability of a new treatment approach including induction chemotherapy (CT) and concurrent chemoradiotherapy (CRT) in unresectable, locally advanced pancreatic cancer (LAPC). PATIENTS AND METHODS: Twenty-four patients with LAPC were enrolled in the study. They first received induction CT consisting of 5-fluorouracil (5FU) (500 mg/m2) and gemcitabine (1000 mg/m2), which were given weekly for 3 weeks of every 4. Patients showing a response or disease stabilization after 2 cycles of induction CT received CRT consisting of external beam radiotherapy (50.4-54 Gy in fractions of 1.8 Gy/day) and gemcitabine (350 mg/m2, weekly for 6 weeks). Patients without disease progression received 2 additional cycles of CT consisting of 5FU plus gemcitabine with the same doses and schedule as given in the induction CT. RESULTS: After the end of the study, 2 (8%) and 5 (21%) patients showed complete and partial responses, respectively. Five patients (21%) had disease stabilization. The grade 3 and 4 toxicities associated with CT were neutropenia (21%) and thrombocytopenia (4%). The grade 3 and 4 toxicities occurring in patients who received CRT were neutropenia (24%), thrombocytopenia (24%), diarrhea (18%), and nausea (12%). The median progression-free survival for all patients was 6 months (95% CI, 3.6-8.4), and the median overall survival was 11 months (95% CI, 8.16-13.84). CONCLUSIONS: The CRT approach of this study is moderately active and has an acceptable toxicity profile. However, the incorporation of combination CT into CRT at the present schedule could not produce any additional benefit over CRT alone. Newer agents with more systemic activity are clearly warranted.     

Phase I/II docetaxel plus concurrent hyperfractionated radiotherapy in locally advanced unresectable head and neck cancer (TAX.ES1.102 study)

Introduction

Concurrent chemotherapy and radiotherapy is recommended for the treatment of locally advanced unresectable head and neck (H&N) cancer.

Objective

The primary purpose of the Phase I part of the study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose (RD) of docetaxel with hyperfractionation radiotherapy. The primary objective of the Phase II part was to determine the response rate to the RD of treatment and, secondarily, to assess the toxicity of the schedule, time to progression, duration of response and overall survival (OS).

Materials and methods

Patients (n=9 in Phase I; n=19 in Phase II) had unresectable H&N cancer. The starting docetaxel dose was 20 mg/m² plus hyperfractionated radiotherapy. Ramping of docetaxel was 5 mg/m² if MTD was not reached.

Results

MTD of docetaxel was 20 mg/m². Limiting toxicities were grade 4 pneumonia and grade 4 mucositis. The RD was 15 mg/m2. Phase II initial response was 76% (CR=18%; PR=9%); updated response was 89% (CR=59%; PR=29%). The median progression-free survival was 7.8 months (95%CI: 0?C22.3) and the median OS was 15.1 months (95%CI: 0?C35.9). Grade 3?C4 toxicities included mucositis (91%), pneumonia (27%) and fatigue (27%). There were 5 toxic deaths (2 from intestinal perforation, 3 from pneumonia).

Conclusions

Weekly docetaxel+hyperfractionation radiotherapy is active but with high toxicity rates and, hence, this treatment regimen would be difficult to justify.     

Phase I trial of gemcitabine in patients with advanced pancreatic cancer

BACKGROUND: Gemcitabine is the most promising new agent currently being tested in pancreatic cancer. The present study was conducted to confirm the tolerability of a weekly schedule of gemcitabine at a dose of 1000 mg/m2 in Japanese patients with advanced pancreatic cancer. METHODS: The primary end-point was to evaluate the frequency of dose-limiting toxicity. Gemcitabine 1000 mg/m2 was administered over 30 min weekly in two schedules: gemcitabine x3 every 4 weeks (Schedule 1) and gemcitabine x7 followed by a week of rest and then gemcitabine x3 every 4 weeks thereafter (Schedule 2). At least three patients entered each schedule and three additional patients were treated in the presence of dose-limiting toxicity. RESULTS: Eleven chemo-naive patients with a good Karnofsky performance status of > or =80 points and distant metastasis were entered into this trial. In Schedule 1, no dose-limiting toxicity was observed in the three patients. In Schedule 2, the evaluation of dose-limiting toxicity was complete in six of the eight enrolled patients and two patients showed dose-limiting toxicity in this Schedule; one patient experienced both grade 4 leukocytopenia and grade 4 neutropenia, and both grade 4 neutropenia and grade 3 GOT/GPT increased in another patient. Two patients (18%) showed a partial response and a clinical benefit response was also achieved in two (29%) of the seven evaluable patients. CONCLUSION: Gemcitabine 1000 mg/m2 weekly x7 followed by a week of rest and weekly x3 every 4 weeks thereafter may be tolerated in Japanese patients with advanced pancreatic cancer.     

Phase I/II study of combination chemotherapy with gemcitabine and UFT for advanced pancreatic cancer in a multi-center trial

The aim of this phase I/II study was to evaluate the tolerability and efficacy of combination chemotherapy with gemcitabine (GEM) and UFT for advanced pancreatic cancer. In phase I study UFT was given orally every day for 14 days and GEM was infused on day 1 and 8 at three dose levels (800, 900, 1,000 mg/m(2)/week) every 21 days. GEM 1,000 mg/m(2) and UFT 400 mg/m(2) did not reach the maximum tolerated dose. We decided that the recommended dose (RD) was GEM 1,000 mg/m(2)and UFT 400 mg/m(2). In phase II study 27 patients were enrolled and received GEM and UFT at RD. The tumor response rate was 17.6%, and the median survival was 221 days, which was very similar to that of GEM monotherapy. Due to adverse events, especially liver dysfunction, protocol therapy was discontinued in 12 patients. This study could not revealed the superiority of the GEM monotherapy.     

Neoadjuvant chemotherapy followed by late-course accelerated hyperfractionated radiation therapy for locally advanced non-small-cell lung cancer: long-term results of a phase I/II clinical trial

Toxicity, response, and long-term results of a definitive chemotherapy/radiation therapy (RT) protocol in patients with unresectable stage III non-small-cell lung cancer (NSCLC) were evaluated. Two cycles of cisplatin-based chemotherapy were delivered before RT, and another 2 cycles were added for patients who responded to the first 2 cycles of chemotherapy. The first course of radiation covered the primary lesion and elective nodal regions, given in 2 Gy per fraction, 5 days a week for a dose of 40 Gy. Late-course hyperfractionated accelerated RT was delivered to the gross tumor twice a day for an additional 27 Gy within 2 weeks, using 1.5 Gy per fraction. Fifty-three patients with unresectable stage IIIA (N2) and IIIB NSCLC were eligible for analysis. Twelve patients developed grade 3 neutropenia, and 3 patients developed grade 4 neutropenia. Grade 2 or 3 esophagitis was observed in 14 and 2 patients, respectively, and grade 2 or 3 pneumonitis was observed in 9 and 1 patient, respectively. Six patients developed grade 2 and 1 patient developed grade 3 late lung toxicity. The median survival time was 15.5 months. Twenty-six of 53 patients (49%) have died of locoregional progression inside the thorax. The distant metastasis rate was 59.5% (22 of 37 patients) for those who did not respond to chemotherapy and 18.8% (3 of 16 patients) for those who responded to chemotherapy (P = 0.006). Late-course hyperfractionated accelerated RT combined with induction chemotherapy was well tolerated and yielded long-term results that compare favorably with those of studies using 2 cycles of induction chemotherapy and conventional fractionated RT. However, local control was still discouraging.     

同期放化疗治疗局部晚期不可手术的直肠癌近期疗效观察

目的：观察同期放化疗治疗局部晚期不可手术的直肠癌患者的近期疗效及耐受性。方法：３８例经病理证实的局部晚期或局部 区域复发的直肠癌患者接受全盆腔三维适形放疗ＤＴ４６～５０Ｇｙ／２３～２５ｆ,后缩野至肿瘤区继续推量至ＤＴ６４～６６Ｇｙ／３２～３３ｆ,同期接受奥沙利铂１３０ｍｇ／ｍ^２ｄ_１,氟尿嘧啶３５０ｍｇ／ｍ^２ｄ_１～ｄ_５,甲酰四氢叶酸２００ｍｇ／ｍ^２ｄ_１～ｄ_５,４周为１周期,共２个周期。结果：获ＣＲ７例（１９.４％）,ＰＲ１６例（４４.４％）,ＳＤ６例（１６.７％）,ＰＤ７例（１９.４％）,总有效率（ＣＲ＋ＰＲ）为６３.９％;疼痛症状缓解率为１００％;全身状况好转率７２.２％;中位生存时间为２２个月,１年和２年总生存率分别为６７.７％和２１.３％。治疗相关的毒副反应以中性粒细胞减少、腹泻、恶心呕吐以及周围神经毒性反应为主,其３级毒副反应的发生率分别为１９.４％、１６.７％、１３.９％和１１.１％,均无３级以上毒副反应发生。结论：以奥沙利铂为基础的化疗同期联合放疗对局部晚期不可手术直肠癌患者具有较好的姑息治疗作用,其治疗依从性高,治疗相关毒性可以接受,值得临床进一步推广。     

Escalated hyperfractionated accelerated radiation therapy for locally advanced non-small cell lung cancer: a clinical phase II trial.

BACKGROUND AND PURPOSE: To evaluate the feasibility, toxicity and the efficacy for locally advanced non-small cell lung cancer (NSCLC) treated with escalated hyperfractionated accelerated radiation therapy (EHART) combined with chemotherapy. PATIENTS AND METHODS: The EHART consisted of irradiation delivered twice per day with >6-h interval and five treatment days per week. In the first and second weeks, 1.2 Gy/fraction b.i.d, was given, and then 1. /fraction b.i.d in the third week; 1.4 Gy/fraction b.i.d in the fourth week; and 1. /fraction b.i.d in the fifth week, respectively. The total tumor dose delivered was 66 Gy/50 fractions/5 weeks. All patients received neoadjuvant and adjuvant chemotherapy. The chemotherapeutic regimen used was either MVP (mitomycin C, vindesine, cis-platinum), or EP (etoposide and cis-platinum). RESULTS: From February 1997 to February 1999, 73 eligible patients were registered. All were in stage IIIb with median age of 60 years (33-70). Of the 73 patients, 12 cases were withdrawn from the study due to Grade (Gr) III acute complications, distant metastases, or intercurrent diseases. Sixty-one patients completed the combined treatment as planned. A median of 4 cycles of chemotherapy (1-7) was administered and 66 Gy/50 fractions/36 days was delivered finally. The most common acute complication was radiation esophagitis, which occurred in 56 cases (77%), with Gr III in 11 cases (15%). Twenty-nine patients (40%) had acute pulmonary toxicity; with Gr III in 6 cases (8%). The median survival time was 13 months for the entire group. The 1-year and 2-year survival rates were 51 and 10%, respectively. Of the 61 patients who finished EHART, 34 were found to have locoregional progression. Thirty-two patients failed inside radiation fields, and 2 patients, outside radiation fields. The 1-year and 2-year locoregional progression-free rates were 71 and 34%, respectively. The 1-year and 2-year distant metastasis rates were 57 and 84%, respectively. CONCLUSIONS: EHART combined with chemotherapy could be tolerated by most of the stage IIIb NSCLC patients with acceptable complications. Locoregional control was improved, but the long survival was not prolonged significantly predominantly due to distant metastases.     

Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer

Background:

Patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin.

Methods:

Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg⁻¹ verteporfin. After 60–90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently.

Results:

In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm³ at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple''s pancreaticoduodenectomy.

Conclusions:

Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.     

Phase II trial of chemoradiotherapy with S‐1 plus cisplatin for unresectable locally advanced head and neck cancer (JCOG0706)

We conducted a phase II study to evaluate the efficacy and safety of chemoradiotherapy concurrent with S‐1 plus cisplatin in patients with unresectable locally advanced squamous cell carcinoma of the head and neck. Chemotherapy consisted of S‐1 twice daily on days 1–14 at 60 mg/m²/day and cisplatin at 20 mg/m²/day on days 8–11, repeated twice at a 5‐week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently starting on day 1. For patients achieving an objective response after chemoradiotherapy, two additional cycles of chemotherapy were administered. Of the 45 enrolled patients, the percentage of clinical complete remission, the primary endpoint, was 64.4% (8 complete response, 21 good partial response) on central review. After a median follow‐up of 3.52 years, 3‐year local progression‐free survival was 62.2%, with 3‐year progression‐free survival of 60.0%, 3‐year overall survival of 64.4%, and 3‐year time to treatment failure of 48.9%. Grade 3 or 4 toxicity included pharyngeal mucositis (46.7%), oral mucositis (44.4%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%), and febrile neutropenia (4.4%). No treatment‐related deaths were observed. This combination showed promising efficacy with acceptable toxicities.     

Phase II trial of gemcitabine and S-1 for patients with advanced pancreatic cancer

Purpose

To evaluate the efficacy and safety of combined gemcitabine and S-1 as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer.

Methods

This study included patients who had been diagnosed with unresectable, locally advanced or metastatic adenocarcinoma arising from the pancreas, which was histologically or cytologically confirmed and involved at least 1 unidimensionally measurable lesion. The regimen consisted of intravenous 1,000 mg/m² gemcitabine on day 1 and 8 combined with oral S-1 on days 1–14 every 21 days. The dosage of S-1 was based on the body surface area (BSA) as follows: 40 mg bid (total 80 mg/day) for a BSA of <1.25, 50 mg bid (total 100 mg/day) for a BSA of ≥1.25 but <1.5, and 60 mg bid (total 120 mg/day) for a BSA of ≥1.5. Treatment consisted of at least 2 courses unless rapid disease progression was noted. The primary end points were the response and disease control rates, and the secondary end points were toxicity and survival.

Results

Thirty-seven patients were enrolled between August 2005 and December 2010. The median number of chemotherapy cycles was 4 (range 1–28 cycles). Response to treatment could be evaluated in 31 patients. None of the patients showed complete response, but 5 achieved partial response. The response rate was thus 13.5 % [95 % confidence interval (CI) 2.7–24.3 %] in the intent-to-treat population. Sixteen patients (43.2 %; 95 % CI 27–59.5 %) showed stable disease, and the overall disease control rate was 56.8 % (95 % CI 40.6–72.9 %). For all 37 patients, the median progression-free survival was 4.6 months (95 % CI 1.8–7.6 month), and the median overall survival was 9.4 month (95 % CI 5.8–12.6 month). Chemotherapy-related grade 3/4 hematological toxicities were neutropenia (36.1 %), leucopenia (22.2 %), and anemia (13.9 %). The non-hematological toxicities were generally mild.

Conclusions

Combination chemotherapy with gemcitabine and S-1 was effective, convenient, and safe in patients with advanced pancreatic cancer.     

Phase I study of hyperfractionated accelerated radiotherapy and escalating doses of daily cisplatin for patients with locally advanced non-small-cell lung cancer

PURPOSE: To determine if graduates of different types of educational programs obtain similar scores on the Examination in Radiation Therapy administered by the American Registry of Radiologic Technologists. The results will help inform discussions regarding educational requirements for radiation therapists. METHODS AND MATERIALS: Test scores were obtained for 531 candidates who had taken the examination for the first time in 1997, 1998, or 1999. Candidates were divided into the following three categories, based on the type of educational program attended: hospital-based certificate, associate's degree, or bachelor's degree. To determine if test scores were related to the type of educational preparation, analyses of variance were conducted separately to test for differences in total scores and section scores, and scores on test questions intended to measure critical thinking skills. RESULTS: Candidates with an associate's degree scored slightly lower than candidates with a bachelor's degree on the total test (p < 0.10) and lower than candidates with either a certificate or bachelor's degree on Section B of the examination (Treatment Planning and Delivery, p < 0.10). Baccalaureate candidates did not obtain higher scores than those prepared in certificate programs. On critical thinking questions, candidates with certificates scored higher than those with associate's degrees (p < 0.10). Some evidence suggested that candidates with a certificate scored higher on critical thinking than those with a bachelor's degree (p < 0.10), and that candidates with a bachelor's degree scored higher than candidates with an associate's degree (p < 0.10). CONCLUSIONS: Although some of the differences in the mean test scores among the three educational groups were statistically significant, all differences were small and do not support one type of educational preparation over another.     

A phase II trial of induction chemotherapy followed by continuous hyperfractionated accelerated radiotherapy in locally advanced non-small-cell lung cancer

Background and purpose

We conducted a phase II study combining induction chemotherapy with continuous hyperfractionated accelerated radiotherapy (CHART) in locally advanced non-small-cell lung cancer (NSCLC).

Materials and methods

A total of 40 patients with stage III NSCLC were enrolled. All patients received 3 cycles of chemotherapy followed by CHART (56 Gy in 36 fractions over 12 days). The primary outcome measure was radiation toxicity. Secondary endpoints were response rate, overall survival, disease-free survival and loco-regional progression-free survival.

Results

Acute radiation toxicity was minimal and there were no significant late toxicities. The response rate after completion of chemoradiation was 65%. The median and 2-year overall survival, progression-free survival and loco-regional progression-free survivals were 15.7 months, 28%; 12.1 months, 23%; and 26.4 months, 51%, respectively.

Conclusions

Induction chemotherapy can be safely combined with CHART. The survival results are consistent with previous studies of chemotherapy followed by accelerated radiotherapy. This approach should be compared with synchronous chemoradiation to determine if it represents a less toxic alternative.     

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

The selective MEK1/2 inhibitor pimasertib has shown anti‐tumour activity in a pancreatic tumour model. This phase I/II, two‐part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m²) in 28‐day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression‐free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58–1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first‐line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.     

Phase I trial of GBS‐01 for advanced pancreatic cancer refractory to gemcitabine

GBS‐01, an extract from the fruit of Arctium lappa L. is an orally administered drug rich in arctigenin, which has been reported to exert antitumor activity by attenuating the tolerance of cancer cells to glucose deprivation. We investigated the maximum tolerated dose of GBS‐01 based on the frequency of the dose‐limiting toxicities (DLTs) and pharmacokinetics in patients with advanced pancreatic cancer refractory to gemcitabine. GBS‐01 was given orally at escalating doses from 3.0 g (containing 1.0 g burdock fruit extract) to 12.0 g q.d. A DLT was defined as a grade 4 hematological toxicity and grade 3 or 4 non‐hematological toxicity appearing during the first 28 days of treatment. Fifteen patients (GBS‐01 dose level 1 [3.0 g], three patients; dose level 2 [7.5 g], three patients; and dose level 3 [12.0 g], nine patients) were enrolled. None of the patients at any of the three dose levels showed any sign of DLTs. The main adverse events were increased serum γ‐glutamyl transpeptidase, hyperglycemia, and increased serum total bilirubin; however, all the toxicities were mild. Of the 15 patients, 1 showed confirmed partial response and 4 patients had stable disease. The median progression‐free and overall survival of the patients were 1.1 and 5.7 months, respectively. The pharmacokinetic study revealed a high bioavailability of arctigenin and rapid conjugation of the drug with glucuronic acid. The recommended dose of GBS‐01 was 12.0 g q.d, and favorable clinical responses were obtained. This trial was registered at UMIN‐CTR ( http://www.umin.ac.jp/ctr/index-j.htm ), identification number UMIN000005787.