Invest New Drugs (2014) 32:710–716 DOI 10.1007/s10637-014-0096-3
PHASE I STUDIES
Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors Brian A. Costello & Mitesh J. Borad & Yingwei Qi & George P. Kim & Donald W. Northfelt & Charles Erlichman & Steven R. Alberts
Received: 24 January 2014 / Accepted: 30 March 2014 / Published online: 18 April 2014 # Springer Science+Business Media New York 2014
Summary Background A Phase I trial of the 2-drug regimen of everolimus plus gemcitabine (Cohort I) and the 3-drug regimen of everolimus plus gemcitabine and cisplatin (Cohort II) was performed to determine the maximally tolerated dose (MTD) of both combinations. An expansion cohort (Cohort III) of patients with cholangiocarcinoma or gallbladder carcinoma was treated at the MTD. Methods A standard 3+3 design dose escalation was used. Everolimus was given on Monday/Wednesday/Friday or daily depending upon the dose level. Gemcitabine and cisplatin were administered on days 1 and 8 of each 21 day cycle. Results Twelve patients were entered in Cohort I and 15 in Cohort II. The MTD for Cohort I was everolimus 5 mg on Monday/Wednesday/ Friday and gemcitabine 800 mg/m2. For Cohort II, it was everolimus 5 mg on Monday/Wednesday/Friday, gemcitabine 600 mg/m2, and cisplatin 12.5 mg/m2. All DLTs in this study were hematologic. Complete responses (CR) were seen in a patient with primary peritoneal carcinoma and another with recurrent pancreatic cancer. Partial responses (PR) were seen in 3 patients: breast, ampullary carcinoma and pheochromocytoma. Of 10 patients enrolled in Cohort III, six patients had stable disease and 4 had progressive disease. Conclusions This Phase I clinical trial has demonstrated that these 2-drug and 3-drug combinations are generally well
Supported in part by Novartis Pharmaceuticals and in part by Mayo Clinic Cancer Center (CA15083) This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. B. A. Costello (*) : M. J. Borad : Y. Qi : G. P. Kim : D. W. Northfelt : C. Erlichman : S. R. Alberts Mayo Clinic Cancer Center, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected]
tolerated and safely administered. The main DLTs in both regimens were hematologic, specifically thrombocytopenia. The 3-drug combination can be considered as a platform for future studies in specific tumor types. Keywords Phase I . Everolimus . Gemcitabine . Cisplatin . Cholangiocarcinoma . Gallbladder cancer
Introduction Combining cytotoxic chemotherapy with targeted agents is an active area of investigation in treating solid tumors. One such targeted agent, everolimus, is an orally administered analogue of rapamycin that is currently approved by the Food and Drug Administration (FDA) for pancreatic neuroendocrine tumors, subependymal giant cell astrocytomas, renal cell carcinoma, and hormone receptor-positive, HER2-negative breast cancer. Everolimus is also actively being tested in other malignancies [1]. In Phase I trials, weekly doses of up to 30 mg were found to be well tolerated [2,3]. The main toxic events noted in Phase I studies include headaches, fatigue, mucositis, elevations of serum lipids and oral aphthous ulcers. Myelosuppression was not seen at these doses. Everolimus is able to potentiate the effect of commonly-used cytotoxic drugs such as paclitaxel, doxorubicin, gemcitabine and cisplatin [4]. Gemcitabine is a pyrimidine antimetabolite and has a wide range of activity in a variety of tumor types [5,6]. It is a drug that can be given in patients with underlying mild to moderate hepatic dysfunction [7,8]. Cisplatin, an inorganic platinum coordination complex, has been assessed clinically against a variety of tumors because of its antineoplastic activity. Since its approval, cisplatin has been a critical chemotherapeutic agent and has been widely used, either alone or in combination with other antineoplastic agents.
Invest New Drugs (2014) 32:710–716
Used individually, both gemcitabine and everolimus have potential activity in a variety of cancers. Combining an mTOR inhibitor with gemcitabine may enhance the activity of gemcitabine. In a previously reported in vitro study of the mTOR inhibitor CCI-779 and gemcitabine, CCI-779 appeared to enhance sensitivity of pancreatic cancer cells to gemcitabine [9]. A prior Phase I trial of gemcitabine and everolimus attempted to establish the maximally tolerated dose (MTD) of gemcitabine added to a fixed dose of everolimus at 20 mg weekly [10]. It was not possible to establish the MTD using this approach due to myelosuppression. The trial we performed assessed lower doses of everolimus and attempted to escalate the doses of both gemcitabine and everolimus using a standard Phase I design. The combination of the two drugs may provide a meaningful new treatment option for patients. The combination of cisplatin with gemcitabine is commonly used in clinical practice in such cancers as bladder, nonsmall cell lung, and, more recently, biliary tract cancers [11]. Cholangiocarcinoma and gallbladder carcinoma are uncommon cancers. With a growing incidence of cholangiocarcinoma, it is becoming increasingly important to develop meaningful treatment options. A variety of chemotherapy agents have been used in these diseases, but in general the response to chemotherapy has been poor [12–16]. Now with gemcitabine and cisplatin having been established as the standard of care for advanced biliary cancers, one may postulate that addition of a third novel agent to this regimen may improve outcomes. We designed and implemented a Phase I clinical trial of the 2-drug combination of gemcitabine plus everolimus, and the 3-drug regimen of gemcitabine, cisplatin and everolimus principally to determine the maximally tolerated dose (MTD) and to describe the toxicities of these combinations as well as to describe any preliminary evidence of antitumor activity. Once the 3-drug regimen MTD was determined, this treatment was evaluated in a group of patients with cholangiocarcinoma or gallbladder carcinoma.
Patients and methods Eligibility criteria To enroll in Cohort I or Cohort II, patients required histologic proof of malignancy that was unresectable and was not amenable to all standard treatment for the disease with the exception of cancers in which gemcitabine was considered an appropriate initial treatment option. For Cohort III, patients required histologic proof of advanced intrahepatic or extrahepatic cholangiocarcinoma, or gallbladder carcinoma. They were not allowed to have received previous treatment for metastatic disease; though, patients were allowed to enroll who received gemcitabine ≥ 6 months prior as part of adjuvant therapy. Patients were required to be at least 18 years of age,
711
have a life expectancy of ≥12 weeks, and have an Eastern Cooperative Oncology Group (ECOG) performance score of 0–2. Key serum study parameters included an absolute neutrophil count ≥1,500/μL, platelets ≥100,000/μL, hemoglobin ≥9.0 g/dL, creatinine ≤1.5 × the upper limit of normal (ULN), and ALT and AST ≤2.5 × ULN. Exclusion criteria for this study included uncontrolled intercurrent illness, and current active other malignancy except non melanoma skin cancer and carcinoma in situ of the cervix. Patients who received everolimus previously were excluded, though there was no limit as to the number of other prior therapies. Prior chemotherapy, radiation therapy, immunotherapy, and biologic therapy were required to be completed greater than 4 weeks prior to registration. Mitomycin-C and nitrosoureas were required to be completed greater than 6 weeks prior to registration. Prior radiation of greater than 25 % of the bone marrow was not allowed. Brain and central nervous system metastases were allowed but were required to be treated and stable for at least 4 weeks prior to registration without the ongoing use of steroids. Exclusion criteria also included severe hepatic impairment or cirrhosis (Child-Pugh class C), severely impaired lung function with an FEV1
PHASE I STUDIES
Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors Brian A. Costello & Mitesh J. Borad & Yingwei Qi & George P. Kim & Donald W. Northfelt & Charles Erlichman & Steven R. Alberts
Received: 24 January 2014 / Accepted: 30 March 2014 / Published online: 18 April 2014 # Springer Science+Business Media New York 2014
Summary Background A Phase I trial of the 2-drug regimen of everolimus plus gemcitabine (Cohort I) and the 3-drug regimen of everolimus plus gemcitabine and cisplatin (Cohort II) was performed to determine the maximally tolerated dose (MTD) of both combinations. An expansion cohort (Cohort III) of patients with cholangiocarcinoma or gallbladder carcinoma was treated at the MTD. Methods A standard 3+3 design dose escalation was used. Everolimus was given on Monday/Wednesday/Friday or daily depending upon the dose level. Gemcitabine and cisplatin were administered on days 1 and 8 of each 21 day cycle. Results Twelve patients were entered in Cohort I and 15 in Cohort II. The MTD for Cohort I was everolimus 5 mg on Monday/Wednesday/ Friday and gemcitabine 800 mg/m2. For Cohort II, it was everolimus 5 mg on Monday/Wednesday/Friday, gemcitabine 600 mg/m2, and cisplatin 12.5 mg/m2. All DLTs in this study were hematologic. Complete responses (CR) were seen in a patient with primary peritoneal carcinoma and another with recurrent pancreatic cancer. Partial responses (PR) were seen in 3 patients: breast, ampullary carcinoma and pheochromocytoma. Of 10 patients enrolled in Cohort III, six patients had stable disease and 4 had progressive disease. Conclusions This Phase I clinical trial has demonstrated that these 2-drug and 3-drug combinations are generally well
Supported in part by Novartis Pharmaceuticals and in part by Mayo Clinic Cancer Center (CA15083) This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. B. A. Costello (*) : M. J. Borad : Y. Qi : G. P. Kim : D. W. Northfelt : C. Erlichman : S. R. Alberts Mayo Clinic Cancer Center, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected]
tolerated and safely administered. The main DLTs in both regimens were hematologic, specifically thrombocytopenia. The 3-drug combination can be considered as a platform for future studies in specific tumor types. Keywords Phase I . Everolimus . Gemcitabine . Cisplatin . Cholangiocarcinoma . Gallbladder cancer
Introduction Combining cytotoxic chemotherapy with targeted agents is an active area of investigation in treating solid tumors. One such targeted agent, everolimus, is an orally administered analogue of rapamycin that is currently approved by the Food and Drug Administration (FDA) for pancreatic neuroendocrine tumors, subependymal giant cell astrocytomas, renal cell carcinoma, and hormone receptor-positive, HER2-negative breast cancer. Everolimus is also actively being tested in other malignancies [1]. In Phase I trials, weekly doses of up to 30 mg were found to be well tolerated [2,3]. The main toxic events noted in Phase I studies include headaches, fatigue, mucositis, elevations of serum lipids and oral aphthous ulcers. Myelosuppression was not seen at these doses. Everolimus is able to potentiate the effect of commonly-used cytotoxic drugs such as paclitaxel, doxorubicin, gemcitabine and cisplatin [4]. Gemcitabine is a pyrimidine antimetabolite and has a wide range of activity in a variety of tumor types [5,6]. It is a drug that can be given in patients with underlying mild to moderate hepatic dysfunction [7,8]. Cisplatin, an inorganic platinum coordination complex, has been assessed clinically against a variety of tumors because of its antineoplastic activity. Since its approval, cisplatin has been a critical chemotherapeutic agent and has been widely used, either alone or in combination with other antineoplastic agents.
Invest New Drugs (2014) 32:710–716
Used individually, both gemcitabine and everolimus have potential activity in a variety of cancers. Combining an mTOR inhibitor with gemcitabine may enhance the activity of gemcitabine. In a previously reported in vitro study of the mTOR inhibitor CCI-779 and gemcitabine, CCI-779 appeared to enhance sensitivity of pancreatic cancer cells to gemcitabine [9]. A prior Phase I trial of gemcitabine and everolimus attempted to establish the maximally tolerated dose (MTD) of gemcitabine added to a fixed dose of everolimus at 20 mg weekly [10]. It was not possible to establish the MTD using this approach due to myelosuppression. The trial we performed assessed lower doses of everolimus and attempted to escalate the doses of both gemcitabine and everolimus using a standard Phase I design. The combination of the two drugs may provide a meaningful new treatment option for patients. The combination of cisplatin with gemcitabine is commonly used in clinical practice in such cancers as bladder, nonsmall cell lung, and, more recently, biliary tract cancers [11]. Cholangiocarcinoma and gallbladder carcinoma are uncommon cancers. With a growing incidence of cholangiocarcinoma, it is becoming increasingly important to develop meaningful treatment options. A variety of chemotherapy agents have been used in these diseases, but in general the response to chemotherapy has been poor [12–16]. Now with gemcitabine and cisplatin having been established as the standard of care for advanced biliary cancers, one may postulate that addition of a third novel agent to this regimen may improve outcomes. We designed and implemented a Phase I clinical trial of the 2-drug combination of gemcitabine plus everolimus, and the 3-drug regimen of gemcitabine, cisplatin and everolimus principally to determine the maximally tolerated dose (MTD) and to describe the toxicities of these combinations as well as to describe any preliminary evidence of antitumor activity. Once the 3-drug regimen MTD was determined, this treatment was evaluated in a group of patients with cholangiocarcinoma or gallbladder carcinoma.
Patients and methods Eligibility criteria To enroll in Cohort I or Cohort II, patients required histologic proof of malignancy that was unresectable and was not amenable to all standard treatment for the disease with the exception of cancers in which gemcitabine was considered an appropriate initial treatment option. For Cohort III, patients required histologic proof of advanced intrahepatic or extrahepatic cholangiocarcinoma, or gallbladder carcinoma. They were not allowed to have received previous treatment for metastatic disease; though, patients were allowed to enroll who received gemcitabine ≥ 6 months prior as part of adjuvant therapy. Patients were required to be at least 18 years of age,
711
have a life expectancy of ≥12 weeks, and have an Eastern Cooperative Oncology Group (ECOG) performance score of 0–2. Key serum study parameters included an absolute neutrophil count ≥1,500/μL, platelets ≥100,000/μL, hemoglobin ≥9.0 g/dL, creatinine ≤1.5 × the upper limit of normal (ULN), and ALT and AST ≤2.5 × ULN. Exclusion criteria for this study included uncontrolled intercurrent illness, and current active other malignancy except non melanoma skin cancer and carcinoma in situ of the cervix. Patients who received everolimus previously were excluded, though there was no limit as to the number of other prior therapies. Prior chemotherapy, radiation therapy, immunotherapy, and biologic therapy were required to be completed greater than 4 weeks prior to registration. Mitomycin-C and nitrosoureas were required to be completed greater than 6 weeks prior to registration. Prior radiation of greater than 25 % of the bone marrow was not allowed. Brain and central nervous system metastases were allowed but were required to be treated and stable for at least 4 weeks prior to registration without the ongoing use of steroids. Exclusion criteria also included severe hepatic impairment or cirrhosis (Child-Pugh class C), severely impaired lung function with an FEV1
