BACKGROUND:A major obstacle in translating the therapeutic potential of chimeric antigen receptor (CAR) T cells to children with central nervous system (CNS) tumors is the blood-brain barrier. To overcome this limitation, preclinical and clinical studies have supported the use of repeated, locoregional intracranial CAR T-cell delivery. However, there is limited literature available describing the process for the involvement of an investigational drug service (IDS) pharmacy, particularly in the setting of a children's hospital with outpatient dosing for CNS tumors. OBJECTIVES:To describe Seattle Children's Hospital's experience in clinically producing CAR T cells and the implementation of IDS pharmacy practices used to deliver more than 300 intracranial CAR T-cell doses to children, as well as to share how we refined the processing techniques from CAR T-cell generation to the thawing of fractionated doses for intracranial delivery. METHODS:Autologous CD4+ and CD8+ T cells were collected and transduced to express HER2, EGFR, or B7-H3-specific CAR T cells. Cryopreserved CAR T cells were thawed by the IDS pharmacy before intracranial delivery to patients with recurrent/refractory CNS tumors or with diffuse intrinsic pontine glioma/diffuse midline glioma. RESULTS:The use of a thaw-and-dilute procedure for cryopreserved individual CAR T-cell doses provides reliable viability and is more efficient than typical thaw-and-wash protocols. Cell viability with the thaw-and-dilute protocol was approximately 75% and was always within 10% of the viability assessed at cryopreservation. Cell viability was preserved through 6 hours after thawing, which exceeded the 1-hour time frame from thawing to infusion. CONCLUSION:As the field of adoptive immunotherapy grows and continues to bring hope to patients with fatal CNS malignancies, it is critical to focus on improving the preparatory steps for CAR T-cell delivery.
BACKGROUND:The diversity in the genomic landscape of advanced and metastatic tumors calls for combination therapies based on the genomic signature associated with each tumor. Determining safe and tolerable doses for novel combinations of oncology drugs is essential for a precision medicine approach, but can also require dose reductions. Trametinib, palbociclib, and everolimus are among the targeted therapies most often used in novel combinations at our precision medicine clinic.OBJECTIVE:To evaluate the safe, tolerable dosing of trametinib, palbociclib, and everolimus when used as part of novel combinations with other agents for the treatment of advanced or metastatic solid tumors.METHODS:This retrospective study included adult patients with advanced or metastatic solid tumors who received trametinib, everolimus, or palbociclib plus other therapies as a part of novel combinations between December 2011 and July 2018 at the University of California San Diego. Patients were excluded if they received trametinib, everolimus, or palbociclib in standard combinations, such as dabrafenib plus trametinib, everolimus plus fulvestrant, everolimus plus letrozole, and palbociclib plus letrozole. Dosing and adverse events were determined through a review of the electronic medical records. A safe, tolerable drug combination dose was defined as being tolerated for at least 1 month, with no clinically significant serious adverse events.RESULTS:A safe, tolerable dose was determined for 76% of the 71 patients who received trametinib, 88% of the 48 patients who received everolimus, and 73% of the 41 patients receiving palbociclib when used in combination with other therapies. For patients with clinically significant adverse events, dose reductions were attempted in 30% of the trametinib recipients, in 17% of everolimus recipients, and in 45% of palbociclib recipients. When used in combination with other therapies, the optimal dosing of trametinib, palbociclib, and everolimus was lower than the standard single-agent dosing: it was 1 mg daily for trametinib; 5 mg daily for everolimus; and 75 mg daily, for 3 weeks on and 1 week off for palbociclib. Of note, everolimus could not be given concomitantly with trametinib at these doses.CONCLUSION:Safe and tolerable dosing of novel combination therapies that includes trametinib, everolimus, or palbociclib is feasible for a precision medicine approach. However, neither results from this study nor results from previous studies could support the use of everolimus in combination with trametinib, even at reduced doses.
BACKGROUND:Phase 1 clinical trials have challenges relative to later-phase clinical trials. As of April 2020, there were 71 active phase 1 cancer clinical trials at the Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center (SKCCC), and limited clinical pharmacy services are dedicated to the unique needs of phase 1 clinical trials. OBJECTIVES:To characterize the current phase 1 cancer-specific clinical pharmacy services at National Cancer Institute (NCI)-designated institutions, and to develop a framework for the implementation of these services at Johns Hopkins Medicine SKCCC. METHODS:We queried the current pharmacy practices for phase 1 cancer clinical trials at NCI-designated institutions through an e-mailed 20-question national online survey to 208 pharmacists. The recipients were asked to rate how often specific pharmacy services were performed, using a 4-point Likert scale of rarely/never (<10%), sometimes (10%-49%), often (50%-80%), or almost always (>80%). The services were grouped into pretrial implementation support, phase 1 trial implementation support, medication profile review, medication therapy management, and miscellaneous support. Using the survey results, a framework for phase 1 trial clinical pharmacy services was developed concurrently to prioritize protocol complexity, monitoring requirements, and clinical pharmacy interventions. RESULTS:Of the 208 surveys e-mailed, 45 recipients responded, for an overall survey response rate of 22%. The responses were divided into 2 subgroups for the institutions that currently conduct phase 1 cancer clinical trials, including institutions with >40 active phase 1 cancer clinical trials and institutions with ≤40 active phase 1 cancer clinical trials. The institutions with >40 active phase 1 cancer clinical trials were more likely to have pharmacists involved with direct participant care (47% vs 18.8%, respectively) and document medication lists for phase 1 trial participants (41% vs 18.8%, respectively) than institutions with ≤40 active phase 1 cancer clinical trials. The survey results assisted in developing a framework to classify drug regimens as platinum level (ie, higher complexity) or standard level (ie, lower or average complexity) to prioritize clinical pharmacy services based on their complexity level. CONCLUSION:Our analysis of current phase 1 clinical trial pharmacy practices at NCI institutions enabled the development of a framework for increased collaboration with research teams and phase 1 clinical trial-specific clinical pharmacy services within Johns Hopkins Medicine SKCCC.
BACKGROUND:The National Cancer Institute's (NCI) Division of Cancer Treatment and Diagnosis (DCTD), as an investigational new drug sponsor, may provide early access to investigational agents for treatment use. Until recently, the NCI had 3 protocol mechanisms for distributing investigational agents through the Treatment Referral Center (TRC), a service provided by the Pharmaceutical Management Branch (PMB) within the Cancer Therapy Evaluation Program of the NCI's DCTD. The first mechanism is the Group C protocol, the second mechanism is the TRC protocol, and the third, and most common, mechanism is the Special Exception protocol.OBJECTIVES:The purpose of this article is to describe and report on the activities of the TRC at the PMB since 2000 through the end of 2011.METHODS:Capital Technology Information Services performed PMB data mining for all treatment protocols from January 1, 2000, to December 31, 2011. Requests to PMB were sorted in spreadsheet format by disposition, either as referred, approved, or denied, and were counted by type, either as Group C, TRC, or Special Exception.RESULTS:More than 60% of requests were either referred or approved between 2000 and 2011. The peak number of requests was 1664 between 2000 and 2011 and occurred in 2003. The peak was mostly a result of Special Exception requests; however, more than 400 TRC requests and 20 Group C requests were approved that year. The total number of requests dropped precipitously after 2003, and since 2008 have totaled fewer than 50 annually. All Group C and TRC protocols were completed by March 2006. The lowest number of treatment use requests occurred in 2011.CONCLUSION:Providing agents through the Special Exception mechanism is one way that promising investigational new drug agents can get to patients with life-threatening illnesses. In general, the PMB's TRC is a useful drug information resource for sites conducting clinical research in oncology, and it provides a valuable service to the oncology community.
