Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer.

PURPOSE: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. RESULTS: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. CONCLUSION: Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib. CLINICALTRIALS. GOV IDENTIFIERS: NCT02243150; NCT02499770; NCT02514447.

Phase 2 study of combination SPI-1620 with docetaxel as second-line advanced biliary tract cancer treatment.

BACKGROUND: This multicentre, open-label study evaluated the efficacy and safety of SPI-1620, an analogue of endothelin-1, administered in combination with docetaxel as second-line treatment for patients with advanced biliary tract cancer (ABTC). METHODS: Eligible patients received continuous cycles of combination therapy with SPI-1620 (11 µg m-2) and docetaxel (75 mg m-2) intravenously every 3 weeks until disease progression (PD) or intolerable toxicity. Tumour response was evaluated using computed tomography or magnetic resonance imaging every 2 cycles (6 weeks). The primary efficacy end point was progression-free survival (PFS); secondary end points included overall response rate (ORR), duration of response, and overall survival (OS) that were estimated using the Kaplan-Meier method. RESULTS: Of the 30 enrolled patients, 25 patients had qualifying events (PD or death), 1 patient was nonevaluable, and 4 patients were censored at the time of their last tumour assessment. Our primary end point of PFS ⩾5 months was not reached. Median PFS was 2.6 months (95% confidence interval (CI): 1.4-2.8), ranging from 0.7 to 8.4 months. The ORR was 10.3% (95% CI: 0.02-0.27). Eleven additional patients achieved stable disease. The OS was 4.87 months. The most common grade 3-4 toxicities were febrile neutropenia and neutropenia. CONCLUSIONS: The addition of docetaxel to SPI-1620 in second-line ABTC did not meet the pre-specified primary end point of PFS ⩾5 months in unselected patient population.

A multicenter phase II study of G17DT immunogen plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan.

BACKGROUND: The G17DT is a novel human immunogen that raises antibodies to the growth factor gastrin 17 (G17). The purpose of this study was to determine the safety and efficacy of G17DT in combination with irinotecan in patients refractory to irinotecan, and to correlate efficacy with anti-G17 immune response. METHODS: Patients received G17DT immunogen as a single intramuscular injection of 500 µg at weeks 1, 5, 9, and 26. Irinotecan was administered as an intravenous infusion of 125 mg/m(2) over 90 min starting at week 5. Each cycle of treatment consisted of irinotecan administered once weekly for 4 weeks, followed by a 2-week rest period. RESULTS: Of 161 patients who received G17DT, the best overall tumor response in the intent-to-treat population was complete response 0 (0 %), partial response 3 (3 %), stable disease 32 (32 %), and progressive disease 64 (65 %). Median survival was 217 days. About 94 (62 %) subjects evaluable for antibody titers were anti-G17 responders. Survival was significantly longer for anti-G17 responders compared with non-responders (9.0 vs. 5.6 months; P < 0.001). Toxicity was consistent with irinotecan (diarrhea, nausea, anemia, vomiting, fatigue, constipation, anorexia, and neutropenia) except for injection site reactions (pain 42 %, induration 13 %, edema 11 %, erythema 10 %, and three abscesses) attributed to G17DT in 52 % of the patients. CONCLUSION: Treatment with G17DT in combination with irinotecan results in an acceptable anti-G17 immune response, which correlated with promising survival activity in patients refractory to irinotecan-based chemotherapy.

Oxaliplatin induced disseminated intravascular coagulation: A case report and review of literature.

Oxaliplatin in combination with a fluoropyrimide is a treatment option for colorectal cancer patients in the adjuvant and metastatic settings. Very few hematological emergencies have been reported associated with Oxaliplatin. These include autoimmune hemolytic anemia, thrombocytopenia and pancytopenia. We present a case report of a patient who developed hematuria and disseminated intravascular coagulation while receiving the second cycle of FOLFOX and bevacizumab for metastatic colon cancer.

Preoperative docetaxel/cisplatin/5-fluorouracil chemotherapy in patients with locally advanced gastro-esophageal adenocarcinoma.

Perioperative chemotherapy plus surgery improves survival compared to surgery alone in GE junctional (GEJ) and gastric adenocarcinomas. The docetaxel/cisplatin/5-fluorouracil (DCF) combination is superior to CF in patients with metastatic gastric cancer. We retrospectively evaluated the safety and efficacy of preoperative DCF chemotherapy in patients with locally advanced gastric and GEJ cancer. Twenty-one gastric and 10 gastroesophageal junctional (GEJ) cancer patients received 2-3 cycles of preoperative docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, 5-FU 750 mg/m(2) (continuous infusion) on days 1-5 every 3 weeks. Clinical response was evaluated by comparing pre- and postchemotherapy CT scans. Overall survival (OS) and progression-free survival (PFS) were calculated from the initiation of chemotherapy. None of the patients achieved complete clinical remission while 11 (35%) patients achieved partial clinical remission. Ten patients with GEJ cancer (100%) and 13 with gastric cancer (62%) underwent curative surgery (P = 0.023). Seventeen (55%) patients experienced grade 3-4 chemotherapy-related adverse events. The most common adverse events were anemia, nausea/vomiting, diarrhea, and febrile neutropenia. At a median follow-up of 17.0 months, median OS and PFS were 26.1 months (95% CI: 22.7-29.5) and 18.8 months (95% CI: 9.9-27.7), respectively. The DCF regimen is active in patients with gastric and GEJ adenocarcinoma in the preoperative setting.

EUS-FNA with rescue fluorescence in situ hybridization for the diagnosis of pancreatic carcinoma in patients with inconclusive on-site cytopathology results.

BACKGROUND: Detection of chromosomal abnormalities by fluorescence in situ hybridization (FISH) analysis has not been well-studied in FNA samples of pancreatic masses. Selective use of FISH in patients with inconclusive on-site cytopathology results may improve the sensitivity of EUS for malignancy. OBJECTIVE: To determine the sensitivity and specificity of FISH analysis in patients with inconclusive on-site cytopathology results. DESIGN: Consecutive patients with suspected pancreatic malignancy, nonrandomized cohort study. Final diagnosis was based on either surgical biopsy or disease progression on extended follow-up or death. SETTING: Academic center, tertiary-care referral cancer center. PATIENTS: A total of 212 EUS examinations were performed in 206 patients for solid pancreatic lesions over a 24-month period (January 2009-December 2010). FISH analysis was done for 69 patients with inconclusive or nonavailable on-site cytology results. INTERVENTION: EUS-guided FNA (EUS-FNA) of solid pancreatic masses with cytology and FISH analysis for polysomy of chromosomes 3, 7, and 17 and deletion of 9p21. MAIN OUTCOME MEASUREMENTS: Sensitivity/specificity of cytology, FISH, and a composite of cytology and FISH. RESULTS: Patients with positive on-site cytology (110), neuroendocrine tumors (22), insufficient follow-up (1), FISH not obtained (3), and renal cancer with pancreatic metastasis (1) were excluded. Sixty-nine patients comprised the study cohort, 54 with malignancy and 15 with benign disease. Sensitivity for malignancy of cytology, FISH analysis, and the combination were 61%, 74%, and 85%, respectively (P = .009). FISH detected an additional 13 cases of pancreatic adenocarcinoma missed by cytology. There was no false-positive FISH analysis in 15 patients with benign disease. No major complications occurred from EUS-FNA. LIMITATIONS: Single center, selected patients underwent FISH analysis, limited number of patients with benign disease. CONCLUSION: In patients with suspected pancreatic cancer, FISH analysis can detect additional cases missed by cytology without compromising specificity. FISH analysis to detect polysomy of chromosomes 3, 7, and 17 and deletion of 9p21 should be considered when cytology is negative for malignancy in patients with a known pancreatic mass.

Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma?

BACKGROUND: It is unclear whether delays in commencing adjuvant chemotherapy after surgical resection of colon adenocarcinoma adversely impact survival. METHODS: Patients with stage II-III colon adenocarcinoma who received adjuvant chemotherapy at 2 centers were identified through the institutional tumor registry. Time to adjuvant chemotherapy, overall survival (OS), and relapse-free survival (RFS) were calculated from the day of surgery. Patients were dichotomized into early (time to adjuvant chemotherapy ≤ 60 days) and late treatment (time to adjuvant chemotherapy >60 days) groups. OS and RFS were compared using log-rank test and multivariate analysis by the Cox proportional hazards model. RESULTS: Of 186 patients included in the study, 49 (26%) had received adjuvant chemotherapy >60 days after surgical resection. Thirty percent of the delays were system related (eg, late referrals, insurance authorizations). Time to adjuvant chemotherapy >60 days was associated with significantly worse OS in both univariate analysis and a Cox proportional hazards model (hazard ratio, 2.17; 95% confidence interval, 1.08-4.36). Although difference in RFS between the 2 groups favored time to adjuvant chemotherapy <60, this did not reach statistical significance. CONCLUSIONS: Adjuvant chemotherapy delay >60 days after surgical resection of colon cancer is associated with worse OS.

Recent developments in palliative chemotherapy for locally advanced and metastatic pancreas cancer.

In spite of advances made in the management of the other more common cancers of the gastrointestinal tract, significant progress in the treatment of pancreatic cancer remains elusive. Nearly as many deaths occur from pancreatic cancer as are diagnosed each year reflecting the poor prognosis typically associated with this disease. Until recently, the only treatment with an impact on survival was surgery. In the palliative setting, gemcitabine (Gem) has been a standard treatment for advanced pancreatic cancer since it was shown a decade ago to result in a superior clinical benefit response and survival compared with bolus 5-fluorouracil. Since then, clinical trials have explored the pharmacokinetic modulation of Gem by fixed dose administration and the combination of Gem with other cytotoxic or the biologically "targeted" agents. However, promising trial results in small phase II trials have not translated into survival improvements in larger phase III randomized trials in the advanced disease setting. Two trials have recently reported modest survival improvements with the use of combination treatment with Gem and capecitabine (United Kingdom National Cancer Research GEMCAP trial) or erlotinib (National Cancer Institute of Canada Clinical Trials Group PA.3 trial). This review will focus on the use of systemic therapy for advanced and metastatic pancreatic cancer, summarizing the results of several recent clinical trials and discuss their implications for clinical practice. We will also discuss briefly the second-line chemotherapy options for advanced pancreatic cancer.

Bortezomib with or without irinotecan in relapsed or refractory colorectal cancer: results from a randomized phase II study.

PURPOSE: To evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC). PATIENTS AND METHODS: Patients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m(2) (arm A) or bortezomib 1.3 mg/m(2) plus irinotecan 125 mg/m(2) (arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability. RESULTS: A preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade >or= 3 adverse events reported, per patient, during the study were fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B. CONCLUSION: Bortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.

Oxaliplatin and fixed-rate infusional gemcitabine in the second-line treatment of patients with metastatic colon cancer: final results of a Phase II trial prematurely closed as a result of poor accrual.

BACKGROUND: Second-line therapy of advanced colorectal cancer (CRC) after failure of a combination of irinotecan, a fluoropyrimidine, and bevacizumab includes the use of oxaliplatin and a fluoropyrimidine. In animal models, synergistic effects of gemcitabine and platinum agents have been established. Additionally, superior antitumor activity of prolonged administration of gemcitabine compared with bolus administration has been demonstrated in vivo against murine colon tumors. PATIENTS AND METHODS: A 2-stage phase II trial was developed to assess the efficacy (primary endpoint: response rate) and safety of gemcitabine 1000 mg/m(2) over 100 minutes on days 1 and 15 in combination with oxaliplatin 100 mg/m(2) over 2 hours on days 2 and 16, every 4 weeks. Patients with metastatic CRC in whom irinotecan and a fluoropyrimidine treatment had failed were enrolled. Calcium and magnesium infusion was routinely given before and after oxaliplatin administration. RESULTS: Because of slow accrual as a result of oxaliplatin becoming more commonly used in first-line treatment, the trial was stopped with only 10 patients enrolled. Eight were men and 2 were women. Median age was 58.5 years (range, 47-72 years). Nine patients had an Eastern Cooperative Oncology Group performance status of 0/1. A median of 3.5 cycles was administered (range, 1-9; total, 42). Six patients had stable disease and 1 had progressive disease. Two patients had confirmed partial responses, and 1 patient had a partial response but developed necrotizing fasciitis, declined surgical treatment, and died before a confirmatory scan could be performed. The regimen was otherwise well tolerated: 1 patient developed grade 3 neutropenia. With a median follow-up of 5.5 months, 4 patients have died. The time to treatment failure was 3.7 months. CONCLUSION: Despite premature study closure because of poor accrual, oxaliplatin in combination with fixed-rate infusional gemcitabine seems to be a safe and potentially effective regimen in the treatment of CRC. Further studies should be considered with the addition of targeted therapy.

Emphysematous cholecystitis in a patient with gastrointestinal stromal tumor treated with sunitinib.

A 50-year-old man had a metastatic gastrointestinal stromal tumor that was refractory to imatinib. He was prescribed a 6-week course of treatment with oral sunitinib 50 mg/day. During the fourth week of his first cycle of treatment with the drug, the patient developed acute-onset, right upper quadrant pain associated with nausea, vomiting, and fever; laboratory tests revealed leukocytosis and mild hyperbilirubinemia. He was diagnosed with acute emphysematous cholecystitis, which was treated with broad-spectrum antibiotics and percutaneous cholecystostomy. His symptoms resolved, and he successfully completed his course of therapy with sunitinib. Using the Naranjo adverse drug reaction probability scale, a score of 5 was derived, which indicates that the likelihood was probable that this adverse event was caused by sunitinib.

Phase I study of carboplatin in combination with gemcitabine and irinotecan in patients with solid tumors: preliminary evidence of activity in small cell and neuroendocrine carcinomas.

BACKGROUND: The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of carboplatin in combination with gemcitabine and irinotecan in patients with solid tumors. METHODS: Patients with solid tumors who were not candidates for standard chemotherapy received escalating doses of carboplatin, gemcitabine, and irinotecan. RESULTS: Twenty-eight patients were enrolled. Two of 4 patients who received carboplatin at an area under the curve (AUC) of 5 on Day 1 with gemcitabine 800 mg/m(2) and irinotecan 80 mg/m(2) on Days 1 and 8 developed DLT, along with 2 of 12 patients at the immediate-lower dose level: carboplatin at an AUC of 4 on Day 1 with gemcitabine 800 mg/m(2) and irinotecan 80 mg/m(2) on Days 1 and 8. In an attempt to improve drug delivery on Day 8, a different schedule was studied. Carboplatin at an AUC of 2, gemcitabine 800 mg/m(2), and irinotecan 60 mg/m(2), all given on Days 1 and 8, was explored in 12 patients. Two patients were unable to receive therapy on Day 8. Twenty-four patients developed grade 3 or 4 hematologic toxicity. Nonhematologic side effects were mostly mild and reversible with the exception of 1 patient, who developed acute liver failure after the fourth cycle of chemotherapy and died. Objective responses were observed in 7 patients, including 5 patients who had small cell and neuroendocrine carcinomas. CONCLUSIONS: Carboplatin in combination with gemcitabine and irinotecan was feasible. However, compromise of single-agent doses of all 3 drugs was necessary because of toxicity. Additional studies are warranted in patients with small cell and high-grade neuroendocrine carcinomas.

Management of small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive type of lung cancer characterized by rapid growth and early metastasis. It is chemosensitive and radiosensitive, yet decades of research investigating multimodality treatments have failed to control or cure this disease in most patients. First-line treatment of limited-stage disease consists of chemotherapy (often etoposide/cisplatin or etoposide/carboplatin) combined with thoracic radiation therapy (TRT), followed by prophylactic cranial irradiation to decrease brain metastases as a site of disease progression for those who experience complete remission or a very good partial response to multimodality treatment. In a Japanese trial, the combination of irinotecan and cisplatin had initially shown promise in treating patients with extensive-stage SCLC, but a confirmatory trial in the United States did not find a difference in overall survival with irinotecan/cisplatin versus etoposide/cisplatin. Adding a third drug to the etoposide/cisplatin combination, as well as other triplet therapies, has mostly been ineffective in improving outcomes. Variables in chemotherapy administration, including maintenance therapy, alternating non-cross-resistance regimens, and dose intensification, have not been shown to increase survival at large. In terms of radiation therapy, early administration of TRT concurrent with chemotherapy, and hyperfractionation, have been beneficial in treatment of limited-stage disease. In patients who relapse, second-line therapy options consist of reinduction of previous chemotherapy or administration of a single agent. Targeted biological therapies for SCLC are now being investigated, and although a great deal of research remains to be done, these agents and their derivatives may provide the most hope for future treatment of SCLC.

Docetaxel in the management of advanced pancreatic cancer.

The poor outcome of pancreatic cancer with conventional treatment options emphasizes the need for continued research. The benefits of gemcitabine in improving quality of life and survival have been established in patients with advanced pancreatic cancer. Randomized clinical trials studying the addition of a second drug to gemcitabine, either a classic cytotoxic (5-fluorouracil, cisplatin, irinotecan, pemetrexed, oxaliplatin, or exatecan) or targeted agents (ie, the farnesyl transferase inhibitor R115777 or the metalloproteinase inhibitor marimastat) have not resulted in improvement in survival compared with gemcitabine alone. Although limited activity of docetaxel in patients with pancreatic adenocarcinoma has been reported in single-agent studies, attractive efficacy results have been documented with docetaxel in combination with other chemotherapeutic agents for the management of advanced pancreatic cancer. Phase I and II trials of docetaxel in combination with gemcitabine, irinotecan, 5-fluorouracil, or thalidomide, as well as trials of docetaxel and radiotherapy, suggest that docetaxel combinations in pancreatic cancer should be further studied in randomized trials.

Topoisomerase I-based nonplatinum combinations in non-small-cell lung cancer.

Lung cancer is the leading cause of cancer-related death in males and females in the United States. Most patients have advanced disease at diagnosis. Chemotherapy is the treatment of choice for patients with good performance status. Progress in the management ofpatients with advanced disease has been slow, and platinum-based combinations result in a small survival benefit. The topoisomerase I inhibitors are active as single agents and in combination with platinums in non-small-cell lung cancer. Nonplatinum-based doublet combinations are beginning to be explored in an attempt to reduce toxicity and improve efficacy. Data available on some of the nonplatinum doublets that include topoisomerase I inhibitors suggest that these regimens provide efficacy equal to that achieved with platinum-based doublets. This article reviews the topoisomerase I-inhibitor nonplatinum combinations in the management of advanced non-small-cell lung cancer.

Irinotecan and gemcitabine in patients with solid tumors: phase I trial.

Using a day 1 and 8, every-3-week schedule, our purpose was to determine the maximum tolerated dose of irinotecan (CPT-11, Camptosar) that can be administered immediately after gemcitabine (Gemzar) at a dose of 1,000 mg/m2 IV. In this phase I trial, the maximum tolerated dose was defined as the dose level immediately below the level in which two of the first three patients in any cohort, or at least two of six patients in any expanded cohort, experienced dose-limiting toxicity. Dose-limiting toxicity pertained only to toxicity during the first cycle of treatment. Escalation of irinotecan was planned in groups of three patients, with three additional patients added at the first indication of dose-limiting toxicity. A total of 19 patients have been enrolled. Grade 4 diarrhea was the dose-limiting toxicity at the irinotecan dose of 115 mg/m2. Hematologic toxicity was not dose limiting. Three patients required canceling of the day 8 dose due to grade 3 myelosuppression. Three patients, two with pancreatic cancer and one with metastatic carcinoma of unknown primary, had a partial response. The maximum tolerated dose of irinotecan in this combination was 100 mg/m2/dose. The dose-limiting toxicity was diarrhea. The maximum tolerated dose is the recommended starting dose for phase II studies.