NCI10066: a Phase 1/2 study of olaparib in combination with ramucirumab in previously treated metastatic gastric and gastroesophageal junction adenocarcinoma.

BACKGROUND: Our preclinical work revealed tumour hypoxia induces homologous recombination deficiency (HRD), increasing sensitivity to Poly (ADP-ribose) polymerase inhibitors. We aimed to induce tumour hypoxia with ramucirumab thereby sensitising tumours to olaparib. PATIENTS AND METHODS: This multi-institution single-arm Phase 1/2 trial enrolled patients with metastatic gastroesophageal adenocarcinoma refractory to ≥1 systemic treatment. In dose escalation, olaparib was evaluated at escalating dose levels with ramucirumab 8 mg/kg day 1 in 14-day cycles. The primary endpoint of Phase 1 was the recommended Phase 2 dose (RP2D), and in Phase 2 the primary endpoint was the overall response rate (ORR). RESULTS: Fifty-one patients received ramucirumab and olaparib. The RP2D was olaparib 300 mg twice daily with ramucirumab 8 mg/kg. In evaluable patients at the RP2D the ORR was 6/43 (14%) (95% CI 4.7-25.6). The median progression-free survival (PFS) was 2.8 months (95% CI 2.3-4.2) and median overall survival (OS) was 7.3 months (95% CI 5.7-13.0). Non-statistically significant improvements in PFS and OS were observed for patients with tumours with mutations in HRD genes. CONCLUSIONS: Olaparib and ramucirumab is well-tolerated with efficacy that exceeds historical controls with ramucirumab single agent for gastric cancer in a heavily pre-treated patient population.

Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies.

PURPOSE: Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. METHODS: Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. RESULTS: Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. CONCLUSIONS: Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.

A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors.

BACKGROUND: RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. METHODS: Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. RESULTS: Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. CONCLUSIONS: The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.

AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients.

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

Phase I clinical trial of ifosfamide, oxaliplatin, and etoposide (IOE) in pediatric patients with refractory solid tumors.

Oxaliplatin, although related to cisplatin and carboplatin, has a more favorable toxicity profile and may offer advantages in combination regimens. We combined oxaliplatin, ifosfamide, and etoposide (IOE) and estimated the regimen's maximum tolerated dose (MTD) in children with refractory solid tumors. Dose-limiting toxicity (DLT) and MTD were assessed at 3 dose levels in a 21-day regimen: day 1, oxaliplatin 130 mg/m (consistent dose); days 1 to 3, ifosfamide 1200 mg/m/d (level 0) or 1500 mg/m/d (levels 1 and 2) and etoposide 75 mg/m/d (levels 0 and 1) or 100 mg/m/d (level 2). Course 1 filgrastim/pegfilgrastim was permitted after initial DLT determination, if neutropenia was dose limiting. Seventeen patients received 59 courses. Without filgrastim (n=9), DLT was neutropenia in 2 patients at dose level 1. No DLT was observed after adding filgrastim (n=8). There was no ototoxicity, nephrotoxicity >grade 1, or neurotoxicity >grade 2. One patient experienced a partial response and 9 had stable disease after 2 courses. In conclusion, the IOE regimen was well tolerated. Without filgrastim, neutropenia was dose limiting with MTD at ifosfamide 1200 mg/m/d and etoposide 75 mg/m/d. The MTD with filgrastim was not defined due to early study closure. Filgrastim allowed ifosfamide and etoposide dose escalation and should be included in future studies.

A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: a study of the Princess Margaret, Chicago and California Consortia.

OBJECTIVE: Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC. METHODS: We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50mg daily administered on a 4 weeks on-2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate. RESULTS: 34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar-plantar erythrodysesthesia, diarrhea and hematologic. CONCLUSION: Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.

A phase 2 study of oxaliplatin combined with continuous infusion topotecan for patients with previously treated ovarian cancer.

BACKGROUND: Phase 2 trials suggest that prolonged intravenous (IV) infusion of the topoisomerase 1 inhibitor topotecan may be less toxic than when given by standard IV bolus 5-day administration. Oxaliplatin exhibits efficacy in platinum-pretreated disease and shows preclinical synergy with topoisomerase 1 inhibitors. We sought to determine the efficacy and safety of oxaliplatin plus infusion topotecan in recurrent platinum-pretreated ovarian cancer. METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers previously treated with 1 to 2 prior regimens including platinum and taxane received oxaliplatin (85 mg/m(2) day 1 and day 15) and topotecan (0.4 mg/m(2) per day) by continuous IV infusion over 14 days every 4 weeks. The primary objective of the trial was to estimate the objective response rate in platinum-resistant disease (stratum 1) and in platinum-sensitive disease (stratum 2). Toxicities were assessed in all patients. RESULTS: Thirty-eight patients received 144 cycles of therapy (median, 4; range, 1-6). The most common grade 3 and grade 4 toxicities included thrombocytopenia (grade 3, 37%; and grade 4, 19%), neutropenia (grade 3, 37%; grade 4, 11%), and anemia (grade 3, 15%). Response occurred in 4 of 19 patients in stratum I (21%; 95% confidence intervals, 6%-46%) and 9 of 19 patients in stratum 2 (47%; 95% CI, 24%-71%). Three in each stratum had lengthy complete responses. CONCLUSIONS: Biweekly oxaliplatin plus a 14-day continuous IV infusion of topotecan, given monthly, is an active regimen in platinum-pretreated ovarian cancer and merits additional evaluation.

Expanding access to early phase trials: the CATCH-UP.2020 experience.

BACKGROUND: Disparities in cancer outcomes persist for underserved populations; one important aspect of this is limited access to promising early phase clinical trials. To address this, the National Cancer Institute-funded Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) was created. We report the tools developed and accrual metrics of the initial year of CATCH-UP.2020 with a focus on racial, ethnic, geographic, and socioeconomically underserved populations. METHODS: CATCH-UP.2020 is a P30 supplement awarded to 8 National Cancer Institute-designated cancer centers with existing resources to rapidly open and accrue to Experimental Therapeutics Clinical Trials Network (ETCTN) trials with emphasis on engaging patients from underserved populations. Sites used patient-based, community-based, investigator-based, and program-based tools to meet specific program goals. RESULTS: From September 2020 to August 2021, CATCH-UP.2020 sites opened 45 ETCTN trials. Weighted average trial activation time for the 7 sites reporting this was 107 days. In the initial year, sites enrolled 145 patients in CATCH-UP.2020 with 68 (46.9%) representing racial, ethnic, rural, and socioeconomically underserved populations using the broader definition of underserved encompassed in the grant charge. During the initial year of CATCH-UP.2020, a time impacted by the COVID-19 pandemic, 15.8% (66 of 417) and 21.4% (31 of 145) of patients enrolled to ETCTN trials at network and at CATCH-UP sites, respectively, were from racial and ethnic minority groups, a more limited definition of underserved for which comparable data are available. CONCLUSION: Targeted funding accelerated activation and accrual of early phase trials and expanded access to this therapeutic option for underserved populations.

A phase II study of 17-allylamino-17-demethoxygeldanamycin in metastatic or locally advanced, unresectable breast cancer.

Heat shock protein 90 (Hsp90) is an attractive target for breast cancer treatment, as it is required for the proper folding and stabilization of several proteins known to be involved in breast cancer growth and development. These proteins include the epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR), and src. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is an intravenous Hsp90 inhibitor in development for breast cancer treatment. We conducted a phase II study of 17-AAG 220 mg/m(2) on days 1, 4, 8, and 11 every 21 days in patients with metastatic and locally advanced breast cancer. Since we expected the molecular effects of Hsp90 inhibition to extend beyond just ER, PR, and HER2 down regulation and to impact a variety of other cellular proteins, patients were not selected based on ER, PR, or HER2 status. Eleven patients, including 6 patients with triple negative breast cancer, were enrolled and treated. There were no responses and 3 patients had stable disease as their best response. Five patients developed grade 3/4 toxicities, which were primarily hepatic and pulmonary. Based on these results, we do not recommend further study of 17-AAG at this dosing schedule or in unselected breast cancer patients.

Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building.

A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three compounds. The root mean squared error and absolute mean prediction error of the best single-objective hybrid genetic algorithm candidates were a median of 0.2 points higher (range of 38.9 point decrease to 27.3 point increase) and 0.02 points lower (range of 0.98 point decrease to 0.74 point increase), respectively, than that of the final stepwise models. In addition, the best single-objective, hybrid genetic algorithm candidate models had successful convergence and covariance steps for each compound, used the same compartment structure as the manual stepwise approach for 6 of 7 (86 %) compounds, and identified 54 % (7 of 13) of covariates included by the manual stepwise approach and 16 covariate relationships not included by manual stepwise models. The model parameter values between the final manual stepwise and best single-objective, hybrid genetic algorithm models differed by a median of 26.7 % (q1 = 4.9 % and q3 = 57.1 %). Finally, the single-objective, hybrid genetic algorithm approach was able to identify models capable of estimating absorption rate parameters for four compounds that the manual stepwise approach did not identify. The single-objective, hybrid genetic algorithm represents a general pharmacokinetic model building methodology whose ability to rapidly search the feasible solution space leads to nearly equivalent or superior model fits to pharmacokinetic data.

A phase I study of rebeccamycin analog in combination with oxaliplatin in patients with refractory solid tumors.

Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.

The importance of clinical grading of heart failure and other cardiac toxicities during chemotherapy: updating the common terminology criteria for clinical trial reporting.

Although the use of chemotherapy and targeted therapy has improved the clinical benefit, progression-free survival, and overall survival of various cancers in recent years, old and new toxicities have limited their use. To balance the risk with the benefit of treatment, Common Toxicity Criteria and now Common Terminology Criteria for Adverse Events (CTCAE) have been used by the oncology community for more than 20 years to assess toxicity from cancer treatment. This article details the description and grading of cardiac toxicities reported in association with cancer treatment and the use of CTCAE to assess them.

A phase II study of pazopanib in patients with recurrent or metastatic invasive breast carcinoma: a trial of the Princess Margaret Hospital phase II consortium.

PURPOSE: Angiogenesis is an important hallmark of breast cancer growth and progression. Pazopanib, an oral small molecule inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and KIT, has activity across a range of solid tumors. We evaluated the activity of single-agent pazopanib in recurrent or metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with recurrent breast cancer or MBC, treated with up to two prior lines of chemotherapy, were eligible to receive pazopanib, 800 mg daily until progression. The primary endpoint was the objective response rate as measured by Response Evaluation Criteria in Solid Tumors. Secondary endpoints included time to progression, the stable disease rate, and toxicity. Using a two-stage design, confirmed response in three of 18 patients was required to proceed to stage 2. RESULTS: Twenty evaluable patients were treated, with a median age of 56 years; 70% were estrogen receptor positive, all were human epidermal growth factor receptor 2 negative. The majority had one or two prior lines of chemotherapy. One patient (5%) had a partial response, 11 (55%) had stable disease (SD) [four (20%) with SD > or = 6 months], and seven (35%) had progressive disease as their best response. One (5%) was not evaluable. The median time to progression was 5.3 months. Pazopanib did not cause significant severe toxicity aside from grade 3-4 transaminitis, hypertension, and neutropenia in three patients each (14% each) and grade 3 gastrointestinal hemorrhage in one patient (5%). CONCLUSION: Pazopanib provides disease stability in advanced breast cancer. The activity seen is comparable with that of other antiangiogenic agents in this setting. Pazopanib may be of interest for future studies in breast cancer, including in combination with other systemic agents.

Phase II study of sunitinib malate in head and neck squamous cell carcinoma.

BACKGROUND: Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor of RET, VEGFR, PDGFR, and c-KIT. We conducted a phase II trial to evaluate the tolerability and efficacy of sunitinib in metastatic and/or recurrent SCCHN patients. METHODS: Patients who had received no more than two prior chemotherapy regimens were eligible and, depending on ECOG performance status (PS), were entered into either Cohort A (PS 0-1) or Cohort B (PS 2). Sunitinib was administered in 6-week cycles at 50 mg daily for 4 weeks followed by 2 weeks off. Primary endpoint for Cohort A was objective tumor response. A Simon two-stage design required twelve patients to be enrolled in the first stage and if 1 or fewer responses were observed, further study of this cohort would be terminated due to lack of treatment efficacy. Primary endpoint of Cohort B was to determine the feasibility of sunitinib in patients with ECOG performance status 2. RESULTS: Twenty-two patients were accrued (Cohort A - 15 patients, Cohort B - 7 patients). Median age in cohort A and B was 56 and 61 years, respectively. Grade 3 hematologic toxicities encountered were lymphopenia (18%), neutropenia (14%) and thrombocytopenia (5%). There was only one incidence of grade 4 hematologic toxicity which was thrombocytopenia. Fatigue and anorexia were the most common non-hematologic toxicities. Grade 3 fatigue occurred in 23% of patients. The only grade 4 non-hematologic toxicity was one incidence of gastrointestinal hemorrhage. Non-fatal hemorrhagic complications occurred in 8 patients: epistaxis (3 patients), pulmonary hemorrhage (2 patients), gastrointestinal hemorrhage (2 patients) and tumor hemorrhage (1 patient). Four patients were not evaluable for tumor response (Cohort A - 3patients, Cohort B - 1 pt). One partial response was observed in the entire study. Dose reduction was required in 5 patients (Cohort A - 3 patients for grd 3 fatigue, grd 3 mucositis and recurrent grd 3 neutropenia; Cohort B - 2 patients for grd 3 fatigue and grd 3 nausea). Median time to progression for cohort A and B were 8.4 and 10.5 weeks, respectively. Median overall survival for cohort A and B was 21 and 19 weeks, respectively. CONCLUSIONS: Sunitinib had low single agent activity in SCCHN necessitating early closure of cohort A at interim analysis. Sunitinib was well tolerated in PS 2 patients. Further evaluation of single agent sunitinib in head and neck is not supported by the results of this trial.

A phase II study of sunitinib in patients with locally advanced or metastatic cervical carcinoma: NCIC CTG Trial IND.184.

OBJECTIVE: Vascular endothethial growth factor (VEGF) and stem cell factor (c-KIT) signaling may play a role in the development and progression of cervical carcinoma. Sunitinib malate is an oral, multi-targeted tyrosine kinase inhibitor that inhibits receptors for VEGF, c-Kit and platelet-derived growth factor. This multi-centre phase II study was performed to evaluate the activity of sunitinib in women with locally advanced or metastatic cervical carcinoma who had received up to one prior line of chemotherapy for advanced disease. METHODS: Sunitinib, 50 mg/day, was administered in 6-week cycles (4 weeks on followed by 2 weeks off treatment). The primary endpoint was the objective response rate. RESULTS: Sixteen (84%) of 19 patients enrolled had stable disease (median duration 4.4 months, 2.3-17 months), but no objective response was observed. Median time to progression was 3.5 months (range, 2.7-7.0 months). Four patients had fistulae develop on study treatment and an additional patient developed a fistula 3.5 months after discontinuation of therapy. All five patients had received either prior chemoradiation or radiation. CONCLUSIONS: A higher rate of fistula formation (26.3%) was observed than would be expected and is of concern. Sunitinib has insufficient activity as a single agent in cervical cancer to warrant further investigation.

Paclitaxel plus oxaliplatin for recurrent or metastatic cervical cancer: a New York Cancer Consortium Study.

OBJECTIVE: Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and less toxic regimens are needed. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer, especially after prior cisplatin exposure, is disappointing, with a response rate of only 13%. Oxaliplatin has preclinical activity in cisplatin-resistant tumors and may have synergic activity when combined with paclitaxel. Our objective is to determine the efficacy and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer. METHODS: Patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible. Treatment consisted of paclitaxel 175 mg/m(2) IV and oxaliplatin 130 mg/m(2) IV every 21 days. The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria and were assessed every 9 weeks, with subsequent confirmation as required. Sample size determinations were made using a Simon's two-stage design with a projected overall response proportion of 13% with cisplatin alone. Survival rates were calculated with Kaplan-Meier methods. RESULTS: Of the 35 patients enrolled, 32 were evaluable. The median age was 56 (27-78); 30 had had prior radiation (23 concomitant with cisplatin). Patients completed a mean of 4.2 cycles (1-11). There were 2 complete and 5 partial responses for a total response rate of 7/32 (22%; 95% CI: 9.3%-40.0%). Eight patients had stable disease for an overall clinical benefit rate of 15/32 (47%; 95% CI: 29.1%-65.3%). The mean time to best response was 13.5 weeks (95% CI: 10.6, 16.4). The mean progression-free survival was 21 weeks (95% CI: 14.7, 27.2) and mean overall survival was 52 weeks (95% CI: 39.4, 64.8). A total of 135 cycles were administered. There were 28 (20.1%) grade 3/4 hematologic toxicities and 46 (34.1%) grade 3/4 non-hematologic toxicities, which were predominantly sensory neuropathy. There were 13 treatment delays, 4 dose reductions, and no treatment-related deaths. CONCLUSIONS: The combination of paclitaxel and oxaliplatin is an effective regimen in patients with recurrent or persistent cervical cancer including a majority previously exposed to cisplatin. Further study and comparison with other platinum-based regimens is warranted.

Novel designs and end points for phase II clinical trials.

The large number of negative phase III trials in oncology over the last several years has renewed interest in refining phase II oncology clinical trials to maximize the chances of success in phase III testing. More efficient phase II study designs will improve our ability to identify promising agents for testing while accurately identifying nonefficacious agents. Recognizing that new paradigms of phase II trial designs need to be developed, the Clinical Trial Design Task Force of the National Cancer Institute (NCI) Investigational Drug Steering Committee has tackled the question of improving efficiency of phase II clinical trials. In this issue of CCR Focus, four of the major topics discussed are presented. First, the task force recommended that alternate phase II end points should be studied. Second, depending on the characteristics of the specific trial and study population, historical controls or a randomized design may be more appropriate. Third, rational incorporation of biomarkers into phase II trials should be encouraged. Last, novel imaging modalities will be critical in evaluating the clinical benefit of new cytostatic agents.

Randomized phase II designs.

As the use of molecularly targeted agents, which are anticipated to increase overall survival (OS)and progression-free survival (PFS) but not necessarily tumor response, has increased in oncology, there has been a corresponding increase in the recommendation and use of randomized phase II designs. Such designs reduce the potential for bias, existent in comparisons with historical controls, but also substantially increase the sample size requirements. We review the principal statistical designs for historically controlled and randomized phase II trials, along with their advantages, disadvantages, and statistical design considerations. We review the arguments for and against the use of randomization in phase II studies, the situations in which the use of historical controls is preferred, and the situations in which the use of randomized designs is preferred. We review methods used to calculate predicted OS or PFS values from historical controls, adjusted so as to be appropriate for an experimental sample with particular prognostic characteristics. We show how adjustment of the type I and type II error bounds for randomized studies can facilitate the detection of appropriate target increases in median PFS or OS with sample sizes appropriate for phase II studies. Although there continue to be differences among investigators concerning the use of randomization versus historical controls in phase II trials, there is agreement that each approach will continue to be appropriate, and the optimal approach will depend upon the circumstances of the individual trial.

Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors.

PURPOSE: We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma. METHODS: This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy. RESULTS: Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m2 IV + AT7519 21 mg/m2 IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug. CONCLUSIONS: Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue.

Improving the quality of abstract reporting for phase I cancer trials.

PURPOSE: Conference abstracts of phase I trials (P1T) communicate important anticancer drug development information. Our objectives were to determine elements essential for good P1T abstract reporting, to assess the quality of P1T abstracts submitted to American Society of Clinical Oncology (ASCO) meetings, and to propose reporting guidelines. EXPERIMENTAL DESIGN: A survey of developmental therapeutics experts established elements of P1T reporting quality, and a scoring system was generated. All P1T abstracts published in ASCO Annual Proceedings from 1997 to 2006 were reviewed, and the scoring system was applied. RESULTS: A survey was distributed twice to 69 experts, with a response rate of 39% (27 of 69). Experts rated 37 elements using a five-point scale, and elements with mean ratings over 3.75 were included in the final scoring system. One thousand six hundred and eighty three P1T abstracts were reviewed. A positive and linear association was observed between average expert rating of the elements and the proportion of P1T abstracts including those elements (Spearman correlation coefficient, rho = 0.60, P < 0.001). The median for all 1,683 abstracts was 62.5% (range, 25-95%; SD, 12.3%). Year of presentation was found to be significantly associated with higher quality scores (rho = 0.20, P < 0.001), with later years possessing better quality scores. The quality score was statistically significant as a predictor of type of presentation (odds ratio, 1.10; 95% confidence interval, 1.02-1.19 per 10% increase; P = 0.014), with oral presentations having the highest scores. CONCLUSIONS: The quality of P1T abstract reporting at ASCO has improved over time, although there is room for optimization. The quality of P1T abstract reporting may be enhanced using guidelines derived from our expert consensus.