Objective Disease Progression Research Articles

Time to Second Objective Disease Progression (PFS2): An Emerging Clinical Trial Endpoint with Regulatory and Reimbursement Implications

Introduction: Overall survival (OS) continues to be the preferred endpoint for measuring sustained clinical benefits in oncology trials. In some cases, measuring OS can be problematical due to trial design, multiple lines of treatment (Tx), long survival times, and other factors. In this context, there is growing interest in the time to second objective disease progression (PFS2) for Txs with good toxicity profiles.The European Medicines Agency (EMA) recommends the use of PFS2 to help understand the relevance of meaningful improvements in PFS when OS cannot be measured (e.g. maintenance Tx, increased number of “induction” cycles) (EMA, 2012). PFS2 is defined as “time from randomisation to objective tumour progression on next-line treatment or death from any cause. In some cases, time on next-line therapy may be used as proxy for PFS.”PFS2 is likely to become an important endpoint for regulatory and reimbursement evaluations in Europe and elsewhere as a result of the recent EMA guidance. Therefore there is a need to optimally understand the role PFS2 is likely to play in clinical trial results and their application.Methods: We undertook a search on clinicaltrials.gov for cancer trials that include PFS2 as an endpoint (search terms: cancer AND PFS; cancer AND PFS2). Through mapping of drugs vs. other endpoints, stage of development, likely or current indications, and other factors, we considered whether PFS2 would have a role in a potentially new or changed indication and therefore in regulatory and health technology assessment (HTA) submissions. Based on this, we have identified critical areas where understanding and use of PFS2 data may pose challenges in the submission processes, from the perspectives of the clinical trial sponsor and regulatory agency.Results: As of July 2014, a total of 7,957 cancer trials list PFS as an endpoint; 14 of these include PFS2. In all cases, PFS2 is listed as a secondary endpoint. PFS is the primary endpoint in 13/14, with time to failure as the primary endpoint in 1 trial. OS is not a primary endpoint in any trial that lists PFS2, but is a secondary endpoint in 13 of the 14 trials. It is being studied in the context of either maintenance (10/14 trials) or sequential Tx (3/14) and has the potential for inclusion in regulatory and HTA submissions in all cases.The types of oncology trials in which PFS2 is being assessed included multiple myeloma (n = 3), prostate cancer (n = 2), breast cancer (n = 2), head and neck cancer (n = 1), colorectal cancer (n = 4), non-small cell lung cancer (n = 1), and pancreatic cancer (n = 1). There are 6 phase 2 and 8 phase 3 trials that are listed as either not yet recruiting (n = 4), ongoing (n = 4), or recruiting (n = 6).We identified a number of issues for key groups that may arise from the inclusion of PFS2 in clinical trials. For healthcare professionals there is a need to understand the clinical relevance of a new endpoint that may provide additional and complementary information on Tx of progressive disease from both medical and patient (pt) perspectives. For trial sponsors, clear and clinically relevant communication of PFS2 results is needed and data must be included in medical and economic models. Agencies evaluating regulatory or HTA submissions must understand the benefits shown by an improved PFS2, whether or not there is an improvement in OS, and methodologies for evaluating the medical and economic value of PFS2 are required.Restricting our search to clinicaltrials.gov was associated with some limitations. For example, some trials in which PFS2 has been measured could have been missed due to ongoing updates to publically available information. Also, in some cases, post-hoc analyses may have evaluated PFS2 without a change to website details. Trials in which PFS2 has been measured and data published were not part of the search strategy.Conclusions: PFS2 is emerging as a secondary endpoint in a growing number of clinical oncology trials assessing the benefits of maintenance or sequential Tx. Although data are currently limited, the results of trials currently listed on clinicaltrials.gov will help to determine how PFS2 provides additional and complementary information about Tx of progressive disease from both medical and pt perspectives. DisclosuresMbanya:PHMR Associates: Consultancy. Chadda:PHMR Associates: Consultancy.

Activity and safety of sunitinib in patients with advanced radioactive iodine-refractory differentiated thyroid carcinoma in clinical practice

Our aim was to evaluate the effectiveness of off-label use of sunitinib in patients with advanced differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) therapy. We performed a retrospective analysis of patients treated in the setting of clinical practice in a University General Hospital. Eleven consecutive patients (5 women, 6 men, mean age 63.0±12.9year) with advanced papillary (n=7) or follicular (n=4) thyroid carcinoma not suitable for curative surgery or RAI therapy were studied. Two patients were treated with one line of tyrosine kinase inhibitors before sunitinib therapy. All patients had evidence of objective progressive disease (PD). We analysed the objective response rate (ORR) and changes in thyroglobulin levels during therapy. Complete response was achieved in 1 patient (9%) and partial response (PR) in 2 patients (18%). Five patients (45%) had stable disease (SD). Therefore, ORR was 27% and disease control rate was 72%. We found that the decrement in thyroglobulin concentrations was significantly higher in patients with radiological disease control than in patients with PD. Most frequent grade 1 and 2 adverse events were fatigue, mucositis, hand-and-foot syndrome, hyporexia, rash, hypertension, and edema. In routine clinical practice, sunitinib appears to be effective and feasible in patients with advanced RAI-refractory DTC. Most patients achieved SD or PR, despite having PD at the start of treatment, and safety profile was consistent with that reported in previous clinical trials.

Lenalidomide and Rituximab For The Treatment Of Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results Of Planned Interim Analysis

Based on data previously presented by our group demonstrating the safety and efficacy of lenalidomide (L) and rituximab (R) in the upfront setting, we are conducting an open-label, phase 2 trial single center trial to evaluate this combination as treatment for patients with relapsed or refractory CLL. MethodsPatients started L at 5 mg per day and could escalate to 25 mg/day if tolerated. Patients received L for 21 of 35 days for cycle 1, then 21 of 28 days for cycles 2 to 7. Rituximab was started at the end of C1 at 50 mg/m2 on Day 29, 325 mg/m2 on day 31 and 33, then 375mg/m2 weekly x4 for cycle 2, and on day 1 for cycles 3-7. Patients who achieved a response but had residual disease after 7 cycles were given the option to continue single-agent L in a consolidative manner for 6 additional cycles. All patients received allopurinol 300mg daily and aspirin 81mg daily, unless contraindicated. The primary endpoint was overall response rate by iwCLL guidelines following 7 cycles. This abstract reports on the planned interim analysis of the safety and efficacy. ResultsBy April 2013, 24 patients were enrolled and received treatment. 63% of patients were male (15/24). The median age at the start of study treatment was 67 years (range 53-83), with median 2.5 prior therapies (range 1-7). 75% (18/24) had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 25% (6/24) had unfavorable cytogenetics (del 17p or del 11q).5 patients stopped therapy early due to toxicity. 2 patients stopped treatment due to grade 3 tumor flare reaction. 1 patient developed grade 4 tumor lysis requiring hemodialysis. 1 patient had grade 4 neutropenia within days of starting L. 1 patient developed a deep vein thrombosis during cycle 2 while off aspirin for transient thrombocytopenia. These patients tended to have a higher baseline absolute lymphocyte count, but this association did not meet statistical significance. Treatment was otherwise well tolerated. Neutropenia was the most common adverse event (AE), with grade 4 (by CTCAE 4) in 9 patients, and grade 3 in 6 patients out of 21 evaluable patients. There was a single instance of grade 4 thrombocytopenia, and 4 patients had grade 3 thrombocytopenia. 3 patients had grade 3 anemia. The only other grade 3 or higher AE was fatigue (5%). Of note, grade 2 superficial thrombophlebitis occurred in 3 patients.Out of the 20 patients whose primary endpoints were assessed, the overall response rate (ORR) was 70% (14/20) with 15% nodular partial response (3 patients) and 55% partial response (PR) (11 patients). 30% (6/20) were non-responders (NR). Only 1 of the 6 patients with NR had objective progressive disease (PD). The other 5 patients stopped treatment early due to toxicity and were designed as non-responders. Of the responder patients, 8 elected to receive an additional 6 months of consolidation lenalidomide. All maintained the same response without meeting objective criteria for either PD or complete response. After a median follow-up of 17 months from the start of treatment, there have been no deaths among the 24 patients. For the 20 evaluable patients, the median progression free survival (PFS) was 18.4 months and the median treatment free survival was 13.5 months.We did not find any significant association between response, toxicity, or PFS and any demographic or prognostic variable analyzed, including age, ZAP-70, IgVH mutation, cytogenetics, splenomegaly, or CLL cell immunophenotype. ConclusionsThe combination of lenalidomide and rituximab is an effective regimen for the treatment of patients with relapsed or refractory CLL with an ORR and PFS that rivals novel CLL therapies, especially for patients continued on lenalidomide consolidation therapy. The median PFS for all patients is in excess of 1.5 years after a median follow-up of 17 months. A subset of patients encountered adverse events requiring early treatment cessation, but only 1 patient progressed on treatment. Continued accrual will facilitate the identification of biologic or clinical factors that may predict such outcomes. Disclosures:Choi:Celgene: Research Funding. Castro:Celgene: Research Funding. Kipps:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

PFS2 In Elderly Patients With Newly Diagnosed Multiple Myeloma (NDMM): Results From The MM-015 Study

IntroductionIn a phase 3 trial of transplant non-eligible elderly (≥ 65 yrs) patients (pts) with NDMM, the combination of melphalan-prednisone-lenalidomide (LEN) followed by LEN maintenance (MPR-R) reduced the risk of progression by 60% compared with 9 cycles of MP (HR=0.40; P < 0.001) and by 51% compared with 9 cycles of MPR (HR=0.49; P < 0.001) (Palumbo, NEJM. 2012). The progression-free survival (PFS) benefit was seen in all patient types. With a median follow-up of 53 mos, the median overall survival (OS) was similar across the 3 treatment (Tx) groups (54 mos for MPR-R vs. 52 mos for MPR vs. 55 mos for MP) (Dimopoulos, ASH 2012; abstract 944). The similar OS benefit seen across the 3 arms could be due in part to the availability of more effective Tx options in subsequent lines of therapy. Assessment of PFS2, defined as the time from initial randomization to time of objective disease progression (PD) after next-line of therapy or death from any cause, has recently been proposed as a surrogate for OS, particularly for trials evaluating maintenance Tx (EMA guideline, www.ema.europa.eu). Therefore, data from MM-015 were analyzed to estimate PFS2 in pts treated with MPR-R, MPR, or MP. MethodsThe MM-015 study design has been previously described (Palumbo, NEJM. 2012). Refractory multiple myeloma pts who progressed during MM-015 study could receive LEN 25 mg (D1–21/28-day cycle) ± dexamethasone 40 mg (on days 1–4, 9–12, and 17–20) as part of an open-label extension phase, or any other anti-myeloma Tx outside of the protocol as part of the follow-up phase. The data of PD following 2nd-line Tx was not collected prospectively; therefore, the start of 3rd-line Tx was used as a surrogate for analyzing the PFS2 endpoint. The assessment included data up to July 31, 2012 (median follow-up: 53 mos after initial randomization). ResultsA total of 459 pts were randomized to MPR-R (n= 152), MPR (n= 153), or MP (n= 154). At the time of the data cut-off, fewer pts in the MPR-R group had started 2nd-line Tx (53%) compared with the MPR and MP groups (77% and 82%, respectively) due to the improved PFS seen with MPR-R in the 1st-line setting. Most pts in the MP group “crossed over” to receive LEN as 2nd-line Tx (72%); choice of 2nd-line Tx in the MPR-R group was heterogeneous (Table). Median PFS2 was significantly higher with MPR-R (39.7 mos) vs. MP (28.5 mos; HR=0.71; log-rank P = 0.013) (Figure). The safety profile of continuous therapy with LEN was predictable and manageable with little evidence of cumulative toxicity and low second primary malignancy risk (Delforge, IMW 2013: abstract O-17). [Display omitted] ConclusionPFS2 was markedly improved in the MPR-R group vs. the MP group. LEN provided a durable progression-free interval also when including the impact of 2nd-line Tx, confirming the clinical benefits of continuous LEN Tx. The benefit of MPR-R was apparent regardless of subsequent Tx; long-term treatment with LEN did not affect the efficacy of subsequent therapy. Use of continuous LEN in the 1st-line setting in combination with MP is more beneficial than sequential use of MP and LEN. PFS and PFS2 were improved with MPR-R; OS was similar among the 3 Tx groups; the reason for this is unclear, but may be related to the impact of subsequent Tx (i.e., 3rd and 4th line), which was more frequently needed in the MPR and MP groups. Disclosures:Dimopoulos:Orthobiotech: Honoraria; Celgene Corporation: Honoraria. Off Label Use: Lenalidomide in the frontline and maintenance treatment of multiple myeloma. Petrucci:Celgene Corporation: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Catalano:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yu:Celgene Corporation: Employment, Equity Ownership. Grote:Celgene Corporation: Employment, Equity Ownership. Jacques:Celgene Corporation: Employment, Equity Ownership. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naïve castration-resistant prostate cancer

Background:The mammalian target of rapamycin (mTOR) pathway is deregulated in castration-resistant prostate cancer (CRPC). We investigated the efficacy and toxicity of temsirolimus, an mTOR inhibitor, in chemotherapy-naïve CRPC.Methods:In this phase II open label study, eligible patients received IV temsirolimus at 25 mg weekly until objective disease progression, unacceptable toxicity or investigator's discretion. Toxicity was assessed every 4 weeks and responses every 8 weeks. Primary end point was calculating the overall response (OR) rate as well as measuring stable disease (SD) to assess the overall clinical benefit calculated as OR+SD. Secondary end points included prostatic-specific antigen (PSA) changes and time to progression biochemically and radiographically. Correlative studies included prospective assessment of quality of life (QoL) using two previously validated scales.Results:Although the sponsor halted the study early, 21 patients were enrolled of which, 15 were evaluable for efficacy and OR. Median age was 74 (range: 57–89), median PSA was 237.5 ng ml−1 (range: 8.2–2360), visceral disease present in 11 patients (52%), and 17 patients (81%) patients had Gleason score (7–10). Two patients had a partial response (PR) and eight had SD. The OR was 13% (2/15) and the overall clinical benefit (OR+SD) was 67% (10/15). Median time to radiographic disease progression was 2 months (range 2–10 months). Biochemical response assessment was available for 14/15 patients. Any PSA decline was observed in four patients (28.5% 4/14) with one patient (7%) having >50% PSA decline. Median time to progression by PSA was 2 months (range 1–10 months). With a median follow-up of 32 months, median overall survival (OS) was 13 months (range: 2–37) and three patients remain alive at the data cutoff (5/2013) for an OS of 14% at 4 years on an intent-to-treat analysis. Major non-haematologic toxicities included fatigue (19%) and pneumonia (14%). Main laboratory toxicities included hyperglycaemia (24%) and hypophosphatemia (14%). Also, 52% of enrolled patients had serious adverse events. Other toxicities were consistent with previously reported adverse events with temsirolimus. Despite these observed adverse events, temsirolimus did not adversely impact QoL.Conclusion:Temsirolimus monotherapy has minimal activity in chemotherapy-naïve CRPC.

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12 Years of Follow-up

BackgroundTrials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization. ObjectiveBased on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences. Design, setting, and participantsEORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0–4 N0–2 M0 PCa patients. Outcome measurements and statistical analysisTime to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival. Results and limitationsAfter a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3–5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05–1.39; p [noninferiority]=0.72, p [difference] = 0.0085). ConclusionsThis study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease.

Low doses of ketoconazole and prednisone in patients with castration resistant prostate cancer (CRPC): A retrospective study on 73 patients.

e16099 Background: The management of rising PSA in metastatic CRPC remains controversial. In Italy, abiraterone and enzalutamide are not at all approved in this setting of patients (pts). Ketoconazole is an inhibitor of adrenal androgen synthesis that has shown anti-tumor activity by interfering with C-17,20-lyase and could be used as secondary hormonal manipulation. In this retrospective study we report our experience with low doses of ketoconazole and prednisone in the treatment for CRPC. Methods: From March 2007 to March 2012, 73 pts with progressive CRPC who were previously treated with maximal androgen blockade received 200 mg ketoconazole orally 2 times daily, orally replacement prednisone (5 mg bid) and maintained LHRH-agonists. Overall, 40/73 (55%) pts had only bone metastases, 13/73 (18%) had nodal metastases, 20/73 (27%) both. Pts were monitored clinically and with serial PSA measurements every month. Partial biochemical response (PR) was defined as a &gt;50% fall in PSA from baseline. Progressive disease (PD) was defined by objective disease progression or PSA increase of &gt;50% above nadir or &gt;25% above baseline. The endpoints of the study were biochemical response (BR), progression free survival (PFS), overall survival (OS) and adverse events assessment. Results: Median age was 74 (70-78) years; median baseline PSA was 33.09 (1.18-1348.8) ng/ml; median duration of the treatment was 5.05 (0-56.8) months. Twenty out 73 pts (27%) showed a decrease in PSA &gt;50%, with a median duration of PSA response of 3.56 (1.17-33.58) months and 3 pts (4%) a PD. Fifty out 73 pts (68%) achieved a SD with an overall disease control (PR+SD) of 85%. PFS was 10 months for pts who achieved PR and 4 months for those with SD. Differences in PFS stratified according to site of metastases showed better prognosis in patients with only lymph nodes disease (p&lt;0.05). Treatment with Ketoconazole was well tolerated and grades 3-4 toxicities occurred in only 3% of patients. Conclusions: Low-dose ketoconazole is an effective and well-tolerated treatment in pts with CRPC and should be considered in the subset of pts with low tumor burden and a rising PSA level despite maximal androgen blockade.

Relationship of sipuleucel-T with time to first use of opioid analgesics (TFOA) in patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) on the IMPACT trial.

74 Background: Sipuleucel-T (sip-T) is an autologous cellular immunotherapy which was shown to prolong survival in pts with mCRPC in the pivotal IMPACT trial (NCT00065442) (Kantoff PW et al. N Engl J Med 2010;363:411-22). TFOA was a prespecified secondary end point but was subsequently removed as an end point following a protocol amendment to expand enrollment to include minimally symptomatic pts in addition to asymptomatic pts. TFOA data were nevertheless collected in the 512 pts enrolled in the trial. Methods: At baseline, pts were required to have an average pain score &lt;4 on a 10-point visual analog scale and no ongoing opioid analgesic use (OAU). Concomitant medications were collected until confirmed objective disease progression. OAU was identified by medical review of preferred drug names in the coded concomitant medication information on case report forms (CRFs). OAU unrelated to cancer pain (e.g. meperidine used for infusion reactions) was excluded by medical review of CRFs. Pts not reporting OAU were censored at the time of protocol amendment. TFOA was analyzed using a Cox regression model with adjustment for baseline PSA and LDH. Results: 341 sip-T- and 171 placebo-treated patients were evaluated. Median TFOA was 11.9 months (mo) with sip-T vs 8.3 mo for placebo (hazard ratio=0.727; 95% confidence interval 0.536, 0.987; p=0.041). Censoring rate was high (sip-T, 66.9%; placebo, 61.4%). Median follow-up for OAU was 5.2 mo (sip-T, 5.3 mo; placebo, 5.0 mo). Kaplan-Meier estimates of being opioid free at 12 mo were 48.7% for sip-T vs 39.7% for placebo; curve separation began at 6 mo. Significant independent baseline predictors of shorter TFOA were: higher PSA, alkaline phosphatase; younger age; higher number of bone metastases; Gleason score ≥8; ECOG performance status 1; higher weight; and prior primary radiotherapy. Conclusions: Relative to placebo, sip-T delays the TFOA in patients with asymptomatic or minimally symptomatic mCRPC. Clinical trial information: NCT00065442.

Efficacy of Exemestane in Korean Patients with Metastatic Breast Cancer after Failure of Nonsteroidal Aromatase Inhibitors

PurposeExemestane has shown good efficacy and tolerability in postmenopausal women with hormone receptor-positive metastatic breast cancer. However, clinical outcomes in Korean patients have not yet been reported.MethodsData on 112 postmenopausal women with metastatic breast cancer were obtained retrospectively. Clinicopathological characteristics and treatment history were extracted from medical records. All patients received 25 mg exemestane daily until objective disease progression. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR=complete response+partial response+stable disease for 6 months).ResultsThe median age of the subjects was 55 years (range, 28-76 years). Exemestane treatment resulted in a median PFS of 5.7 months (95% confidence interval [CI], 4.4-7.0 months) and median OS of 21.9 months (95% CI, 13.6-30.3 months). ORR was 6.4% and CBR was 46.4% for the 110 patients with evaluable lesions. Symptomatic visceral disease was independently associated with shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001), compared with bone-dominant disease in a multivariate analysis of PFS after adjusting for age, hormone receptor, human epidermal growth factor receptor 2, Ki-67 status, dominant metastasis site, and sensitivity to nonsteroidal aromatase inhibitor (AI) treatment. Sensitivity to previous nonsteroidal AI treatment was not associated with PFS, suggesting no cross-resistance between exemestane and nonsteroidal AIs.ConclusionExemestane was effective in postmenopausal Korean women with hormone receptor-positive metastatic breast cancer who failed previous nonsteroidal AI treatment.

Open-label phase III randomized controlled trial comparing taxane-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+ metastatic breast cancer: Interim analysis (IA) of NCIC CTG MA.31/GSK EGF 108919.

LBA671 Background: The relative efficacy of L vs T when combined with Tax chemotherapy in the first-line setting of metastatic breast cancer (BC) is unknown. Methods: MA.31 compares Tax-based therapy, paclitaxel 80mg/m2 wkly or docetaxel 75mg/m2 3 wkly for 24 wks in combination with L or T. The L dose was 1,250 mg po daily with Tax followed by 1,500 mg daily (LTax/L). After a loading dose, the T dose was 2 mg/kg wkly or 6 mg/kg 3 wkly + Tax followed by T 6 mg/kg 3 wkly (TTax/T). Stratification was by prior neo/adjuvant HER2 therapy, prior neo/adjuvant Tax, planned Tax (paclitaxel vs docetaxel), and liver metastases. The primary endpoint is ITT progression-free survival (PFS), defined as time from randomization to objective progressive disease based on RECIST criteria or death from any cause. The protocol-specified IA was performed after observing 333 PFS events; the trial was to stop if the 2-sided p-value from the stratified log-rank test was less than 0.03. The NCIC CTG’s independent DSMC reviewed IA results and recommended disclosure because the superiority boundary was crossed. A secondary analysis utilized central laboratory-confirmed HER2 + status. Results: Between July 17 2008 and Dec 1 2011, 652 pts were accrued. Data from 636 pts (525 HER2 centrally confirmed) were included in the IA with clinical cutoff date of Nov 7 2011 and database lock of Apr 13 2012. Median follow-up was 13.6 mos, 12.9 mos for LTax/L pts and 14.0 mos for TTax/T patients. In the ITT analysis, PFS was inferior with LTax/L compared to TTax/T hazard ratio (HR) =1.33; 95% CI 1.06-1.67; p=0.01. LTax/L had median PFS 8.8 mos (95% CI 8.3-10.6) compared to TTax/T 11.4 mos (95% CI 10.8-13.7). PFS in the centrally confirmed HER2+ had HR 1.48 (95%CI 1.15-1.92; p=0.003) (LTax/L to TTax/T). No difference in overall survival was detected (LTax/L to TTax/T) HR= 1.1 (95% CI 0.75-1.61; p=0.62). More grade 3-4 diarrhea and rash was observed with LTax/L (p&lt;0.001). Conclusions: LTax/L therapy is associated with a shorter PFS compared to TTax/T as first line therapy for HER2+ metastatic BC. ClinicalTrials.gov: NCT00667251. CCSRI grant: 021039. Supported by GlaxoSmithKline.

Efficacy of low-dose ketoconazole in the treatment of castration-resistant prostate cancer (CRPC): A single-institution experience.

e15133 Background: The management of rising PSA in CRPC remains controversial. Secondary hormonal manipulations are commonly used before starting chemotherapy. Ketoconazole, an antimycotic that affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer. This retrospective study describes our experience with low doses of ketoconazole and prednisone treatment for CRPC. Methods: From 4/2007 to 12/2011, 65 patients with progressive CRPC who were previously treated with maximal androgen blockade received 200 mg ketoconazole orally bid with orally replacement prednisone (5 mg bid) and maintained LHRH-agonists. Performance status of all patients was ECOG0. Overall, 34/65 (52.3%) patients had only bone metastases, 12/65 (18.5%) had nodal metastases, 17/65 (26.2%) both and only 2/65 (3.1%) had bone plus lung mets. All patients had low tumor burden and PSADT &gt;6 months. Thirty-six out of 53 patients with bone mets received concomitant zoledronic acid. PSA response was defined as a &gt;50% fall in PSA from baseline and PSA nadir was calculated. Progression was defined by objective disease progression or PSA increase of &gt;50% above nadir or &gt;25% above baseline. Patients were monitored clinically and with serial PSA measurements every 1-month. Results: Median age was 74.05 (range: 52.8-84.4) years; median baseline PSA was 29.95 (range: 1.18-1348.8) ng/ml; median duration of the treatment was 5.87 (range: 0.57-52.4) months. All pts were evaluable for PSA response. At a median F.U.of 15.4 mos. 19/65 patients (29.2%) showed a decrease in PSA &gt;50%, with a median TTP of 17.23 mos for responders. Overall TTP was 5.86 mos and it was not affected by metastatic sites (p= 0.71).Toxicity was mild and no patients discontinued therapy because of side-effects. Five out of 65 patients had G2 (CTC.AE 4) nausea and moderate elevated transaminases. No acute hepatitis or adrenal insufficiency was observed. Conclusions: Our data confirm that low-dose ketoconazole is an effective and well-tolerated treatment in patients with CRPC and should be considered in the subset of patients with low-volume disease and a rising PSA level despite maximal androgen blockade.

683 ESTIMATING THE OVERALL SURVIVAL BENEFIT OF SIPULEUCEL-T IN THE IMPACT TRIAL ACCOUNTING FOR CROSSOVER TREATMENT IN CONTROL SUBJECTS WITH AUTOLOGOUS IMMUNOTHERAPY GENERATED FROM CYROPRESERVED CELLS

You have accessJournal of UrologyProstate Cancer: Advanced I1 Apr 2012683 ESTIMATING THE OVERALL SURVIVAL BENEFIT OF SIPULEUCEL-T IN THE IMPACT TRIAL ACCOUNTING FOR CROSSOVER TREATMENT IN CONTROL SUBJECTS WITH AUTOLOGOUS IMMUNOTHERAPY GENERATED FROM CYROPRESERVED CELLS Leonard Gomella, Chadi Nabhan, Todd DeVries, James Whitmore, Mark Frohlich, and Daniel George Leonard GomellaLeonard Gomella Philadelphia, PA More articles by this author , Chadi NabhanChadi Nabhan Park Ridge, IL More articles by this author , Todd DeVriesTodd DeVries Seattle, WA More articles by this author , James WhitmoreJames Whitmore Seattle, WA More articles by this author , Mark FrohlichMark Frohlich Seattle, WA More articles by this author , and Daniel GeorgeDaniel George Durham, NC More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.765AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sipuleucel-T, an autologous cellular immunotherapy produced from each patient's freshly isolated immune cells, is approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. In the pivotal IMPACT trial, control subjects who demonstrated objective disease progression were offered 3 infusions of an autologous cellular therapy (APC8015F) produced from cells frozen at the time of control product generation. An exploratory analysis was performed to estimate how APC8015F impacted the overall survival (OS) benefit of sipuleucel-T in the IMPACT study. METHODS A rank-preserving structural failure time (RPSFT) model was applied to account for the effect of APC8015F and to estimate the treatment effect of sipuleucel-T relative to control had no crossover to APC8015F occurred. RESULTS In the IMPACT study (n=512), there was a 4.1-month improvement in median OS (25.8 vs. 21.7 months) for sipuleucel-T compared with control (HR=0.78; 95% CI: 0.61, 0.98; p=0.032). 109/171 (64%) of control patients received APC8015F; other post-progression interventions were similar. The frequency of acute infusion toxicities was greater following APC8015F than control, but lower than sipuleucel-T. Median OS was 23.8 months for control patients receiving APC8015F and 11.6 months for patients not receiving APC8015F. Median APC8015F cumulative CD54 upregulation, a measure of APC activation, was 22.2 and was similar to the 28.7-fold increase with sipuleucel-T. Controlling for some of the known prognostic factors at the time of progression, the treatment effect persists, suggesting APC8015F may have extended survival of control subjects. Using the RPSFT model, and assuming APC8015F was equally as effective as sipuleucel-T, the estimate of median OS for control would be 18.0 months, representing a 7.8 month improvement in median OS in favor of sipuleucel-T (HR=0.60, 95% CI: 0.41, 0.96). Results from the RPSFT model that assumed a lesser treatment effect of APC8015F will be presented. CONCLUSIONS Post-progression treatment with APC8015F may have extended the survival of control subjects in the IMPACT study. Adjusting for use of APC8015F resulted in an increase in median OS benefit with sipuleucel-T of up to 7.8 months. These results suggest a greater treatment effect of sipuleucel-T than reported in IMPACT, and should be factored into future studies without APC8015F crossover. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e278-e279 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Leonard Gomella Philadelphia, PA More articles by this author Chadi Nabhan Park Ridge, IL More articles by this author Todd DeVries Seattle, WA More articles by this author James Whitmore Seattle, WA More articles by this author Mark Frohlich Seattle, WA More articles by this author Daniel George Durham, NC More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study.

144 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Our previous analyses on the effect of salvage crossover treatment with a product constructed from previously frozen cells (APC8015F) on OS in the control arms of mCRPC studies of sipuleucel-T suggested a positive treatment effect with salvage therapy (George DJ et al. JCO 2011;29:abstr 139). To quantify how treatment with APC8015F might have impacted the OS of the IMPACT study, we performed an exploratory analysis adjusting for the potential bias that salvage APC8015F might have had in estimating the OS advantage of sipuleucel-T. Methods: After objective disease progression, patients (pts) in the control arm were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. A rank-preserving structural failure time (RPSFT) model, as previously described, was applied to adjust the sipuleucel-T treatment effect. Results: In the 512-pt IMPACT study, there was a 4.1-month median improvement in OS (25.8 vs 21.7 months) for sipuleucel-T compared to control (HR=0.78; 95% CI: 0.61, 0.98; p=0.032). 109/171 (64%) of control pts received APC8015F; other post-progression interventions were balanced. Median OS was 23.8 months for control pts receiving APC8015F and 11.6 months for control pts not receiving APC8015F. Using the RPSFT model, and assuming APC8015F was equally as effective as sipuleucel-T, the estimate of median OS for control was 18.0 months (HR=0.60, 95% CI: 0.41, 0.95), representing a 7.8-month median improvement in OS in favor of sipuleucel-T. Results from extensions of the RPFST model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: Adjusting for a positive effect of APC8015F in the control arm resulted in a sipuleucel-T OS treatment benefit in the IMPACT study ranging from 4.1 to 7.8 months. These results support a greater treatment effect of sipuleucel-T than reported in the IMPACT study and should be factored into future studies without APC8015F crossover.

Long-Term Follow-Up Result of Hydroxyurea Chemotherapy for Recurrent Meningiomas

ObjectiveMeningiomas represent 18-20% of all intracranial tumors and have a 20-50% 10-year recurrence rate, despite aggressive surgery and irradiation. Hydroxyurea, an inhibitor of ribonucleotide reductase, is known to inhibit meningioma cells by induction of apoptosis. We report the long-term follow-up result of hydroxyurea therapy in the patients with recurrent meningiomas.MethodsThirteen patients with recurrent WHO grade I or II meningioma were treated with hydroxyurea (1000 mg/m2/day orally divided twice per day) from June 1998 to February 2012. Nine female and 4 male, ranging in age from 32 to 83 years (median age 61.7 years), were included. Follow-up assessment included physical examination, computed tomography, and magnetic resonance imaging (MRI). Standard neuro-oncological response criteria (Macdonald criteria) were used to evaluate the follow-up MRI scans. The treatment was continued until there was objective disease progression or onset of unmanageable toxicity.ResultsTen of the 13 patients (76.9%) showed stable disease after treatment, with time to progression ranging from 8 to 128 months (median 72.4 months; 6 patients still accruing time). However, there was no complete response or partial response in any patients. Three patients had progressive disease after 88, 89, 36 months, respectively. There was no severe (Grade III-IV) blood systemic disorders and no episodes of non-hematological side effects.ConclusionThis study showed that hydroxyurea is a modestly active agent against recurrent meningiomas and can induce long-term stabilization of disease in some patients. We think that hydroxyurea treatment is well tolerated and convenient, and could be considered as an alternative treatment option in patients with recurrent meningiomas prior to reoperation or radiotherapy.

Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial

There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).

Sipuleucel-T in Metastatic Castration-Resistant Prostate Cancer†

Sipuleucel-T is an autologous active cellular immunotherapy used in the treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). It is the first therapeutic cancer vaccine to receive US FDA approval. Approximately 3 days prior to each infusion of sipuleucel-T, patients undergo a leukapheresis procedure for collection of autologous peripheral blood mononuclear cells. Preparation of sipuleucel-T involves enrichment for antigen-presenting cells from the leukapheresis product and activation ex vivo with a recombinant fusion protein (PA2024). In the randomized, double-blind, placebo-controlled IMPACT study in patients with metastatic CRPC, sipuleucel-T was associated with a 22% relative reduction in the risk of death (hazard ratio 0.78; p = 0.03), which was the primary endpoint of the trial. After a median follow-up period of 34.1 months, median survival was 4.1 months longer with sipuleucel-T than placebo (25.8 vs 21.7 months). There was no significant between-group difference for the median time to objective disease progression (a secondary endpoint). Almost all patients treated with sipuleucel-T in clinical trials reported an adverse event, although these were mild or moderate in severity (grade 1 or 2) in most patients. The most common adverse events (e.g. infusion-related events, such as chills and fever) generally occurred within the first day after administration of sipuleucel-T and resolved within 2 days.

Sipuleucel-T : un vaccin contre le cancer de la prostate : « mode d’emploi » pour les urologues

Sipuleucel-T is the first approved vaccine for prostate cancer, opening the pathway for this new treatment approach. The treatment process consists in isolating the patient dentritic cells via leukapherisis, stimulate and infuse them into the patient. These enhanced cells are then able to stimulate patient T lymphocytes to target the tumour cells. The median survival in the pivotal study, IMPACT, as well as in the previously reported randomised trials, was 4.1 months longer in the sipuleucel-T group. The estimated probability of survival 36 months after randomisation was 31.7% in the sipuleucel-T group and 23.0% in the placebo group. However, the median time to objective disease progression was similar in the two groups (hazard ratio: 0.95; 95% CI, 0.77 to 1.17; P=0.63). We report herein, the treatment modalities, side effects and results in the light of recently published randomised trials.

Post-progression treatment with APC8015F may have prolonged survival of subjects in the control arm of sipuleucel-T phase III studies.

4534 Background: Sipuleucel-T is an autologous cellular immunotherapy approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Methods: After disease progression, subjects in the control arms of 3 randomized controlled trials (RCT) of sipuleucel-T were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. Results: 165/249 (66.3%) of the control group received APC8015F. Median time from randomization to first APC8015F infusion was 5.2 months (range 1.8 to 33.1), and from objective disease progression to first infusion was 2.2 months (range 0.5 to 14.6). 145 subjects (87.9%) received all 3 infusions. APC8015F-treated subjects had improved post-progression survival relative to untreated controls (HR = 0.52 [95% CI: 0.37, 0.73]; unadjusted Cox regression; P = 0.0001, log rank test), with median survival times of 20.0 and 9.8 months, respectively. APC...

Treatment with olaparib in a patient with PTEN-deficient endometrioid endometrial cancer

A 58-year-old woman presented with metastatic endometrioid endometrial adenocarcinoma after being previously treated with surgery and adjuvant radiotherapy for early-stage endometrial cancer. She had received several lines of chemotherapy for multiple relapses over 9 years and displayed a profound sensitivity to platinum-containing regimens. CT scans demonstrated progressing liver, lung and peritoneal metastases and MRI detected multiple intracerebral metastases. New brain metastases secondary to progressive endometrioid endometrial carcinoma. On the basis of her sensitivity to repeated platinum treatment she was treated with the oral poly(ADP)-ribose polymerase (PARP) 1 inhibitor olaparib as part of a phase I trial. Repeat MRI scan at week 10 of treatment showed a significant reduction in the size of the brain metastases without steroid treatment or radiotherapy and the patient reported subjective improvement in tumor-related symptoms. After 8 months of olaparib treatment the patient developed objective disease progression. The tumor biopsy was negative for somatic BRCA1 and BRCA2 mutations, but displayed loss of PTEN, which has been suggested to be another predictive marker for sensitivity to PARP inhibitors. The patient remained alive for 10 months after completing olaparib, having gone on to derive further clinical benefit from repeat exposure to platinum-based therapy.

Subsequent treatment with APC8015F and its effect on survival in the control arm of phase III sipuleucel-t studies.

139 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for metastatic castrate resistant prostate cancer. Methods: After disease progression, subjects in the control arms of 3 randomized controlled sipuleucel-T trials were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. Results: Of 249 control subjects, 165 (66.3%) received APC8015F; the median time from randomization to first infusion was 5.2 months (range 1.8 to 33.1), median time from objective disease progression to first APC8015F infusion was 2.2 months (range 0.5 to 14.6), and 145 subjects (87.9%) received all 3 infusions. The frequency of infusional toxicities was increased following APC8015F relative to control infusion, but was slightly lower than following sipuleucel-T. APC8015F-treated subjects (n=155) had improved post-progression survival relative to untreated controls (n=61) (HR=0.52 [95%CI 0.37, 0.73] p=0.0001, log rank test, unadjusted Cox regression); however, APC8015F-treated subjects had more favorable prognostic features than untreated controls. A Cox regression analysis adjusting for baseline PSA and LDH demonstrated that APC8015F therapy remained a predictor of survival in control subjects (HR=0.56 [95%CI 0.40, 0.80]; p=0.001). A Cox regression model adjusting for age, PSA, LDH and post-randomization docetaxel use (yes/no), also showed a significant effect for salvage treatment among control subjects (HR=0.55 [95%CI 0.39, 0.78] p&lt;0.001). Examination of APC8015F product characteristics demonstrated that cumulative CD54 upregulation was associated with survival following first infusion in subjects who progressed and received APC8015F (p=0.03), consistent with previous reports of correlations between sipuleucel-T product parameters and overall survival. Conclusions: Although confounded with measured and unmeasured factors influencing outcome, these analyses suggest that post-progression treatment with APC8015F may have extended the survival of subjects in the control arms of these studies. [Table: see text]