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ASCO and FDA to Help Patients Access Investigational Therapies
Elsevier Global Medical News. 2010 Jun 4, R Hyer

CHICAGO (EGMN) - A new online resource will help seriously ill patients and their physicians request expanded access to investigational therapies when they have exhausted all other treatment options and the patients are not eligible for a clinical trial, it was announced June 4 at a joint news conference of the American Society of Clinical Oncology and the Food and Drug Administration.

"Most clinical trials have quite stringent eligibility criteria, and many patients are not eligible to enroll," said ASCO President-Elect George W. Sledge Jr., of Indiana University Simon Cancer Center, Indianapolis.

"In those instances when preliminary scientific evidence suggests that treatment with an unapproved therapy might be beneficial, the FDA's expanded access regulations allow physicians to request access to an investigational agent, outside of the clinical trial setting, for seriously ill patients," he said.
Expanded access has been allowed since the 1970s, but many physicians have been uncertain about how to request it, what regulations apply, and the legal ramifications. All of these issues are clarified in the new Web site.

"It's been clear to the agency that there was room for progress," said FDA Principal Deputy Commissioner Dr. Joshua M. Sharfstein, addressing the press conference on the opening day of ASCO's annual meeting.

"This is about the opportunity for the FDA to work with a medical specialty society, in this case ASCO, in what really should be a model for the agency - and work together to develop a program to reach out to clinicians and help them understand something that can be a little confusing at first," he said.
The new resources are available immediately to all patients and physicians, free of charge, through ASCO's physician education Web site, ASCO University (

The material is presented in three online modules, which introduce the expanded access regulations, outline the process for requesting expanded access, and explain the physicians' legal responsibilities for treating patients with an investigational agent outside of a clinical trial.

The modules also contain resources such as a glossary, an expanded access request checklist, and various templates (letter to manufacturer, consent form, etc.) to help physicians with the paperwork.

In August 2009, the FDA issued updated regulations and attempted to clarify the rules in two publications, "Expanded Access to Investigational Drugs for Treatment Use," and "Charging for Investigational Drugs." The new Web site goes a step further.

To clarify the new rules for patients and the medical community, ASCO consulted the main stakeholders, including representatives from patient advocacy groups, manufacturers, institutional review boards, and the FDA, as well as physicians. Although these tools were made with the oncology community in mind, these resources should be helpful to doctors from other medical specialties as well.

Role of luteinizing hormone-releasing hormone analog (LHRHa) triptorelin (T) in preserving ovarian function during chemotherapy for early breast cancer patients: Results of a multicenter phase III trial of Gruppo Italiano Mammella (GIM) group.

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 528)
Abstract No: 528

Author(s): L. Del Mastro, L. Boni, A. Michelotti, T. Gamucci, N. Olmeo, M. Giordano, S. Gori, O. Garrone, C. Bighin, M. Venturini, GIM Group; National Institute for Cancer Research, Genoa, Italy; Istituto Toscano Tumori, Firenze, Italy; U.O. Oncologia Medica, Pisa, Italy; Medical Oncology Unit, ASL Frosinone, Frosinone, Italy; Oncologia Medica ASL, Sassari, Italy; Santa Anna Hospital, Como, Italy; Azienda Ospedaliera Perugia, Perugia, Italy; Santa Croce General Hospital, Cuneo, Italy; Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy


Background: To evaluate the role of LHRHa-induced ovarian suppression in preserving the ovarian function (OF) during chemotherapy (CT), a phase III trial was carried out. Methods: Main eligibility criteria: stage I-III premenopausal BC patients (pts), age 18 to 45; hormone receptor (HR) status positive or negative. Arm A: CT alone; arm B: CT + T. T (supplied by Ipsen, Italy) was given every 4 wks during all CT cycles. Allowed CT regimens: CEF or EC (cyclophosphamide, epirubicin, fluorouracil); A (doxorubicin) C; CEF or EC followed by paclitaxel or docetaxel; A or E followed by CMF; CMF. Pts with HR+ tumor received tamoxifen after CT. Primary endpoint: incidence of early menopause (defined by postmenopausal levels of both FSH and estradiol [E2] and no menstrual activity) 1 yr after the end of CT. Study design: multicenter, open-label, randomized, phase III trial. Assuming an incidence of permanent menopause of 60%, for alpha = 0.05 (2-sided) and beta = 0.1 (90% power), 140 pts per arm were needed to detect a 20% absolute reduction in CT+T arm. Results: From Oct 2003 to Jan 2008, 281 pts were randomized: 133 in arm A and 148 in arm B. In both arms median age was 39 and median number of CT cycles was 6. Median cumulative dose of C was 3,840 mg (0-6,930) in arm A and 3,940 mg (0-7,200) in arm B. One yr after CT, early menopause was observed in 43 pts (32.3%; 95% CI 25-41) in arm A and in 20 pts (13.5%; 95% CI 80-91) in arm B (p = 0.0002), with a 19% absolute reduction (95% CI 8-29). Resumption of menstrual activity and/or premenopausal E2 levels was observed in 77 pts (58%; 95% CI 49-66) in arm A and in 114 pts (77%; 95% CI 69-83) in arm B (p = 0.006). Logistic regression analysis confirmed that treatment with T was independently associate with a higher probability of OF preservation (p = 0.001). Conclusions: Temporary ovarian suppression with T during CT is associated with a significant increase in OF preservation in BC pts.

ACOSOG Z1031: A randomized phase II trial comparing exemestane, letrozole, and anastrozole in postmenopausal women with clinical stage II/III estrogen receptor-positive breast cancer.

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr LBA513)
Abstract No: LBA513

Author(s): M. J. Ellis, A. Buzdar, G. W. Unzeitig, L. Esserman, A. M. Leitch, K. Deshryver, D. C. Allred, V. Suman, K. Hunt, J. A. Olson; Siteman Cancer Center at Washington University, St. Louis, MO; University of Texas M. D. Anderson Cancer Center, Houston, TX; Doctors Hospital of Laredo, Laredo, TX; University of California, San Francisco, San Francisco, CA; University of Texas Southwestern Medical Center, Dallas, TX; Mayo Clinic Rochester, Rochester, MN; M. D. Anderson Cancer Center, Houston, TX; Duke University Cancer Center, Durham, NC

Background: Neoadjuvant aromatase inhibitor (AI) therapy is a rational and effective approach to improving the breast conservation surgery (BCS) rate for postmenopausal patients with large, estrogen receptor (ER) rich breast cancers. Barriers to adopting this strategy include lack of experience in this management approach in the US and uncertainty regarding the comparative effectiveness of the three approved aromatase inhibitors for this indication. Methods: ACOSOG Z1031 is a multicenter, open-label, neoadjuvant phase III screening study that randomized postmenopausal women with clinical stage II/III ER rich (Allred score 6-8) breast cancer to 16 weeks of either exemestane (EXE) 25 mg daily, letrozole (LET) 2.5 mg daily, or anastrozole (ANA) 1 mg daily. At baseline study participants were either marginal for BCS (MBCS), candidates for mastectomy only (MO), or inoperable (IO). Planned enrolment was 125 patients per arm in order that the likelihood of the treatment with the "best" 16-week clinical response rate (based on caliper measurements) by WHO criteria (cRR) was included among the subset of treatments with "similar" cRR (90% power). Secondary endpoints included: extent of surgery, radiologic and pathologic response rates. Results: From 4/1/2006 to 10/1/2009, 377 postmenopausal women with clinical stage II or III ER rich breast cancer were enrolled. 374 women began treatment and were included in an intent-to-treat analysis. Median age was 66 yrs (range: 43-90 yrs), Median tumor size was 4.0 cm (range: 2-13 cm). The 16-week cRR was 60.5% (95%CI: 51.3-69.1%) for EXE; 70.9% (95% CI: 62.2-78.6%) for LET, and 66.7% (95% CI: 57.6-74.9%) for ANA. Seventeen patients did not have surgery due to refusal (12 pts), progression (3 pts) or other medical conditions (2 pts). The BCS rate was 78% (163/207) in MBCS group; 42% (77/163) in MO group; and 75% in IO group (3/4). Surgeons made the decisions regarding procedure choice 75% of the time in both the MBCS and the MO categories. Conclusions: This large multicenter screening trial selected non-steroidal AIs for further development due to their higher observed cRR. The study demonstrates that high response and breast conservation rates and low rates of disease progression can be achieved through patient selection based on high ER expression. We are currently refining our approach for early detection of poor response to AIs through an assessment of the tumor Ki67 proliferation index at 2 to 4 weeks (Z1031 Cohort B).

Mature results from ABCSG-12: Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine-responsive early breast cancer.

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 533)
Abstract No: 533

Author(s): M. Gnant, B. Mlineritsch, H. Stoeger, G. Luschin-Ebengreuth, S. Poestlberger, P. C. Dubsky, R. Jakesz, C. F. Singer, H. Eidtmann, R. Greil; Medical University of Vienna, Vienna, Austria; Paracelsus University of Salzburg, Salzburg, Austria; Medical University of Graz, Graz, Austria; Hospital of the Sisters of Mercy, Linz, Austria; Medical University of Vienna, General Hospital, Vienna, Austria; University of Schleswig-Holstein, Kiel, Germany; University Hospital Salzburg, Salzburg, Austria

Background: The ABCSG-12 trial examined the efficacy of ovarian suppression using goserelin in combination with anastrozole (ANA) or tamoxifen (TAM) ± zoledronic acid (ZOL) in premenopausal patients (pts) with endocrine-responsive breast cancer (EBC). The first efficacy analysis at ASCO 2008, showed no difference between TAM and ANA, but adding ZOL significantly reduced the risk of disease-free survival (DFS) events by 36% (p = 0.01). Longer follow-up is now available. Methods: 1,803 premenopausal pts with EBC were randomized to goserelin (3.6 mg q 28 d) and TAM (20 mg/d) or ANA (1 mg/d) ± ZOL (4 mg q 6 mo). Endpoints were DFS and overall survival (OS); both were analyzed using log-rank test and Cox models. Compared with 2008 data, we now report on 34% more DFS events and 55% more deaths, based on a December 1, 2009, data cutoff. Results: With a median follow-up of 62 mo, 183 DFS events and 65 deaths were reported. Overall, ZOL reduced the risk of DFS events by 32% (HR = 0.68 [95% CI = 0.51, 0.91]; p = 0.009). The risk reduction by ZOL was identical in the TAM and ANA strata (HR = 0.68 [0.44, 1.05] for TAM, HR = 0.68 [0.45, 1.02] for ANA), and for N- and N+ pts. With respect to OS, ZOL reduced the risk of death by 34% (HR = 0.66 [0.41, 1.09]; 0 = 0.10). The OS benefit was even more pronounced in the N+ subgroup (HR = 0.61; p= NS). There was no difference in DFS between pts who received TAM alone vs ANA alone (HR = 1.11 [0.84, 1.50]; P = .44). However, ANA pts did worse with respect to OS (HR = 1.74 [1.05, 2.87]; p = 0.03) vs TAM, probably due to differences in post-relapse treatment. Treatments were generally well tolerated. There was no case of renal failure or osteonecrosis of the jaw (ONJ). Conclusions: With longer follow-up of ABCSG-12, the addition of ZOL (4 mg q 6 mo) consistently improves both DFS and OS in the ANA and TAM subgroups, and in N+ and N- pts. There was no DFS difference between ANA and TAM, but ANA pts had inferior OS vs TAM; probably because ANA pts lack palliative aromatase inhibitor treatment. Based on these results and the known anticancer activity of adjuvant ZOL, this treatment should be considered for premenopausal pts with EBC.

First results from the Patient's Anastrozole Compliance to Therapy (PACT) program evaluating the influence of a standardized information service on compliance in postmenopausal women with early breast cancer (EBC).

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 523)
Abstract No: 523

Author(s): N. Harbeck, P. Hadji, C. Jackisch, M. Landthaler, V. Heilmann, B. Baier, M. Blettner, H. Lück, A. Rexrodt von Fircks, R. Kreienberg; Department of Obstetrics and Gynecology, Breast Center, University of Cologne, Köln, Germany; Phillipps University, Marburg, Germany; Klinikum Offenbach GmbH, Offenbach, Germany; University Hospital of Regensburg, Regensburg, Germany; Gynecological Practice, Guenzburg, Germany; Gynecological Practice, Dachau, Germany; Johannes Gutenberg-Universität, Mainz, Germany; Dr. Horst Schmidt Klinik, Wiesbaden, Germany; Author, Ratingen, Germany; Universitätsfrauenklinik, Ulm, Germany

Background: Retrospective data show that compliance to adjuvant endocrine therapy for early breast cancer (EBC) may drop below 80% after 1 year and as low as 50% by year 4. PACT aims to increase treatment adherence in postmenopausal women taking adjuvant anastrozole via a standardized information service. Methods: PACT is a prospective, randomised, two-arm parallel group trial with 60 months follow-up. Women on anastrozole for hormone receptor-positive (HR+) EBC were randomized to routine clinical care alone or additional standardized information for the first 12 months of adjuvant therapy. Primary endpoint is the compliance rate after 12 months. Secondary endpoints include reasons for noncompliance, influence of baseline characteristics, and clinical outcome parameters. Compliance is evaluated via patient questionnaires, prescription data and physician recall. Results: 4,924 women were enrolled by November 2008, the average age was 64.7 years. 97.7% were ER+, 8.4% HER2+, mean tumour size 21.4 mm, 74.5% had received breast preserving surgery, 23.5% a mastectomy, 6.7% had had neoadjuvant chemotherapy and almost 40% received adjuvant chemotherapy. 85% were scheduled for adjuvant radiotherapy. Analysis of the primary endpoint compliance at 12 months will be performed after data base lock in February 2010. Conclusions: PACT is the largest prospective trial to date on compliance in HR+ EBC and aims to clarify whether standardized information services throughout year one may improve compliance to adjuvant endocrine treatment and influence outcomes in postmenopausal women with HR+ EBC. Sponsored by AstraZeneca.

Recurrence risk of node-negative and ER-positive early-stage breast cancer patients by combining recurrence score, pathologic, and clinical information: A meta-analysis approach.

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 509)
Abstract No: 509
Author(s): G. Tang, J. Cuzick, C. Wale, J. P. Costantino, M. Crager, S. Shak, N. Wolmark, M. Dowsett, J. F. Forbes; National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; Queen Mary, University of London, London, United Kingdom; Genomic Health, Redwood City, CA; National Surgical Adjuvant Breast and Bowel Project and Allegheny General Hospital, Pittsburgh, PA; The Royal Marsden Hospital, London, United Kingdom; University of Newcastle, Newcastle-upon-Tyne, United Kingdom

Background: The 21-gene Oncotype DX Recurrence Score (RS) is widely used for assessment of recurrence risk and prediction of chemotherapy benefit in patients with early stage ER-positive breast cancer. Pathologic and clinical factors such as tumor size and grade, and patient age also provide independent prognostic utility and might be combined with the RS to achieve more prognostic power. Methods: All patients in the NSABP trial B-14 and the ATAC study who had ER-positive tumor specimens with successful Oncotype DX RS assay were included. B-14 patients were node-negative and were treated with tamoxifen. ATAC patients were node-positive or node-negative, and were treated with tamoxifen or anastrozole. Meta-analysis methods were used to assess the risk of distant recurrence by combining the individual study multivariate risk assessments using RS-pathologic-clinical (RSPC) information. A RSPC risk index was defined a priori as the predicted risk of distant recurrence at 10 years with predetermined cut-offs at 12% and 20% risk. Results: The meta- analysis included 647 B-14 patients and 1088 ATAC patients. RSPC prognosis combining clinical and pathology information with RS is more powerful than using RS alone (likelihood ratio test p-value < 0.001). The RSPC risk index was shown superior to RS in risk discrimination among node-negative, ER+, tamoxifen-treated patients. Compared with RS risk stratification, fewer patients were classified as intermediate risk by the RSPC index (18% vs 26%; p-value 0.001), and 72% of pts with intermediate RS 18-30 were either up-staged or down-staged. Average risk in the low, intermediate- and high-risk classes were similar between the RSPC and RS classifications. Conclusions: The RSPC index combining RS with pathology and clinical information with RS supplied more powerful prognosis for early stage breast cancer patients than RS alone. It was estimated that its application would reduce patients with intermediate risk by 30% and enhance personalized treatment decisions in oncology practice.



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